Document ID: EPA-HQ-OPP-2007-0461-0016
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-07-10T04:00Z

UNITED STATES

ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:  June 08, 2009

SUBJECT:	Mandipropamid; Human Health Risk Assessment for Proposed Use on
Hops.

PC Code: 036602	DP Number: 365918

Decision No.: 391631	Registration No.: 100-1254

Petition No.: 8F7342	Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical, Aggregate	Case No.: NA

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

MRID No.: 47384904-9; 47217301-02	40 CFR§180.637

	          	

FROM:	Debra Rate, Ph.D., Biologist

		Alternative Risk Integration and Assessment (ARIA)

		Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD; 7505P)

		

THROUGH:	William Cutchin, Acting Senior Branch Scientist

		ARIA/RIMUERB/RD (7505P)

		

		Christina Swartz, Chemist

Registration Action Branch 2 (RAB2)

		Health Effects Division (HED; 7509P)

TO:		Tony Kish / Rosemary Kerns 22

		Fungicide Branch (FB)/RD (7505P)

The ARIA team of RD/RIUMERB completed a human health risk assessment for
the fungicide mandipropamid in conjunction with proposed uses under
Petition No. 8F7342 (memorandum, D. Rate, 1/21/09, D355217).  This
revised risk assessment has been completed to clarify the lack of
concern for potential immunotoxic effects and the acceptability of the
analytical enforcement method; in addition, the cited data gap for a
90-day dermal toxicity study, which is not required, and the discussion
of the proposed use on tobacco have been removed.

Table of Contents  TOC \o "1-3" \h \z \u    HYPERLINK \l
"_Toc232219338"  1.0	Executive Summary	  PAGEREF _Toc232219338 \h  4  

  HYPERLINK \l "_Toc232219339"  2.0	Ingredient Profile	  PAGEREF
_Toc232219339 \h  9  

  HYPERLINK \l "_Toc232219340"  2.1	Structure and Nomenclature	  PAGEREF
_Toc232219340 \h  10  

  HYPERLINK \l "_Toc232219341"  2.2	Physical and Chemical Properties	 
PAGEREF _Toc232219341 \h  10  

  HYPERLINK \l "_Toc232219342"  2.3	Summary of Proposed Uses	  PAGEREF
_Toc232219342 \h  11  

  HYPERLINK \l "_Toc232219343"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc232219343 \h  11  

  HYPERLINK \l "_Toc232219344"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc232219344 \h  11  

  HYPERLINK \l "_Toc232219345"  3.1.1	Database Summary	  PAGEREF
_Toc232219345 \h  11  

  HYPERLINK \l "_Toc232219346"  3.1.2	Toxicological Effects	  PAGEREF
_Toc232219346 \h  12  

  HYPERLINK \l "_Toc232219347"  3.1.3	Dose-response	  PAGEREF
_Toc232219347 \h  13  

  HYPERLINK \l "_Toc232219348"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc232219348 \h  13  

  HYPERLINK \l "_Toc232219349"  3.3	FQPA Considerations	  PAGEREF
_Toc232219349 \h  14  

  HYPERLINK \l "_Toc232219350"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc232219350 \h  14  

  HYPERLINK \l "_Toc232219351"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc232219351 \h  14  

  HYPERLINK \l "_Toc232219352"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc232219352 \h  14  

  HYPERLINK \l "_Toc232219353"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc232219353 \h  14  

  HYPERLINK \l "_Toc232219354"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc232219354 \h  14  

  HYPERLINK \l "_Toc232219355"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc232219355 \h  14  

  HYPERLINK \l "_Toc232219356"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc232219356 \h  15  

  HYPERLINK \l "_Toc232219357"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc232219357 \h  15  

  HYPERLINK \l "_Toc232219358"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc232219358 \h  16  

  HYPERLINK \l "_Toc232219359"  3.5.1	Acute Reference Dose (aRfD) -
Females age 13-49 & General Population	  PAGEREF _Toc232219359 \h  16  

  HYPERLINK \l "_Toc232219360"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc232219360 \h  16  

  HYPERLINK \l "_Toc232219361"  3.5.3	Dermal Absorption	  PAGEREF
_Toc232219361 \h  16  

  HYPERLINK \l "_Toc232219362"  3.5.4	Dermal Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc232219362 \h  17  

  HYPERLINK \l "_Toc232219363"  3.5.5	Inhalation Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc232219363 \h  17  

  HYPERLINK \l "_Toc232219364"  3.5.6	Level of Concern for Margin of
Exposure	  PAGEREF _Toc232219364 \h  18  

  HYPERLINK \l "_Toc232219365"  3.5.7	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc232219365 \h  18  

  HYPERLINK \l "_Toc232219366"  3.5.8	Classification of Carcinogenic
Potential	  PAGEREF _Toc232219366 \h  18  

  HYPERLINK \l "_Toc232219367"  3.5.9	Summary of Toxicological Doses and
Endpoints for Mandipropamid for Use in	  PAGEREF _Toc232219367 \h  19  

  HYPERLINK \l "_Toc232219368"  Human Risk Assessments	  PAGEREF
_Toc232219368 \h  19  

  HYPERLINK \l "_Toc232219369"  3.6	Endocrine Disruption	  PAGEREF
_Toc232219369 \h  20  

  HYPERLINK \l "_Toc232219370"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc232219370 \h  20  

  HYPERLINK \l "_Toc232219371"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc232219371 \h  20  

  HYPERLINK \l "_Toc232219372"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc232219372 \h  20  

  HYPERLINK \l "_Toc232219373"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc232219373 \h  20  

  HYPERLINK \l "_Toc232219374"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc232219374 \h  21  

  HYPERLINK \l "_Toc232219375"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc232219375 \h  22  

  HYPERLINK \l "_Toc232219376"  5.1.4	Analytical Methodology	  PAGEREF
_Toc232219376 \h  23  

  HYPERLINK \l "_Toc232219377"  5.1.5	Environmental Degradation	 
PAGEREF _Toc232219377 \h  24  

  HYPERLINK \l "_Toc232219378"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc232219378 \h  25  

  HYPERLINK \l "_Toc232219379"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc232219379 \h  26  

  HYPERLINK \l "_Toc232219380"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc232219380 \h  26  

  HYPERLINK \l "_Toc232219381"  5.1.9	Drinking Water Residue Profile	 
PAGEREF _Toc232219381 \h  28  

  HYPERLINK \l "_Toc232219382"  5.1.10	Food Residue Profile	  PAGEREF
_Toc232219382 \h  28  

  HYPERLINK \l "_Toc232219383"  5.1.11	International Residue Limits	 
PAGEREF _Toc232219383 \h  29  

  HYPERLINK \l "_Toc232219384"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc232219384 \h  29  

  HYPERLINK \l "_Toc232219385"  6.0	Residential and Other Exposures
(Spray Drift, etc.)	  PAGEREF _Toc232219385 \h  30  

  HYPERLINK \l "_Toc232219386"  7.0 	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc232219386 \h  31  

  HYPERLINK \l "_Toc232219387"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc232219387 \h  31  

  HYPERLINK \l "_Toc232219388"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc232219388 \h  31  

  HYPERLINK \l "_Toc232219389"  9.1	Short-/Intermediate-Term
Occupational Handler Risk	  PAGEREF _Toc232219389 \h  32  

  HYPERLINK \l "_Toc232219390"  9.2	Short-/Intermediate-Term
Occupational Postapplication Risk	  PAGEREF _Toc232219390 \h  33  

  HYPERLINK \l "_Toc232219391"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc232219391 \h  33  

  HYPERLINK \l "_Toc232219392"  10.1	Toxicology	  PAGEREF _Toc232219392
\h  33  

  HYPERLINK \l "_Toc232219393"  10.2 	 Residue Chemistry	  PAGEREF
_Toc232219393 \h  34  

  HYPERLINK \l "_Toc232219394"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc232219394 \h  34  

  HYPERLINK \l "_Toc232219395"  11.0	References:	  PAGEREF _Toc232219395
\h  34  

  HYPERLINK \l "_Toc232219396"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc232219396 \h  36  

  HYPERLINK \l "_Toc232219397"  A.1  Toxicity Data Requirements	 
PAGEREF _Toc232219397 \h  36  

  HYPERLINK \l "_Toc232219398"  A.2  Toxicity Profiles	  PAGEREF
_Toc232219398 \h  37  

  HYPERLINK \l "_Toc232219399"  Appendix B:  Metabolism Assessment	 
PAGEREF _Toc232219399 \h  43  

  HYPERLINK \l "_Toc232219400"  Appendix C:  Tolerance Assessment
Summary and Table	  PAGEREF _Toc232219400 \h  48  

  HYPERLINK \l "_Toc232219401"  Appendix D:  Review of Human Research	 
PAGEREF _Toc232219401 \h  48  

  HYPERLINK \l "_Toc232219402"  Appendix E: Other Toxicity Studies	 
PAGEREF _Toc232219402 \h  48  

 1.0	Executive Summary

Mandipropamid (experimental name of NOA 446510) 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.  The previous
risk assessment conducted for manipropamid was completed in conjunction
with its registration as a new active ingredient (D. McNeilly, D340784,
9/12/2007).  

Syngenta submitted a petition for a new use on hops, and the
establishment of a permanent tolerance for residues of the fungicide
mandipropamid, [4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]-
α-(2-propynyloxy)-benzeneacetamide], in/on the following raw
agricultural commodity (RAC): 

     Hop, dried cones	50 ppm.

The petition (8F7342) reflects new uses on food and non-food use crops. 
The end-use product (EP) associated with these petitions is Revus™
(EPA Reg. No. 100-1254), which contains 23.3% active ingredient (2.08 lb
ai/gal).  The EP is proposed for multiple foliar applications using
ground, irrigation, or aerial equipment at a maximum seasonal rate of
0.40 lb ai/A for hops.  The proposed preharvest interval (PHI) is 7
days.  No residential uses are registered or proposed.

TOXICITY/HAZARD

The toxicity data base for mandipropamid is adequate for risk assessment
and tolerance setting; however, under current EPA regulations (40
CFR§158) several new toxicity requirements were recently introduced. 
Therefore the registration should remain conditional until the following
study requirements are adequately fulfilled:

An immunotoxicity study in rats is required under the current EPA
regulations (40 CFR Part 158).  This study was not submitted to the
Agency in support of the registration for products containing
mandipropamid.  Therefore, the lack of this study will remain a data gap
and registration of mandipropamid should remain conditional pending
receipt of an acceptable immunotoxicity study.

Mandipropamid has low or minimal acute toxicity via the oral (Category
IV), dermal (Category IV), and inhalation routes of exposure (Category
IV).  It is minimally irritating to the eye (Category IV) and
non-irritating to the skin (Category IV).  Recently reviewed studies (DP
Num: 355979, M. Hashim, 07/SEP/2008) classified mandipropamid as
negative for skin sensitization.

Liver toxicity was the primary effect and was observed in rats, mice and
dogs.  In the 24-month rat study, nephrotoxicity was observed in males
only.  The lack of liver toxicity in this long-term study was probably
due to the lower doses when compared with the 90-day study.  In a 90-day
rat study, there was slight hepatotoxicity in both sexes; there was the
suggestion of effects on the liver in the 90-day mouse study in which
increased liver weights in both sexes and microscopic pathology were
observed.  In the 90-day dog study liver effects included increased
cholesterol, increased liver weights and liver enzymes (alkaline
phosphatase activity, alanine aminotransferase) and increased pigment in
hepatocytes and Kupffer cells in both sexes.  Additionally,
centrilobular hepatocyte vacuolation in females was observed.  In the
combined chronic/carcinogenicity rat study, no effects on the liver were
noted at doses up to and including the highest dose tested (HDT) of
61/70 mg/kg/day (M/F); however, increased nephrotoxicity occurred in
males.  No liver effects were observed in the mouse carcinogenicity
study at doses up to 223/285 mg/kg/day (M/F).  The following effects on
the liver were present in the 1-year dog study:  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.  Therefore, effects on the liver of
rats, mice and dogs appear within 90-days (also in the 1-year dog
study); whereas, in the 24-month rat study, only nephrotoxicity was
observed and, in the 18-month mouse study, only decreased body weight
and food utilization were noted.

There was no evidence of teratogenicity or indications of increased
neonatal sensitivity in the developmental and reproduction toxicity
studies.   In the rat and rabbit developmental toxicity studies, there
were no treatment-related maternal or developmental effects observed up
to the limit dose of 1000 mg/kg/day.  In the two-generation rat
reproduction study, the only parental/systemic effects were decreased
body weights, body weight gains, food consumption and food utilization
in males.  No effects on reproduction were observed at any dose. 
Offspring effects were decreased pup body weights in both sexes, but
this effect occurred at doses which also caused effects in parental
animals.

Dermal exposure to mandipropamid for 28 days in the rat did not result
in systemic or dermal toxicity up to the limit dose of 1000 mg/kg/day. 
There was no evidence of developmental effects, neurotoxicity,
mutagenicity or carcinogenicity after exposure to mandipropamid.

DOSE RESPONSE

For chronic dietary exposure, the 1-year study in dogs was used to
calculate the chronic reference dose (cRfD) of 0.05 mg/kg/day.  The No
Observed Adverse Effect Level (NOAEL) of 5 mg/kg/day was selected based
upon the Lowest Observed Adverse Effect Level (LOAEL) of 40 mg/kg/day
which was 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).  A 90-day dietary rat study was
used to select the dose and endpoint for short and intermediate term
inhalation exposure.  The NOAEL of 41 mg/kg/day and LOAEL of 260
mg/kg/day were based on decreased body weights, body weight gains and
food utilization in males as well as slight hepatotoxicity in both
sexes.  No appropriate endpoints (toxic effects) were identified for
acute dietary exposure (general population including infants and
children; females 13-49 years of age) or for dermal risk assessment.



Exposure Scenario	

Dose	

Endpoint	

Study/Effect

Chronic dietary	

NOAEL = 5 mg/kg/day	

cRfD and cPAD = 0.05 mg/kg/day	

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) at the LOAEL of 40 mg/kg/day. 

Inhalation Short-(1-30 days) and Intermediate-term (1-6 months)	

NOAEL = 

41 mg/kg/day

Inhalation Absorption Factor (IAF) =100%

	

Target MOE = 100 (occupational)	90-day oral toxicity – rats-Decreased
body weights, body weight gains and food utilization in males and slight
hepatotoxicity in both sexes at the LOAEL of 260 mg/kg/day.

FQPA ASSESSMENT

HED previously recommended that the FQPA SF be reduced to 1X because
there is no evidence of increased susceptibility, there are no/low
concerns and no residual uncertainties regarding pre- and/or postnatal
toxicity, there is no evidence of neurotoxicity in the database and a
DNT study is not required.  Although the data base is missing the
immunotoxicity study as per the revised 40 CFR§158 (FR/Vol. 72, No.
207), the toxicological database is adequate for risk assessment and
based on available toxicity data, there is no need for an additional
uncertainty factor while the immunotoxicity study is completed.  The
toxicology database of mandipropamid does not show any evidence of
biologically relevant effects on the immune system. The overall weight
of evidence in terms of hematology, clinical chemistry, organ weights,
and/or histopathology suggests that mandipropamid does not directly
target the immune system. Therefore HED does not believe that conducting
a functional immunotoxicity study will result in a lower point of
departure (POD) than currently selected for overall risk assessment, and
therefore, a database uncertainty factor (UFDB) is not needed to account
for the lack of this study.  Furthermore, the exposure assessments are
based on reliable data and reasonable worst-case assumptions and will
not likely underestimate risks.

RESIDUE CHEMISTRY

The nature of the residue in plants, rotational crops, and ruminants is
adequately understood.  For the purposes of tolerance establishment, the
terminal residue of concern in plants, animals, and rotational crops is
the parent mandipropamid.  For the purposes of dietary risk assessment,
the residue of concern is the parent only, except for root and tuber
vegetables where the residues of concern are the parent plus the
metabolite SYN 500003.  In drinking water, the residues of concern are
the parent plus the metabolites SYN 500003 and SYN 504851.  

The maximum seasonal application proposed for the new uses on tobacco
and hops is less than or equal to currently registered use rates.  As
such, a previously modeled Tier I drinking water assessment for the
established mandipropamid uses conducted by Environmental Fate and
Effects Division (EFED) was used in this dietary assessment (DP Num:
339258, I. Abdel-Saheb; 23/APR/2007).  The assessment includes
mandipropamid and two aquatic degradates (SYN 500003 and SYN 504851) as
requested by HED.  The metabolism data indicate that there is no
reasonable expectation of finite residues in milk, meat, and/or meat
byproducts (40 CFR §180.6, Category 3) as a result of the proposed
uses.  There are no poultry feed items associated with the proposed
uses.

Liquid chromatography with tandem mass spectrometry (LC/MS/MS) Method
415/01 was used for data collection and submitted as a tolerance
enforcement method for residues of mandipropamid in/on plant
commodities.  The validated method limit of quantitation (LOQ) is 0.01
ppm.  Method 415/01 was adequately validated by the petitioner as well
as by an independent laboratory.  The method was forwarded to Analytical
Chemistry Branch (ACB)/Biological and Economic Analysis Division (BEAD)
for a petition method validation.  The ACB recommended that the
petitioner provide information for a second MS/MS ion transition to
provide a confirmation of analyte identity.  The petitioner has recently
submitted an LC/MS/MS method with two monitored ion transitions for the
determination of residues of mandipropamid in/on crop commodities (DP
Num: 352322, D. Rate, 11/DEC/2008).  The method is based on German
multiresidue method DFG S-19 and was submitted as a confirmatory method
for mandipropamid in crops.  ARIA has concluded the method meets the
criteria for an acceptable tolerance enforcement method.

Adequate crop field trial data have been submitted for to support the
recommended tolerance in/on hops, dried cones at 50 ppm.  However, a
revised Section F to correct the commodity definition from hops to hop,
dried cones, should be submitted.  Also, minor label and Section B
revisions, including the following rotational crop restrictions:  “Do
not plant any crop which is not registered for use with mandipropamid
for a period of 30 days after the last application,” should be
submitted (See Section 2.3 and Section 10.2 for details).

DIETARY EXPOSURE AND RISK ESTIMATES

The dietary analysis was conducted using DEEM-FCID.  Chronic (food and
water) dietary exposure for mandipropamid is below ARIA’s level of
concern.  The DEEM-FCID chronic dietary exposure estimate for the
highest exposed population subgroup, children 1-2 years of age, is 30%
of the cPAD, and it is 23% of the cPAD for the general U.S. population. 
The chronic exposure analysis assumed 100% crop treated and
ARIA-recommended and tolerance-level residues.  No acute dietary
endpoint was identified in the toxicity database; so an acute dietary
exposure analysis was not performed.  A cancer assessment was also not
performed since mandipropamid is classified as “not likely to be
carcinogenic to humans”.

RESIDENTIAL EXPOSURE

Residential exposures are not assessed because the proposed uses of
mandipropamid do not involve applications by homeowners or by commercial
applicators in residential settings.  



AGGREGATE RISK

No residential uses are proposed or registered for mandipropamid. 
Therefore, the chronic aggregate risk calculations include exposures
only from food and water sources.  Chronic aggregate risk estimates
associated with exposure to mandipropamid residues in food and water do
not exceed ARIA’s level of concern.  Acute and cancer aggregate risks
were not assessed due to the absence of an acute dietary endpoint and
mandipropamid is not likely to be carcinogenic to humans.

OCCUPATIONAL EXPOSURE/RISK

Mandipropamid is a fungicide to be applied as a foliar spray by aerial
equipment, chemigation, groundboom equipment, and airblast equipment. 
Occupational exposure is expected to be short-(1-30 days) and
intermediate-term (1-6 months) in duration.  No long-term (more than 6
months) exposure is expected from the proposed uses of mandipropamid due
to the limited number of applications.

No chemical-specific exposure data were submitted.  Therefore,
occupational handler assessments for mandipropamid were based on
surrogate unit exposures from the Pesticide Handlers Exposure Database
(PHED).

Dermal handler exposures and risks were not assessed for mandipropamid,
since no short- or intermediate-term dermal endpoints were identified. 
In all scenarios except aerial applicator (where adequate baseline or
open cockpit data are not available), short- and intermediate-term
inhalation risks resulted in MOEs greater than 100 (760,000-9,000,000)
at baseline level of mitigation (i.e., no respirator) and were not of
concern to ARIA.  Inhalation risks to pilots in enclosed cockpits with
no respirator (engineering control scenario) were not of concern.  In
this assessment, ARIA has assumed the maximum application rates allowed
by labels, a 70 kg body weight for the handler, and an average workday
of 8 hours.

Occupational postapplication risks to agricultural workers following
treatments to agricultural crops were not assessed, since dermal
endpoints of concern were not identified.

Restricted Entry Interval

In lieu of a postapplication risk assessment, a restricted-entry
interval of 12 hours is required based on the default of 12 hours in the
Worker Protection Standard (WPS) for Agricultural Pesticides for active
ingredients classified as category III or IV for acute dermal toxicity,
skin irritation potential, and eye irritation potential.  The product
label for RevusTM Fungicide proposes an REI of 4 hours.  Based on newly
reviewed studies (DP Num: 355979, M. Hashim, 07/SEP/2008), mandipropamid
is not classified as a dermal sensitizer and is a low risk pesticide;
therefore it is a candidate for a reduced risk active ingredient REI of
4 hours.  



ENVIRONMENTAL JUSTICE CONSIDERATIONS 

Potential areas of environmental justice concern, 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," (  HYPERLINK
"http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.
pdf_"
http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.p
df ).

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 (as it relates to an imported crop), ARIA
estimatesrisks to population subgroups from pesticide exposures that are
based on patterns of that subgroup’s food consumption.  Extensive data
on food consumption patterns are compiled by the USDA under the
Continuing Survey of Food Intake by Individuals (CSFII) and are used in
pesticide risk assessments for all proposed/registered food
uses/tolerances of a pesticide.  These data are analyzed and categorized
by subgroups based on age, season of the year, ethnic group, and region
of the country.  Additionally, OPP is able to assess dietary exposure to
smaller, specialized subgroups and exposure assessments are performed
when conditions or circumstances warrant.  Further considerations are
currently in development as OPP has committed resources and expertise to
the development of specialized software and models that consider
exposure from traditional dietary patterns among specific subgroups.

Review of Human Research:  

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (listed in Appendix D) have been determined to
require a review of their ethical conduct, and have received that
review.

RECOMMENDATIONS  

Pending resolution of the residue chemistry issues delineated in Section
10.2 (directions for use (label and Section B) and revised Section F),
ARIA recommends for the establishment of a permanent tolerance in/on
hop, dried cones, as specified in Appendix C.

Additional Data Needs.  See Section 10.

2.0	Ingredient Profile

The chemical structure and nomenclature of mandipropamid are presented
in Table 2.1.  The physicochemical properties of the technical grade
mandipropamid are presented in Table 2.2. Mandipropamid is a new
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, tomatoes, Pseudoperonospora cubensis in cucurbits, and
downy mildew (Bremia lactucae) and blue mold (Peronospora effuse) in
leafy vegetables.  A summary of the proposed uses is presented in Table
2.3. 

2.1	Structure and Nomenclature

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-propynylox
y)- benzeneacetamide

CAS registry number	374726-62-2

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

2.2	Physical and Chemical Properties

Table 2.2.   Physical and chemical Properties of the Technical Grade of
Mandipropamid.

Parameter	Value	Reference

Melting point/range	96.4-97.3ºC	MRID 46800006 (100-REIR.doc, S. Mathur,
22/MAY/2007)

Molecular formula/weight	C23H22ClNO4  /  411.9

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

	Density	1.24 x 103 kg/m3 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, pKa	No dissociation constant in the pH range of
1 to 12

	Octanol/water partition coefficient, Log(POW)	3.3 at 25ºC

	

2.3	Summary of Proposed Uses

Table 2.3.  Details of Proposed Uses of 2.08 lb ai/gal FlC (RevusTM) on
Hops.

Application Timing, Type, and Equipment	Maximum Single Application Rate

(lb ai/A)	Maximum Number of Applications per Season	Maximum Seasonal
Application Rate

(lb ai/A)	PHI

(days)

Hops

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	Not specified	0.40	7

	Use Directions and Restrictions:  Begin applications prior to disease
development and continue throughout the season on a 7-10 day interval. 
Make no more than 2 consecutive applications before switching to an
effective non-Group 40 fungicide.  May be tank mixed with another
fungicide labeled for downy mildew that has a different mode of action. 
The addition of a spreading/penetrating type adjuvant such as a
non-ionic based surfactant or blend may improve activity.

The supplemental label for RevusTM is adequate to allow evaluation of
the residue data relative to the proposed uses on hops.  However, a few
minor label revisions are required.  As per 860.1000 and to preclude the
submission of a separate set of data reflecting aerial equipment, the
label should be revised to specify that aerial applications are to be
made in a minimum of 2 gallons water per acre.  In addition, the label
and Section B should be revised to specify the following rotational crop
restrictions:  “Do not plant any crop which is not registered for use
with mandipropamid for a period of 30 days after the last
application.”

3.0	Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary

3.1.1.1	Studies available and considered (animal, human, general
literature)

There are acceptable studies available for endpoint selection that
include: 1) subchronic oral toxicity studies in rats, mice and dogs; 2)
a chronic oral toxicity study in dogs, a chronic/carcinogenicity study
in rats and a carcinogenicity study in mice; 3) developmental studies in
rats and rabbits; 4) a reproduction study in rats; and 5) a subchronic
dermal toxicity study in rats.  There are also a complete mutagenicity
battery, neurotoxicity studies (acute and subchronic) in rats and a
metabolism study in the rat.  Mandipropamid is a relatively new
chemical, and no additional information was gained from a general
literature search of National Library of Medicine TOXNET databases.

In accordance with the revised requirements under Part 158 of 40 CFR, an
immuntoxicity study is required to support continued registration of
products containing mandipropamid.  ARIA has evaluated the existing
toxicity studies for indications of potentially immuntoxic effects, such
as effects on hematology, spleen and thymus organ weights, as well as
clinical chemistry, and none were identified.  Nonetheless, the study is
required and must be submitted as a condition of registration.

3.1.1.2	 Mode of Action

Mandipropamid is a mandelamide and belongs to the chemical family of the
carboxylic acid amides (CAA), or more specifically, the mandelic acid
amides (Fungicide Resistance Action Committee (FRAC) group 40).  The
biochemical mode of action of mandipropamid is not fully known. 
However, preliminary results indicate that it inhibits the biosynthesis
of phospholipids (phosphatidyl choline, lecithin).  Based on a review of
its chemistry, resistance profile and toxicological attributes,
mandipropamid is mechanistically unique and its mode of action is
different from other fungicides - including those within the CAA group.

3.1.1.3	Sufficiency of Studies/Data

Based on the proposed use pattern, the toxicology database for
mandipropamid is adequate for risk assessment.

3.1.2	Toxicological Effects

Mandipropamid has low or minimal acute toxicity via the oral (Category
IV), dermal (Category IV), and inhalation routes of exposure (Category
IV).  It is minimally irritating to the eye (Category IV) and
non-irritating to the skin (Category IV); it is not a skin sensitizer. 
Liver toxicity is the primary effect and was observed in rats, mice and
dogs.  In a 90-day rat dietary admix study, there was slight
hepatotoxicity in both sexes at 260 mg/kg/day (NOAEL = 41/45 mg/kg/day,
M/F).  There was the suggestion of effects on the liver in the 90-day
mouse dietary admix study (increased liver weights in both sexes and
microscopic pathology) at 624/800 mg/kg/day (M/F), with the NOAEL =
248/316 mg/kg/day (M/F).  The 90-day dog study (capsule) had increased
cholesterol, increased liver weights and liver enzymes (alkaline
phosphatase activity, alanine aminotransferase) and increased pigment in
hepatocytes and Kupffer cells in both sexes at 400 mg/kg/day. 
Additionally, centrilobular hepatocyte vacuolation in females was
observed at 400 mg/kg/day with the NOAEL = 100 mg/kg/day.  In the
combined chronic/carcinogenicity dietary admix rat study, no effects on
the liver were noted at doses up to and including the HDT of 61/70
mg/kg/day (M/F); however, increased nephrotoxicity occurred in males. 
No liver effects were observed in the 18-month mouse dietary admix
carcinogenicity study at doses up to 223/285 mg/kg/day (M/F).  The
following effects on the liver were present in the 1-year dog study
(capsule) at 40 mg/kg/day (NOAEL = 5 mg/kg/day):  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.  Liver effects were noted in the
90-day rat, mouse and dog studies as well as in the 1-year dog study. 
In the 24-month rat study, only nephrotoxicity was observed.  In the
18-month mouse study, the only effects seen were decreases in body
weight and food utilization.

There was no evidence of teratogenicity or indications of increased
neonatal sensitivity in the developmental and reproduction toxicity
studies.  In the rat and rabbit developmental toxicity studies, no
maternal or developmental effects were observed at the limit dose of
1000 mg/kg/day.  In the two-generation rat reproduction study, the only
parental/systemic effects were decreased body weights, body weight
gains, food consumption and food utilization in males at the LOAEL of
146/148 mg/kg/day (M/F)(NOAEL = 23/25 mg/kg/day, M/F).  No effects on
reproduction were observed at any dose.  There were decreased pup body
weights in both sexes observed at the LOAEL of 146/148 mg/kg/day (M/F). 
In addition, there was a delay in prepucial separation in F1 males
(group mean days: control = 43.7; 146 mg/kg/day = 44.8) which was
considered to be the result of lower body weights. 

Dermal exposure to mandipropamid for 28 days in the rat did not result
in systemic or dermal toxicity up to the limit dose of 1000 mg/kg/day.  

There was no evidence of neurotoxicity, mutagenicity or carcinogenicity
after exposure to mandipropamid.  In addition, there was no estrogen-,
androgen-, and/or thyroid-mediated toxicity.

3.1.3	Dose-response

For chronic dietary exposure, the 1-year study in dogs (capsule) was
used to calculate the chronic reference dose (cRfD) of 0.05 mg/kg/day. 
The NOAEL of 5 mg/kg/day was selected based upon the LOAEL of 40
mg/kg/day at which there was 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).  A 90-day dietary admix rat study
was used to select the dose and endpoint for short- and
intermediate-term inhalation exposure.  The NOAEL of 41/45 mg/kg/day
(M/F) and LOAEL of 260/260 mg/kg/day (M/F) were based on decreased body
weights, body weight gains and food utilization in males as well as
slight hepatotoxicity in both sexes.  No appropriate endpoints were
identified for acute dietary exposure (general population including
infants and children; females 13-49 years of age).  That is, no toxic
effects associated with a single dose of mandipropamid were observed in
the submitted studies.  Risk assessment was not required for dermal
exposure since no systemic or dermal effects were observed up to the
limit dose of 1000 mg/kg/day in a 28-day dermal toxicity study in rats. 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

≥5% at 3 and/or 300 mg/kg: NOA 458422, NOA 458422 glucuronide, SYN
534133 and CGA 380778.  Differences in metabolic profile were due to
sex, dose and radiolabel position.  Each unknown compound was less than
5%.  Major metabolic transformations involved loss of one or both
propargyl groups followed by glucuronidation and O-demethylation.

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

The database is adequate to characterize potential pre- and/or
post-natal risk for infants and children.  Acceptable/guideline
developmental toxicity studies in rats and rabbits and a reproduction
study in rats, as well as acute and subchronic neurotoxicity studies in
rats were available for FQPA assessment.  There is a data gap for the
immunotoxicity study which was required by the Agency for the proposed
use pattern, as per revised 40 CFR§158 (FR/Vol. 72, No. 207).

3.3.2	Evidence of Neurotoxicity

There was no evidence of neurotoxicity observed in the toxicology
database.  In the acute (gavage) neurotoxicity study, the rats were
dosed with 2000 mg/kg (LIMIT DOSE).  For the 90-day neurotoxicity study
in rats, the animals were given dietary admix doses of 0/0, 7.4/8.4,
37.3/41.0 or 192.5/206.7 mg/kg/day (M/F).  In this subchronic study, the
only effects appeared to be decreased body weight, body weight gain and
food utilization in males.

3.3.3	Developmental Toxicity Studies

There were no treatment-related effects observed in dams or fetuses in
the developmental toxicity studies in rats or rabbits at the limit dose
of 1000 mg/kg/day.

3.3.4	Reproductive Toxicity Study

In the 2-generation rat reproduction study (one litter/generation), the
mean dietary admix premating doses (average of parents from both
generations) were: 0/0, 4.6/5.0, 22.9/24.5 and 146.3/148.2 mg/kg/day,
for males/females, respectively.  For parental/systemic effects, the
NOAEL = 22.9/24.5 mg/kg/day (M/F) and the LOAEL = 146.3/148.2 mg/kg/day
based on decreased body weights, body weight gains, food consumption and
food utilization in males.  There were no effects on reproduction at any
of the doses.  Regarding the offspring, the NOAEL = 22.9/24.5 mg/kg/day
(M/F) and the LOAEL = 146.3/148.2 mg/kg/day based on decreased pup body
weights in both sexes.

3.3.5	Additional Information from Literature Sources 

Mandipropamid is a relatively new chemical, and no additional
information was gained from a general literature search of National
Library of Medicine TOXNET databases.

3.3.6	Pre-and/or Postnatal Toxicity

3.3.6.1	Determination of Susceptibility

There is no concern for increased quantitative and/or qualitative
susceptibility after in utero or postnatal exposure to mandipropamid in
rat and rabbit developmental toxicity studies or in a reproduction study
in rats.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

The purposes of the Degree of Concern analysis are: (1) to determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and (2) to identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment.  If residual
uncertainties are identified, then the Agency determines whether these
residual uncertainties can be addressed by a FQPA safety factor and, if
so, the size of the factor needed.

There is no evidence (quantitative or qualitative) of increased
susceptibility and no residual uncertainties with regard to prenatal
toxicity following in utero exposure to rats or rabbits (developmental
studies) and pre and/or post-natal exposures to rats (reproduction
study).

In addition, ARIA has examined the available toxicity studies for
potential immunotoxicity, including potential susceptibility of the
young.  There was no indication of potential immunotoxicity, either for
the young or adult animals, when parameters typically associated with
immunotoxicity were examined, including hematology, gross organ weights,
clinical chemistry and histopathology.

3.3.7	Recommendation for a Developmental Neurotoxicity Study

There was no evidence of neurotoxicity observed in adults following
acute, subchronic or chronic exposure to mandipropamid or in offspring
following prenatal or postnatal exposure; therefore, a developmental
neurotoxicity study is not required.

3.4	FQPA Safety Factor for Infants and Children

After evaluating the toxicological and exposure data, the mandipropamid
risk assessment team recommends that the FQPA SF be reduced to 1x based
on the following:

The toxicological database for mandipropamid is adequate for risk
assessment.  A data gap remains for the immunotoxicity study; however,
available data indicate no adverse effects are expected to result from
the missing study.

The toxicity data showed no increase in qualitative or quantitative
susceptibility in fetuses and pups with in utero and post-natal
exposure.

The toxicity data indicates that there are no neurotoxic effects. 

The dietary food exposure assessment is based on Agency-recommended
tolerance-level residues and assumes 100% crop treated for all
commodities, which results in very high-end estimates of dietary
exposure.

The dietary drinking water assessment is based on values generated by
model and associated modeling parameters which are designed to provide
conservative, health protective, high-end estimates of water
concentrations.

No residential uses are proposed at this time. 

3.5	Hazard Identification and Toxicity Endpoint Selection

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49 & General
Population 

No appropriate endpoint was identified for these populations, as there
was no toxic effect attributable to a single dose in the mandipropamid
toxicity database.

3.5.2	Chronic Reference Dose (cRfD) 

Study Selected:  Chronic Toxicity-Dog

MRID No:  46800232

Dose and Endpoint for Risk Assessment: NOAEL = 5 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 at 40 mg/kg/day.

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

  = 0.05 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:  

Uncertainty factors (100x) include: 10x interspecies extrapolation, 10x
intraspecies variability.  The NOAEL/LOAEL are protective of effects
seen in the other long-term studies.  The most sensitive
endpoint/species was demonstrated following long-term exposure.

3.5.3	Dermal Absorption

In a dermal penetration study, Ethyl-1-[14C]-NOA 446510 was applied to
the skin (10 cm2) of Alpk:APfSD rats (4 males for each time point at
each dose level). Nominal doses were 0.00152, 0.0076, or 2.54 mg/cm2
skin, with water and/or A12946B commercial formulation blank serving as
the vehicle.  The highest dose would represent a formulation
concentrate, and could be used to assess exposure to mixer/loaders.  The
lower doses were aqueous dilutions representing typical in-use spray
strength dilutions of 1/333 and 1/1667 v/v.

Recovery of the applied dose (mass balance) was 96-112%.  Minimal
absorption, based on the sum of residues in urine, feces, cage wash,
gastrointestinal tract with contents, residual carcass, and blood (<0.17
to 3.44% of applied dose).  The study revealed that the majority of the
administered dose was recovered from the 6-hour skin wash (91-105%).

The greatest amount of absorption was noted in the 1/1667 aqueous
dilution 114 hours after the 6 hour exposure interval.  At this time
3.44% of the applied dose was absorbed.  The amount available for
absorption in the skin at the application site was less than the limit
of detection in all 4 animals (<0.11%).

Note:  No dermal end-points were appropriate for either cancer or
non-cancer effects.

3.5.4	Dermal Exposure (Short- and Intermediate-Term) 

There were no systemic or dermal effects observed up to the limit dose
of 1000 mg/kg/day in a 28-day dermal toxicity study in rats; therefore,
no dermal endpoints were chosen.  In addition, there were no
developmental effects in the rat and rabbit developmental studies and no
neurotoxicity effects in any studies (including the acute or subchronic
neurotoxicity studies). 

3.5.5	Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected:  90-Day Rat

MRID No:  46800216		

Dose and Endpoint for Risk Assessment: NOAEL = 41 mg/kg/day based on

decreased body weights, body weight gains and food utilization in males
as well as slight

hepatoxicity in both sexes at a LOAEL of 260 mg/kg/day. 

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

Comments about Study/Endpoint/Uncertainty Factors:  A 90-day dietary
admix toxicity study in rats was used to select the dose and endpoint
for short- and intermediate-term inhalation exposure.  Uncertainty
factors (100x) include: 10x interspecies extrapolation, and 10x
intraspecies variability.  The duration of the study is considered
appropriate for both short- and intermediate-term risk assessment.  A
100% inhalation exposure is assumed.

NOTE:  In the 2-Generation Reproduction Study, the parental/systemic
NOAEL was 22.9/24.5 mg/kg/day with a LOAEL of 146.3/148.2 mg/kg/day
based on decreased body weight, decreased body weight gain, decreased
food consumption and decreased food utilization, i.e, not much toxicity.
 On the other hand, in the 90-day rat study the NOAEL was 41/45
mg/kg/day with LOAEL of 260/260 mg/kg/day based on decreased body
weight, decreased body weight gain and decreased food utilization as
well as slight hepatotoxicity in both sexes.  The slight hepatotoxicity
is considered to be more "severe" than the LOAEL findings in the
2-generation study.  The lower NOAEL in the 2-Generation study is an
artifact of dose selection.  Therefore, the higher NOAEL of 41 mg/kg/day
was selected and would address the body weight decreases observed in the
2-Generation study. 

3.5.6	Level of Concern for Margin of Exposure

Table 3.5.6  Summary of Levels of Concern (LOCs) and Margins of Exposure
(MOEs) for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	NA	NA	

NA

Inhalation	<100	<100

	Residential Exposure1

Dermal	NA	NA	

NA

Inhalation	<100	<100

	Incidental Oral	<100	<100

	Dietary (Food and Water)	NA

 (acute, 1-day exposure)	NA	Exposure > 100% cPAD 

(chronic exposure)

1It is important to note, that for this action no residential uses have
been proposed.  The toxicology assessment considered residential routes
of exposure, and they are retained here for future reference in the
event a residential use is requested.

The Levels of Concern (LOCs) for the inhalation and incidental oral
routes (MOEs) are based on the conventional interspecies extrapolation
(10X) and intraspecies variation (10X) uncertainty factors.  No
additional uncertainty factors are necessary.  The LOCs for the dietary
route are expressed as a percentage of a maximum acceptable dose (i.e.,
the dose which HED has concluded will result in no unreasonable adverse
health effects).  This dose is referred to as the population adjusted
dose (PAD).  The PAD is equivalent to the RfD divided by the FQPA Safety
Factor (which has been reduced to 1x in the case of mandipropamid).  For
non-cancer chronic exposures, ARIA is concerned when estimated dietary
risk exceeds 100% of the PAD.

3.5.7	Recommendation for Aggregate Exposure Risk Assessments

Under FQPA, ARIA must consider and aggregate pesticide exposures and
risk from three major sources: food, drinking water, and residential
exposures.  Residential exposure to mandipropamid is not expected
(because there are no proposed residential uses) therefore, the
aggregate exposure assessment for this chemical involves considering the
contribution from food and drinking water.

3.5.8	Classification of Carcinogenic Potential

There were no treatment-related increases in tumors in rat and mouse
carcinogenicity studies after exposure to mandipropamid.  Additionally,
there was no evidence of mutagenicity noted. Therefore, mandipropamid is
“Not Likely to be Carcinogenic to Humans.”  

3.5.9	Summary of Toxicological Doses and Endpoints for Mandipropamid for
Use in

            Human Risk Assessments

Table 3.5.9a  Toxicological Doses and Endpoints for Mandipropamid for
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)	N/A

	N/A

	N/A

	No appropriate endpoint was identified, and a risk was not conducted.

Acute Dietary

(Females 13-49 years of age)	N/A

	N/A

	N/A

	No appropriate endpoint was identified, and a risk assessment was not
conducted.

Chronic Dietary (All Populations)	NOAEL = 5 mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Chronic RfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day	Chronic toxicity – dogs

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).

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to
Humans.”  No treatment-related tumors observed in carcinogenicity
studies in rats and mice.

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).  FQPA
SF = FQPA Safety Factor.  PAD = population adjusted dose (c = chronic). 
RfD = reference dose.  N/A = not applicable. 

Table 3.5.9b  Summary of Toxicological Doses and Endpoints for
Mandipropamid  for 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 (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-(1-30 days) and Intermediate-term (1-6 months)	NOAEL = 

41 mg/kg/day

IAF=100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	90-day oral toxicity – rats

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

Cancer (oral, dermal,                                                   
                                  inhalation)	“Not Likely to be
Carcinogenic to Humans.”  No treatment-related tumors observed in
carcinogenicity studies in rats and mice.

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable. 
IAF=inhalation absorption factor.

3.6	Endocrine Disruption			

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

In the available toxicity studies on mandipropamid, there was no
estrogen-, androgen-, and/or thyroid-mediated toxicity.  When additional
appropriate screening and/or testing protocols being considered under
the Agency’s EDSP have been developed, mandipropamid may be subjected
to further screening and/or testing to better characterize effects
related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data

Based on the recent registration of this chemical, usage patterns and
the lack of residential use sites, no incident reports are expected at
this time.  Additionally, no public health or epidemiology data were
found for this chemical when searched in the National Library of
Medicine TOXNET databases.

5.0	Dietary Exposure/Risk Characterization

DP Num: 340784 and 341460, M. Collantes, 12/SEP/2008.

5.1	Pesticide Metabolism and Environmental Degradation

The studies conducted have demonstrated that mandipropamid undergoes
extensive metabolism to form a range of metabolites which are
structurally related to, or more polar than the parent.  The extent of
metabolism appears to be related to preharvest intervals.  In crops with
shorter PHIs, the parent was detected at higher levels with relatively
fewer metabolites.

5.1.1	Metabolism in Primary Crops

46800127.der.doc, D. McNeilly, 28/AUG/2007 (Lettuce)

46800129.der.doc, D. McNeilly, 28/AUG/2007 (Tomato)

46800130.der.doc, D. McNeilly, 28/AUG/2007 (Grape)

46800131.der.doc, D. McNeilly, 28/AUG/2007 (Potato)

The nature of the residue in plants is adequately delineated based on
acceptable metabolism studies conducted on three different crops: 
lettuce (representing leafy vegetables); grapes (representing fruit
crops); potatoes (representing root and tuber vegetables).  The tomato
metabolism study (representing fruiting vegetables) is considered
supplementary due to the radiolableling in the amide bridge between the
two rings.  The terminal residue of concern for the purposes of
tolerance establishment and dietary risk assessments is the parent
mandipropamid.  Unchanged parent was the principal residue component
identified in all analyzed crop matrices.  Mandipropamid accounted for
82-94% of the Total Radioactive Residue (TRR) in lettuce, 54-80% of the 
TRR in grapes, 53-80% of the TRR in tomatoes, and 40-61% of the TRR in
potato leaves, but only 4.2% of the TRR in potato peel.  The grape and
tomato studies have shown that mandipropamid is largely present as
surface residues.  The studies conducted have demonstrated that
mandipropamid undergoes extensive metabolism to form a range of
metabolites which are structurally related to, or more polar than the
parent.  The extent of metabolism appears to be related to preharvest
intervals.  In crops with shorter PHIs, the parent was detected at
higher levels with relatively fewer metabolites.  As the level of the
parent compound decreased, the number of metabolites increased in the
tested crop matrices which were collected at longer PHIs.  A list of the
identified metabolites from these plant studies is presented in Appendix
B.  Overall, no individual metabolite was detected at a level greater
than 4% of the TRR in grapes, lettuce, and tomatoes.  Although the major
metabolite identified in potato tubers (following application of 0.8 lbs
ai/A, ca. 1.6X) accounted for 12.7% of the TRR, this represents 0.006
ppm.

5.1.2	Metabolism in Rotational Crops

46800145.der.doc, D. McNeilly, 28/AUG/2007 (Includes MRIDs 46800146-48)

A confined rotational crop study with mandipropamid has been submitted. 
The test substance, [14C]mandipropamid, was radiolabeled in either the
chlorophenyl (CP label) or methoxyphenyl (MP label) position.  Following
soil treatment, rotational crops of lettuce, radish, and spring wheat
were planted/seeded at plantback intervals (PBI) of 29, 58, and 120
days.  In addition, lettuce and wheat were planted at a 365-day PBI.

TRRs accumulated at ≥0.01 ppm in all rotated crop matrices except
radish roots and tops planted at the 120-day PBI, and lettuce, wheat
forage and wheat grain (CP label only) planted at the 365-day PBI.  The
distribution and nature of the residue in the rotated crops were similar
between the two labels (samples investigated contained TRR ≥0.01 ppm).
 The parent mandipropamid was identified at low levels.  Unchanged
parent was detected at a level greater than 0.01 ppm only in wheat straw
(≤0.023 ppm) but was less than 0.01 ppm in lettuce, radish root,
radish top, wheat forage, and wheat grain.  Two other residue
components, CGA 380778 and NOA 458422, were also detected at low levels.
 Metabolite CGA 380778 was identified at ≤0.006 ppm in lettuce, radish
roots and tops, wheat forage, and wheat straw.  Metabolite NOA 458422
was identified only in wheat straw at 0.008-0.016 ppm.

The principal metabolism routes include the removal of either or both of
the propargyl side chains to generate the corresponding alcohol or
phenol functionalities.  Extensive metabolism may occur yielding small
carbon units followed by incorporation into natural plant constituents
(i.e., cellulose, glucose, proteins, pectins, and lignin) or
alternatively some radioactive components may become covalently bound to
macromolecules in the plant.

5.1.3	Metabolism in Livestock

46800128.der.doc, D. McNeilly, 28/AUG/2007

A goat metabolism study with mandipropamid was submitted.  Two pairs of
lactating goats were dosed (calculated doses were: 27 ppm, 45 ppm, 30
ppm and 49 ppm) separately with [14C]mandipropamid, radiolabeled in
either the chlorophenyl (CP label) or methoxyphenyl (MP label) position.
 The goat fed with the MP label at 49 ppm became ill during the study,
and samples from this goat were not utilized.  Milk was collected twice
daily during the dosing period, and tissue collected at animal sacrifice
included kidneys, liver, omental fat, renal fat, and skeletal muscle
(hind and fore quarters).  The expected livestock dietary burden for
mandipropamid is ca. 0.075 ppm, and therefore these dosing levels are
equivalent to 400-480X the expected level. 

TRR are summarized in the table below.  TRR in collected samples were
initially determined by direct LSC or combustion/LSC, but the TRR
calculated by summation of the extractable and nonextractable
radioactivity were used for all subsequent calculations.  TRR were
highest in liver and kidney, and <0.01 ppm in muscle (both labels) and
all CP-label milk.  TRR were consistently low (≤0.01 ppm) in milk and
appeared to plateau by Day 4 for the MP-label goat.  The majority of the
administered dose was excreted:  31-33% in the feces, 47-49% in the
urine, and <1% in the cage washes.

Table 5.1.3.  TRR in Goat Milk and Tissues (Dosed at either 27/45 ppm or
30 ppm in the feed; equivalent to 400-480X).

Radiolabel Position	

Goat Matrix	TRR (ppm; expressed as parent equivalents)

By Direct Combustion/LSC 

Quantification	By Summation of Extractable and Nonextractable
Radioactivity

Chlorophenyl 1	Liver	0.443	0.480

	Kidney	0.126	0.136

	Fat	0.016	0.0174

	Milk	0.006 3	Not analyzed (NA)

	Muscle	0.005	NA

Methoxyphenyl 2	Liver	0.438	0.472

	Kidney	0.114	0.121

	Fat	0.024	0.0244

	Milk	0.010 4	0.010

	Muscle	0.005	NA

1   Combined samples from two goats administered with test substance at
27/45 ppm in the feed.

2   Samples from a single goat administered with the test substance at
30 ppm in the feed.

3   Maximum residue in combined milk samples, [Day 3 (am) sample].

4   Maximum residue was 0.011 ppm [Day 3 (am) sample].  The value in the
table is the residue in Day 4 (am

    sample), which was analyzed as it had clearly reached plateau.

The metabolite profiles were similar between the two labels with all the
metabolites observed containing both phenyl rings.  The parent
mandipropamid was the major residue component identified in fat and
accounted for 75.1-77.4% of the TRR.  The parent, however, was a minor
residue in MP-label milk at 7.9% of the TRR and liver at 0.8-1.4% of the
TRR.  The parent was not detected in kidney samples.

The metabolite NOA 458422 was a major residue (i.e., greater than 10% of
the TRR) in kidney at 15.0-17.7% of the TRR but was a minor residue in
liver at 5.3-5.8% of the TRR.  Metabolites CGA 380775, CGA 380778, SYN
505503, SYN 521195, and SYN 518495 were identified as minor residues in
kidney and liver.  The remaining residues in goat milk and tissues were
characterized as:  (i) unknowns totaling 12.2% of the TRR in milk,
5.5-17.1% of the TRR in fat, 19.6-27.5% of the TRR in kidney, and
20.0-46.9% of the TRR in liver with individual peaks accounting for
<0.04 ppm; (ii) baseline material accounting for <0.03 ppm; and (iii)
unassigned (TLC) remainder accounting for ≤0.06 ppm.

Based on the results of the study, the petitioner concluded that
mandipropamid undergoes extensive metabolism to produce more polar
metabolites in goats.  Metabolism occurs primarily by (i) the
demethylation of the methoxyphenyl functionality to generate the phenol
moiety; and (ii) the removal of either or both of the propargyl side
chain(s) yielding the corresponding alcohol or phenol functionalities. 
All the molecules, except the parent, have the potential to form polar
conjugates.

The results of the study, conducted at 400-480X, indicate that there is
no reasonable expectation of finite residues in the milk, meat, or meat
byproducts of ruminants (Category 3 of 40 CFR §180.6) as a result of
the proposed uses. 

No poultry feed items are associated with the proposed uses discussed in
this petition.

5.1.4	Analytical Methodology

46800132.der.doc, D. McNeilly, 28/AUG/2007 (Includes MRIDs 46800127 &
46800133)

46800134.der.doc, D. McNeilly, 28/AUG/2007 (Includes MRID 46800135)

47217301.der.doc, D. Rate, 18/SEP/2008 (Includes MRID 47217302)

Syngenta Crop Protection has submitted descriptions and validation data
for a method entitled “Analytical Method RAM 415/01 Residue Analytical
Method for the Determination of NOA 446510 in Crop Samples.  Final
Determination by LC-MS/MS.”  Method RAM 415/01 was the data-collection
method used for the analysis of samples for residues of mandipropamid
from supporting studies (storage stability, crop field trials,
processing, and limited field rotational trials) associated with PP#
6F7057.  It is also the proposed enforcement method.

Using Method RAM 415/01, residues of mandipropamid are extracted from
crop matrices with acetonitrile:water (80:20, v:v) and then centrifuged.
 Aliquots of the extract are diluted with water for cleanup by solid
phase extraction (SPE) using OasisTM HLB cartridges.  The SPE eluate is
concentrated for LC/MS/MS analysis.  Detection is accomplished by
monitoring the transition of [M+1] the molecular ion (m/z 412) to the
daughter ion (m/z 328); quantitation of mandipropamid is done by
external standardization and using the daughter ion.  The LOQ,
determined as the lowest fortification level with adequate recovery, is
0.01 ppm in plant matrices.  The estimated limit of detection (LOD) was
0.0003 μg/mL.  No confirmatory procedures were included in the method,
and no interference study was submitted.

LC/MS/MS Method 415/01 is adequate to quantitate mandipropamid residues
in/on crop matrices.  Initial method validation using control samples of
various representative crop matrices at fortification levels
representing the LOQ (0.01 ppm) and expected residue levels showed
adequate method recoveries.  The method was also successfully validated
by an independent laboratory using cabbage, potato, tomato, and wheat
straw at fortification levels of 0.01 ppm (LOQ) to 3.0 ppm.  Finally,
Method RAM 415/01 was adequately radiovalidated using aged samples of
lettuce obtained from a metabolism study.  The method was forwarded to
ACB/BEAD for a petition method validation.

For the purpose of tolerance enforcement, the Agency requires that
confirmatory methods or interference studies be submitted.  A
confirmatory method for Method RAM 415/01 will not be required pending
clarification that the method monitors two ion transitions during MS/MS
analysis, and the method specifies that analyte identification can be
confirmed by demonstrating that the ion ratio for the two MS/MS ion
transitions acquired during analysis agrees with the average ion ratio
obtained for the calibration standards.  

Although the proposed enforcement method was validated, ACB/BEAD
recommended that the petitioner provide information for a second MS/MS
ion transition to provide a confirmation of analyte identity.  The
petitioner subsequently submitted an LC/MS/MS method with two monitored
ion transitions for the determination of residues of mandipropamid in/on
crop commodities (DP Num: 348229 and 352322, D. Rate, 11/DEC/2008).  The
method is based on German multiresidue method DFG S-19 and was submitted
as a confirmatory method for mandipropamid in crops.  The method is
considered to be adequate for the purpose of tolerance enforcement.

The FDA Multiresidue methods do not appear to be adequate for
determining residues of mandipropamid.  These data will be forwarded to
the U.S. FDA for further evaluation.

5.1.5	Environmental Degradation

In soil, parent mandipropamid is the only major compound detected
(>10%).  According to the OECD Monograph for Mandipropamid (Draft Nov
2006): “Degradation of mandipropamid in soil is considered to be
mainly driven by soil microbial activity and photolysis if located to or
on the surface.”  In the aerobic aquatic metabolism study, SYN 504851
is a major metabolite (29%) and SYN 500003 is a minor metabolite (9.4%).
 Table 5.1.5 summarizes degradates from environmental fate studies.

The parent compound is mobile and also stable based on a half-life of
75-100 days in the field dissipation study.  The two significant
degradates observed in the aerobic aquatic metabolism study were SYN
504851 (maximum 29% of applied material; very mobile) and SYN 500003
(maximum 9.4%; mobile).  Based on the European Union monograph, SYN
500003 has a short residence time in soil (DT50 = 2 days), but is
considerably more stable under aerobic aquatic conditions (DT50 = 30
days).  Five degradates were found in the aerobic soil metabolism study,
but the maximum level of any of these was 4.25% of applied material.

Table 5.1.5  Major degradates found in Environmental Fate Studies

Metabolite/

Degradate	Maximum % found

	Hydrolysis 	Aqueous Photolysis	Soil photolysis	Aerobic soil metabolism
Aerobic aquatic metabolism

CGA380778	-	3.7	4.3	4.25	-

NOA458422	-	3.9	-	0.18	-

CGA380775	-	-	9.4	0.51	-

SYN500003	-	-	-	0.27	9.4

SYN536638	-	-	-	3.1	-

SYN504851	-	-	-	-	29

The degradation of mandipropamid indicates that the Cl-phenyl moiety of
mandipropamid is more stable than the methoxy-phenyl moiety.

5.1.6	Comparative Metabolic Profile

In soil, the parent mandipropamid is the only major compound present
(>10%).  While in surface water, mandipropamid and the metabolite SYN
504851 are major components.  SYN 504851 results from the cleavage of
the amide linkage between the two rings and partial reduction of the
alkyne group.  In the environment and in the presence of light,
mandipropamid is degraded to a large number of compounds.

In plants, the principal metabolism routes include the removal of either
or both of the propargyl side chains to generate the corresponding
alcohol or phenol functionalities.  Amide cleavage which results in
separation of the rings is also observed.  Extensive metabolism yields
small carbon units followed by incorporation into natural plant
constituents (i.e., cellulose, glucose, proteins, pectins, and lignin)
or alternatively some components may become covalently bound to
macromolecules in the plant

In livestock, mandipropamid undergoes extensive metabolism to produce
more polar metabolites.  Metabolism occurs primarily by (i) the
demethylation of the methoxyphenyl functionality to generate the phenol
moiety; and (ii) the removal of either or both of the propargyl side
chain(s) yielding the corresponding alcohol or phenol functionalities. 
The metabolites identified in the metabolism study all contained both
the chlorophenyl and methoxyphenyl moieties, i.e., the amide link
between the two rings remained intact.  In the rat, metabolism was very
similar and involved the loss of one or both propargyl groups, followed
by glucuronidation and demethylation resulting in at least six
metabolites. Parent and the following metabolites were present at ≥5%
of the administered dose in animals treated at 3 and/or 300 mg/kg: NOA
458422, NOA 458422 glucuronide, SYN 534133, and CGA 380778.  

The metabolism studies demonstrate that mandipropamid undergoes
extensive metabolism by removal of the propargyl side chains,
demethylation, and/or amide cleavage to form a range of metabolites
which are structurally related to, or are more polar than, the parent. 
In plants, the extent of metabolism is related to preharvest intervals. 
In crops with shorter PHIs, the parent was detected at higher levels
with relatively fewer metabolites.

5.1.7	Toxicity Profile of Major Metabolites and Degradates

Two significant degradates were observed in the aerobic aquatic
metabolism study were SYN 504851 (maximum 29% of applied material; very
mobile) and SYN 500003 (maximum 9.4%; mobile).  Based on the European
Union monograph, SYN 500003 has a short residence time in soil (DT50 = 2
days), but is considerably more stable under aerobic aquatic conditions
(DT50 = 30 days).  Five degradates were found in the aerobic soil
metabolism study, but the maximum level of any of these was 4.25% of
applied material.

An acute oral and Ames-test were performed for the metabolite SYN
500003.  This metabolite was not detected in rat metabolism studies. 
SYN 500003 was administered once by oral gavage to female rats at doses
of 550 or 2000 mg/kg.  The oral LD50 was calculated to be 1049 mg/kg or
more toxic than the parent compound (however, it is only 0.005-0.006 ppm
or 10.5-12.7% of the TRR in root and tuber crops).  The study is
acceptable/guideline with a Toxicity Category III.  In addition, a
bacterial reverse gene mutation assay (Ames Test) with SYN 500003 was
conducted.  No evidence of induced mutant colonies over background was
detected in that study.

HED noted that SYN 500003 still possesses a propargyl side chain like
those found in the parent.  Loss of this side chain could produce the
reactive compound propiolaldehyde.  The latter is believed to be the
source of the liver toxicity of propargyl alcohol, for which the
petitioner has submitted a 14-day repeat exposure study with rats
showing similar hepatotoxicity as seen with mandipropamid.  Therefore,
HED concluded that metabolites and degradates still having a propargyl
side should be considered comparably as toxic as the parent fungicide.

No toxicity data were submitted for the metabolite SYN 504851.  While
SYN 504851 does not have the propargyl side chain, it could generate a
reactive aldehyde (e.g., acrolein) similar to propiolaldehyde with a
vinyl group instead of the alkyne function.  Therefore, in the absence
of repeated dose studies, HED concluded this degradate should also be
considered toxicologically equivalent to the parent (Mandipropamid:
Report of the Risk Assessment Review Committee (RARC1), 16/AUG/2007).

5.1.8	Pesticide Metabolites and Degradates of Concern 

(Mandipropamid: Report of the Risk Assessment Review Committee (RARC1),
16/AUG/2007)

Table 5.1.8  Summary of Metabolites and Degradates to be Included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Parent mandipropamid

(Parent + SYN 500003 for root and tuber vegetables )	Parent
mandipropamid

	Rotational Crop	Not applicable	Parent mandipropamid*

Livestock

	Ruminant	Not applicable	Not applicable 

	Poultry	Not applicable	Not applicable

Drinking Water

	Parent, SYN 504851 and SYN 500003*	Not Applicable

*Although the parent compound is a residue of concern in rotational
crops, tolerances are not needed for the present uses, based on the
absence of residues in the field rotational crops study following the
label’s 30 day plantback interval. 

Rationale for Primary Crops

In the primary crops grapes and lettuce, parent mandipropamid was by far
the predominant residue at 53.6-93.5% of the TRR.  Various minor
metabolites were identified at levels of <1 to 4% of the TRR.  Similar
results were seen in potato leaves.  In the peel of the potato tuber,
parent was present at only 0.8-4.2% TRR (max. 0.002 ppm) and was not
detected in the flesh from either radiolabel.  The only identified
metabolites found at levels >0.001 ppm in tubers were SYN 500003
(0.005-0.006 ppm, 10.5-12.7% TRR) and SYN 524199 (0.003 ppm, 6.2-7.2%
TRR).  The latter is a glucose conjugate of an hydroxylated chlorophenyl
acetic acid and is expected to be significantly less toxic than the
parent mandipropamid.  As explained below in the discussion on drinking
water residues, SYN 500003 is considered to be comparably toxic as the
parent fungicide.  SYN 500003 was detected in potato field trial samples
at levels of up to 0.016 ppm.  Residues of parent were <0.01 ppm in the
tuber RAC in the field trials.

Taking into account the above considerations, the residue to be used for
tolerance enforcement and dietary risk assessment for all primary crops,
except root and tuber vegetables, is parent mandipropamid.  For Crop
Subgroup 1C, SYN 500003 is present at higher levels than parent and
should be included (along with the parent) in the residue for dietary
risk assessment.  The tolerance for Crop Subgroup 1C in the present
petition is for the parent only, as it can serve as a marker compound to
detect gross misuse.

Rationale for Rotational Crops

The only residues identified in the confined study at levels above 0.01
ppm were parent and NOA 458422 in wheat straw (0.023 and 0.016 ppm,
respectively).  In the field rotational crop study parent was <0.01 ppm
in all analyzed matrices of spinach, radish and wheat following
plantback intervals of 28/31 and 61 days.  Although NOA 458422 was not
measured in the field study, it was found only in wheat straw, a minor
feed item, in the confined study at a very low level.  Therefore, it is
not a residue of concern.  HED concluded that the parent compound is the
only residue of concern in rotational crops.

Rationale for Drinking Water

Based on the fate and toxicity considerations discussed in 5.1.5 and
5.1.7, the residues to be included in drinking water for the dietary
risk assessment are parent mandipropamid and the degradates SYN 504851
and SYN 500003.

5.1.9	Drinking Water Residue Profile

The maximum seasonal application proposed for the new uses on tobacco
and hops is less than or equal to currently registered use rates.  As
such, a previously modeled Tier I drinking water assessment for the
established mandipropamid uses conducted by EFED was used in this
dietary assessment (DP Num: 339258, I. Abdel-Saheb; 23/APR/2007).  The
assessment included mandipropamid and its major aquatic degradates (SYN
500003 and SYN 5044851) in drinking water. 

The SCI-GROW (Version 2.3) model was used to estimate concentrations of
mandipropamid and its degradates (SYN500003 and SYN 504851) that could
be found in drinking water derived from ground water.  The First
(Version 1.1.0) model was used to estimate the concentration of
mandipropamid and the major aquatic degradate SYN 504851 and minor
aquatic degradate SYN500003 that could be found in drinking water
derived from surface water.  The estimated drinking water concentrations
(EDWCs) are based on the highest labeled use pattern of 4 applications
of 0.13 lbs ai/A for a total rate of 0.52 lbs ai/A/Season.  The modeled
EDWCs are shown in the Table 5.1.9.  The EDWC used in the dietary
analysis is 36.5 ppb, the sum of the surface water numbers for
Mandipropamid, SYN500003, and SYN504851.

Table 5.1.9.  Estimated Drinking Water Concentrations for Mandipropamid
and Metabolites for Chronic Dietary Analysis  

	Mandipropamid

       (ppb)	SYN500003

     (ppb)	SYN504851

     (ppb)

	Surface Water	        25.2	        2.32	        8.99	Four applications
at 0.13 lb ai/A with 7 days between applications

Ground Water	     5.22E-02	     5.85E-01	        1.73

	Note:  The chronic drinking water values were incorporated directly
into the dietary assessments under the DEEM-FCID food categories
“water, all sources” and “water, indirect, all sources.”

5.1.10	Food Residue Profile

DP Num: 348229 and 352322, D. Rate, 11/DEC/2008

47384905.der.doc, D. Rate, 18/SEP/2008

47384908.der.doc, D. Rate, 18/SEP/2008 (Includes MRID 47384909)

47384906.der.doc, D. Rate, 18/SEP/2008

47384907.der.doc, D. Rate, 18/SEP/2008

47384909.der.doc, D. Rate, 18/SEP/2008

			In addition, see Mandipropamid.  Section 3 Registration Request to
Register New Uses on Hops and Tobacco.  Summary of Analytical Chemistry
and Residue Data.  DP Num: 348229 and 352322, D. Rate; 11/DEC/2008.

			Crop Field Trials:  The registration requirements for magnitude of
the residue in plants have been evaluated and deemed fulfilled hop,
dried cones.  Residue data for hops were submitted from trials conducted
in the U.S. and Northern Europe.  The trials conducted in the U.S.
reflect the proposed use pattern, and the number and locations of U.S.
trials are in accordance with OPPTS Guideline 860.1500.  Assessing for
the worst-case scenario for possible residues on imported hops and
global harmonization, a tolerance of 50 ppm is recommended.  A revised
Section F to correct the commodity definition from hops to hop, dried
cones, should be submitted.

			Processed food:  Although no processing studies are required for the
RAC, hops, the petitioner has submitted adequate supplemental studies
which have been reviewed.  These data indicate that residues of
mandipropamid did not concentrate in spent hops and beer matrices (wort
after cooking, spent yeast, young beer, and beer) processed with dried
hop cones bearing quantifiable residues.

5.1.11	International Residue Limits

There are no specific Codex, Canadian, or Mexican maximum residue limits
(MRLs) for mandipropamid.

5.2	Dietary Exposure and Risk

DP Num: 356488, D. Rate, 02/DEC/2008

DP Num: 348229, D. Rate, 11/DEC/2008.

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™, Version 2.03) which uses food
consumption data from the USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.

No acute dietary endpoint could be identified based on the toxicology
data currently available for mandipropamid.  There were no
treatment-related tumors observed in carcinogenicity studies in rats and
mice.  Mandipropamid is classified as not likely to be a human
carcinogen.  Therefore, a cancer assessment was not performed.

A tolerance level (unrefined) chronic exposure assessment that assumes
100% crop treated was conducted for the proposed Section 3 uses of
mandipropamid.  The DEEM analysis incorporates estimates of drinking
water concentrations from EFED directly into the analysis.  The chronic
dietary exposure analysis for mandipropamid results in dietary risk
estimates for food and water that are below the Agency’s level of
concern for chronic dietary exposure.  For mandipropamid, the DEEM
chronic dietary exposure estimate was 23% of the cPAD for the U.S.
population and was 30% of the cPAD for the highest exposed population
subgroup, children 1-2 years of age.

Table 5.2  Results of Chronic Dietary Exposure Analysis Using DEEM
FCID.1

Population Subgroup	Chronic Dietary	Cancer

	Dietary Exposure

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.011516	23	N/A	N/A

All Infants (< 1 year old)	0.007931	16

Children 1-2 years old	0.015107	301

Children 3-5 years old	0.014559	29

Children 6-12 years old	0.010925	22

Youth 13-19 years old	0.009203	18

Adults 20-49 years old	0.011577	23

Adults 50+ years old	0.011751	24

Females 13-49 years old	0.011325	23

1The population subgroup with the highest estimated chronic dietary
(food + drinking water) exposure and risk is indicated by bold text.

Note:  % cPAD reported  to 2 significant figures.  

6.0	Residential and Other Exposures (Spray Drift, etc.)

Residential exposures were not assessed because the registered and
proposed uses of mandipropamid do not involve applications by homeowners
or by commercial applicators in residential settings.  

Spray drift is always a potential source of exposure to residents near
spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
mandipropamid.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices.  On a chemical by chemical basis, the Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling.  The Agency has completed its evaluation of
the new database submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

7.0 	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, ARIA must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, ARIA considers both the route and duration of exposure.

There are no residential uses proposed or registered for mandipropamid,
and therefore aggregate risk is equal to that from consumption of food
and water.  Chronic aggregate risk estimates associated with exposure to
mandipropamid residues in food and water do not exceed ARIA’s level of
concern.  See section 5.2.1. for additional details.  Acute and cancer
aggregate risks were not assessed due to the absence of an acute dietary
endpoint and because mandipropamid is not likely to be carcinogenic.

8.0	Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
"available information concerning the cumulative effects” of a
particular pesticide's residues and "other substances that have a common
mechanism of toxicity.”

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to mandipropamid and any other
substances, and mandipropamid does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that mandipropamid has
a common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/"
http://www.epa.gov/pesticides/cumulative/ .

9.0	Occupational Exposure/Risk Pathway 

DP Num: 357873, M. Dow, 28/OCT/2008

DP Num: 359131, M. Dow, 02/DEC/2008

Exposure to pesticide handlers is likely during the occupational use of
mandipropamid in a variety of occupational environments.  The product
may be applied using groundboom equipment, aerial equipment,
chemigation, and airblast equipment (grapes only).  

The quantitative exposure/risk assessment developed for occupational
handlers is based on the following scenarios: (1) mixing/loading liquids
for aerial applications; (2) mixing/loading liquids for chemigation
applications; (3) mixing/loading liquids for groundboom applications;
(4) mixing/loading liquids for airblast applications; (5) applying
sprays with aerial equipment; (6) applying sprays with groundboom
equipment;  (7) applying sprays with airblast equipment; and (8)
flagging for aerial spray applications.  Occupational exposure is
expected to be short- and intermediate-term.  ARIA does not expect long
term exposure, due to the limited number of applications and the fact
that there are no residential uses.

9.1	Short-/Intermediate-Term Occupational Handler Risk

Short- and intermediate-term dermal exposures and risks were not
assessed for mandipropamid, since no short- or intermediate-term dermal
endpoint was identified.

A series of assumptions and exposure factors served as the basis for
completing the occupational handler risk assessments.  Each assumption
and factor is detailed below on an individual basis. The assumptions and
factors used in the risk calculations include:

Occupational handler exposure estimates were based on surrogate data
from the Pesticide Handlers Exposure Database (PHED).

The toxicological endpoints of concern for inhalation risks are not
sex-specific; therefore, the average body weight of an adult handler
(i.e., 70 kg) is used to complete the inhalation non-cancer risk
assessments. 

Short-term and intermediate-term inhalation risk assessments were
completed based on the inhalation toxicity endpoint that was identified.
Long-term handler exposures are not expected to occur based on the uses
of mandipropamid. 

 

Generic protection factors (PFs) were used to calculate exposures when
data were not available.  For example, an 80 percent protection factor
was assumed for the use of a respirator equipped with a quarter-face
dust/mist filter. 

Exposure factors used to calculate daily exposures to handlers are based
on applicable data, if available.  For lack of appropriate data, values
from a scenario deemed similar enough by the assessor might be used.  

For non-cancer assessments, HED assumes the maximum application rates
allowed by labels in its risk assessments. 

The average occupational workday is assumed to be 8 hours.  

The daily areas treated were defined for each handler scenario (in
appropriate units) by determining the amount that can be reasonably
treated in a single day (e.g., acres per day). When possible, the
assumptions for daily areas treated are taken from the Health Effects
Division Science Advisory Committee on Exposure SOP #9.1: Standard
Values for Daily Acres Treated in Agriculture, which was revised on
September 25, 2001.

Daily Exposure: Daily inhalation handler exposures are estimated for
each applicable handler task with the application rate, the area treated
in a day, and the applicable inhalation unit exposure.  The daily
inhalation dose is calculated by normalizing the daily inhalation
exposure by body weight and adjusting with an appropriate inhalation
absorption factor. 

Daily Dose:  The daily inhalation dose is calculated by normalizing the
daily inhalation exposure by body weight and adjusting with an
appropriate inhalation absorption factor.  

Margins of Exposure:  Non-cancer inhalation risks for each applicable
handler scenario are calculated using a Margin of Exposure (MOE), which
is a ratio of the daily dose to the toxicological endpoint of concern.

In all scenarios short- and intermediate-term inhalation risks met or
exceeded the MOE of 100 (ARIA’s level of concern) at baseline level of
mitigation.  A summary of the short- and intermediate-term inhalation
risks for each exposure scenario is presented below in Table 9.1.  

Table 9.1 Summary of Exposure & Risk to Occupational Handlers From
Mandipropamid.

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Mixer/Loader - Liquid - Open Pour

Inhalation           0.0012	0.13 lb ai/A	350 A/day	Inhalation        
0.00078	53,000

Applicator - Air-blast - Open Cab

Inhalation           0.0045	0.13 lb ai/A	40 A/day	Inhalation        
0.00033	124,000

Aerial Applicator (Pilots not required to wear gloves)

Inhalation          0.000068	0.13 lb ai/A	350 A/day	Inhal.             
0.000044	932,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.    Dermal =  Single Layer Work
Clothing No Gloves;  Single Layer  Work Clothing With Gloves;  Inhal. =
Inhalation.  Units = mg a.i./pound of active ingredient handled.  Data
Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2.  Applic. Rate. = Taken from draft supplemental label.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; ExpoSAC SOP  No. 9.1. Revised 5 July 2000.

 70 kg Body Weight.

5.  MOE = Margin of Exposure = NOAEL   ADD.   NOAEL for short- and
intermediate-term duration inhalation exposure = 41 mg ai/kg bw/day.  

9.2	Short-/Intermediate-Term Occupational Postapplication Risk

Occupational post-application exposures/risks were not quantified
because no appropriate dermal endpoints were identified.  The 4-hr
Restricted Entry Interval (REI) appearing on the proposed product label
for RevusTM Fungicide adequately supports the Worker Protection Standard
(WPS).  Based on newly reviewed studies (DP Num: 355979, M. Hashim,
07/SEP/2008), mandipropamid is not classified as a dermal sensitizer and
is a low risk pesticide; therefore it is a candidate for a reduced risk
active ingredient REI of 4 hours.  

10.0	Data Needs and Label Recommendations

10.1	Toxicology

An immunotoxicity study in rats is required under the current EPA
regulations (40 CFR Part 158).  This study was not submitted to the
Agency in support of the registration for products containing
mandipropamid.  Therefore, the lack of this study will remain a data gap
and registration of mandipropamid should be made conditional pending
receipt of an acceptable immunotoxicity study.

10.2 		Residue Chemistry

860.1200 Directions for Use

The supplemental label for RevusTM is adequate to allow evaluation of
the residue data relative to the proposed use on hops.  However, a few
minor label revisions are required.  As per 860.1000 and to preclude the
submission of a separate set of data reflecting aerial equipment, the
label should be revised to specify that aerial applications are to be
made in a minimum of 2 gallons water per acre.  In addition, the label
and Section B should be revised to specify the following rotational crop
restrictions:  “Do not plant any crop which is not registered for use
with mandipropamid for a period of 30 days after the last
application.”

860.1550 Proposed Tolerances

A summary of recommended tolerances along with recommendations to
commodity definitions are presented in Appendix C.  The petitioner
should submit a revised Section F to amend the commodity definition for
hop, dried cones.

860.1380 Storage Stability Data 

Storage stability data for SYN 500003 which covers the entire 32 months
of storage (interim storage stability data for six months were
submitted) are still required as requested in an Agency document (DP
Num: 340784, D. McNeilly, 28/AUG/2007).

10.3	Occupational and Residential Exposure

None.

11.0	References: 

MANDIPROPAMID – Exposure/Risk Assessment for the Proposed Use of
Mandipropamid on Hops and Tobacco, DP Num: 359131, M. Dow, 02/DEC/2008.

MANDIPROPAMID – Exposure/Risk Assessment for the Proposed Uses of 
Mandipropamid on Brassica Vegetables, Bulb Vegetables, Cucurbits,
Fruiting Vegetables, Leafy Green Vegetables, Grapes, Tomatoes, and
Tuberous and Corm Vegetables, DP Num: 357873, M. Dow, 28/OCT/2008.

Mandipropamid.  Section 3 Registration Request to Register New Uses on
Hops and Tobacco.  Summary of Analytical Chemistry and Residue Data.  DP
Num: 348229 and 352322, Debra Rate, 11/DEC/2008.

Mandipropamid.  Request to Register New Food/Feed Uses on Head and Stem
Brassica, Leafy Brassica Greens, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Tuberous and Corm Vegetables, Grapes, and
Onions (Dry Bulb and Green).  Summary of Analytical Chemistry and
Residue Data.  Petition Numbers 6F7057 and 7F7184.  DP Num: 340784,
Dennis McNeilly, 28/AUG/2007.

Mandipropamid: Chronic Dietary (Food and Drinking Water) Exposure and
Risk Assessment for Mandipropamid to Support Section 3 Registration for
Use on Hops and Tobacco.  PC Code:  036602.  DP Num: 356488.  D. Rate. 
02/DEC/2008.

Appendix A:  Toxicology Assessment

A.1  Toxicity Data Requirements

The requirements (40 CFR 158.340) for mandipropamid are in Table A.1.
Use of the new guideline numbers does not imply that the new (1998)
guideline protocols were used.

                 Table A.1.  Toxicology Data Requirements.

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (nonrodent)	

870.4200b   Carcinogenicity (mouse)	

870.4300    Chronic Toxicity /Carcinogenicity (rat)		yes

yes

yes	yes

yes

yes

870.5100    Mutagenicity—Gene Mutation – bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5375    Mutagenicity—Structural Chromosomal Aberrations	

870.5395    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

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

870.6300    Develop. Neuro.		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

yes

870.7800    Immunotoxicity	yes	no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

“-“ = Indicates not available

A.2  Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Test Substance 

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

870.1100	Acute oral rat	46800201	LD50 > 5000 mg/kg 	IV

870.1200	Acute dermal rat	46800202 	LD50 > 5050 mg/kg 	IV

870.1300	Acute inhalation rat	46800204 	LC50 > 5.19 ± 0.55 mg/L 	IV

870.2400	Acute eye irritation rabbit	46800206	Iritis and positive signs
of conjunctivitis clearing within 24 hours.	IV

870.2500	Acute dermal irritation rabbit	46800208	PDI = 0.33 	IV

870.2600	Skin sensitization guinea pig	46800210	Replaced by 47259001.
N/A

870.2600	Skin sensitization mouse	47259001	Test substance is not a
dermal sensitizer.	Negative

	N/A -- not applicable.

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

Guideline No. 	Study Type	MRID No. (year)/ Classification 	Dose levels
Results

870.3100a

	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).

870.3100a

	90-Day oral toxicity (mouse)	46800213 46800217

 (2005)

Acceptable/

Guideline

 	ppm= 0, 300, 800, 2000, 5000

mg/kg/day=

M: 0, 37, 98, 248, 624

F: 0, 47, 129, 316, 800	NOAEL = M/F = 248/316 mg/kg/day

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

870.3150

	90-Day oral toxicity (dog)	46800218

46800219

46800220

(2005)

Acceptable/

Guideline

	mg/kg/day= 

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

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

870.3200

	21/28-Day dermal toxicity (rat)	46800222

46800221

( 2005)

Acceptable/

Guideline	mg/kg/day= 

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

LOAEL = not determined

870.3700a

	Prenatal developmental  (rat)	46800224

46800223

(2005)

46800228

(2001)

Acceptable/ Guideline	mg/kg/day= 

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

LOAEL = not determined

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not determined

870.3700b

	Prenatal developmental (rabbit)	46800227 46800225  46800226 46800229
(2005)

Acceptable/ Guideline	mg/kg/day= 

0, 50, 250, 1000	Maternal NOAEL = 1000 mg/kg/day

LOAEL = not determined

Developmental  NOAEL = 1000 mg/kg/day

LOAEL = not determined

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.

870.4100b

	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.

870.4200b

	Carcinogenicity

(mouse)	46800233 (2005)

Acceptable/

Guideline	ppm = 0, 100, 500, 2000

mg/kg/day= M/F =

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

LOAEL = 223/285 mg/kg/day, based on decreased body weight gain in both
sexes and decreased food utilization in males. 

There was no evidence of carcinogenicity in mice.

870.5100	Bacterial Reverse Mutation Assay 	46800235 (2005)

Acceptable/ Guideline	Tested up to limit dose of 5000 µg/plate	Negative

870. 5300	In Vitro Mammalian Cell Gene Mutation Test – Mouse Lymphoma 
	46800236 (2005)

Acceptable/ Guideline	Tested up to limit dose (4119 µg/mL)

	Negative

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.  

870.7485

	Metabolism and pharmacokinetics

(rat)	46800243-46800246 (2005)

Acceptable/ Guideline	mg/kg/day =

single oral 3 or 300 methoxy label

repeated 3 methoxy label

single oral 3 or 300 methoxy/chloro labels

	After 48 hours, absorption was 67-74% at 3 mg/kg and 30-45% at 300
mg/kg.  Blood Tmax at 3 mg/kg was 8.5 hours for M and 4.5 hours for F;
at 300 mg/kg was 24 hours for M and 10 hours for F (rate of resorption
greater in F; extent and rate greater in low dose).  Recoveries at 168
hours 88-99% (most eliminated by 48 hours). Excluding 3 mg/kg F, most
excreted in feces; at 3 mg/kg F, feces and urine similar.  Elimination
after 48 hours in bile was high at 3 mg/kg (55-73%), but was 22-28% at
300 mg/kg.  Liver had highest concentration at all measurements.  More
radioactivity in  plasma than whole blood.  Identified compounds 66-94%
of administered dose in each group (168 hours).  Parent and following
metabolites at ≥5% at 3 and/or 300 mg/kg: NOA 458422, NOA 458422
glucuronide, SYN 534133 and CGA 380778.  Differences in metabolic
profile due to sex, dose and radiolabel position.  Each unknown 
compound < 5%.  Major metabolic transformations involved loss of one or
both propargyl groups followed by glucuronidation and O-demethylation. 

870.7600	Dermal Penetration (rat)	46800248 (2005)

Acceptable/ Guideline	Nominal doses: mg/cm2 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).

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/cm2 skin = 2570 or 2510	Absorption rate
greatest during first 30 minutes of exposure, 0.715-0.746 µg/cm2/hour. 
Absorption rates over 24 hours were 0.077-0.091 µg/cm2/hour.  

Non-Guideline	In Vitro Dermal Penetration Study, Rat epidermis	46800251
(2005)

Acceptable/ Non-Guideline	µg/cm2 skin = 1.35, 6.69, 2538	Absorption was
poor (recovery of applied radioactivity 99-105%).  Absorption rates over
24 hours were <0.04 µg/cm2/hour in concentrate formulation and 0.01
µg/cm2/hour in aqueous spray dilutions. 

Non-

Guideline	In Vitro Dermal Penetration Study, Pig epidermis	46800249

(2003)

Acceptable/

Non-Guideline	µg/cm2 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/cm2/hour) and was 0.02
µg/cm2/hour over 24 hours.  Absorption rate for acetone was 3.58%
(first hour = 0.56, 24 hours = 0.05 µg/cm2/hour).  Absorption enhanced
by acetone.

Non-

Guideline	In Vitro Dermal Penetration Study, Human epidermis	46800250

(2005)

Acceptable/

Non-Guideline	µg/cm2 skin = 1.35, 6.69, 2538	Recovery of radioactivity
was 95-102%.  Absorption was minimal.  Over 24 hours, absorption was
<0.04 µg/cm2/hour in the concentrate formulation and ≤0.001
µg/cm2/hour in the aqueous spray dilutions.

Appendix B:  Metabolism Assessment

APPENDIX B.	Chemical Names and Structures of Mandipropamid and
Metabolites.  

Common name/code

Matrix

(percentage, if over 10%)	Chemical name	Chemical structure

Mandipropamid/ 

NOA 446510 (parent)

Goat milk, fat (77.4%) & liver;

Grape fruit (80.2%,0-DAT) & leaves (76.1%,0-DAT ); 

Lettuce (93.5% 3-DAT);

Potato tuber & leaves (60.6%, 7-DAT);

Tomato fruit (80.4, 0-DAT) & leaves (787.4%, 14-DAT); and

Rotate⁤敬瑴捵⡥㐱㈮Ⱕ㈠ⴹ慄⁹䉐⥉‬慲楤桳爠潯獴㈨
⸹┸‬㤲䐭祡倠䥂 湡⁤潴獰⠠㌱㠮Ⱕ㔠ⴸ慄⁹䉐⥉‬
湡⁤桷慥⁴潦慲敧⠠㈱ㄮⰥ㔠ⴸ慄⁹䉐⥉‬牧楡⁮…瑳
慲⹷刍瑡⠠㤷〮⸥ܩ敢穮湥慥散慴業敤‬ⴴ档潬潲中嬭
ⴲ㍛洭瑥潨祸㐭⠭ⴲ牰灯湹汹硯⥹

NOA 458422

Goat kidney(17.7%) & liver;

Grape fruit & leaves;

Lettuce;

Potato leaves; 

Tomato fruit & leaves; and 

NOA 458422 glucuron

Rat (46.1%).

	Glucuron conjugate of
2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-2-prop-2-yny
loxy-acetamide

	                             

                       Not available

CGA 380778

Goat kidney & liver;

Grape fruit & leaves;

Lettuce;

Potato leaves;

Tomato fruit & leaves; and

Rotated lettuce, radish roots and tops, and wheat forage & straw.

CGA 380775

Goat kidney & liver;

Grape fruit & leaves;

Lettuce;

Potato tuber 2 & leaves; and

CGA 155705

Grape fruit & leaves; and

SYN 500003

SYN 505503

Goat kidney & liver.

SYN 505503 glucuron

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ࠀphenyl)-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-2-prop-2-ynyloxy-acetamide
                             

                     Not available

SYN 505504 

SYN 505504  glucuron

Rat.

	Glucuron conjugate of
2-(4-chlorophenyl)-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-2-hydroxy-acetamid
e	                             

                      Not available

SYN 508793; malonyl-O-glycoside of NOA 458422

SYN 508792; 

O-glycoside of NOA 458422

Grape fruit & leaves; and

SYN 518495

Goat kidney & liver.

SYN 521195

Goat kidney & liver;

Grape fruit;

Lettuce; and

SYN 524193 

Grape fruit & leaves.

SYN 524194

SYN 524196

SYN 524197

SYN 524198

Grape fruit & leaves.

SYN 524195

SYN 524199

Grape fruit & leaves; and

SYN 524200 

SYN 524201

NOA 458422

NOA 459119 

SYN 504851

Water (29%, aerobic aquatic metabolism study).

SYN 534133 

Rat (10%).

1 Detected at <0.01 ppm in all rotated crops except wheat straw.

2 Only identified at trace levels in potato peel with LC/MS/MS analysis.

Appendix C:  Tolerance Assessment Summary and Table

Appendix C. 	Tolerance Summary for Mandipropamid.

Commodity	Proposed 

Tolerance (ppm)	Recommended 

Tolerance (ppm)	Comments; Correct Commodity Definition

Hops	50	50	Hop, dried cones

Appendix D:  Review of Human Research

"The PHED Task Force, 1995. The Pesticide Handlers Exposure Database,
Version 1.1. Electronic Database. Task Force members Health Canada, U.
S. Environmental Protection Agency, and the National Agricultural
Chemicals Association, released February, 1995."

Appendix E: Other Toxicity Studies

In addition to the toxicology guideline studies, the Registrant also
submitted, at a later date, 14 other studies.  There were two Ames
mutagenic assays (SYN500003 metabolite and SYN545038 impurity), single
dose and 14-day repeated dose studies with propargyl alcohol, an oral
LD50 rat study with SYN500003 metabolite, and the following studies
conducted with mandipropamid: a metabolism study in dogs, acute
high-dose studies in rats and mice, cell proliferation studies in rats
and mice, a 28-day oral gavage study in male rats, an oral
gavage/dietary/intravenous radioactive study in mice, a radioactive in
vivo/in vitro rat liver study, and a radioactive investigative
metabolism study in rats. These studies were considered when writing
this risk assessment; however, a detailed review of these studies is
found in a separate document (Alan Levy; Sept 12, 2007; DP Num: 343579).

Mandipropamid	Risk Assessment Document	DP Num: 365918

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Mandipropamid	Risk Assessment Document	DP Num: 365918

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Mandipropamid	Risk Assessment Document	DP Num: 365918

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Mandipropamid	Risk Assessment Document	DP Num: 365918

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