 							

                   UNITED STATES

ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: Sept 12, 2007

MEMORANDUM

SUBJECT:	Mandipropamid: Human Health Risk Assessment for Proposed 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) and Processed Commodities.

		     PC Code: 036602.  Petition Numbers 6F7057 and 7F7184.

Decisions: 366489, 375236.

DP Barcodes: D340784 & D341460

		Regulatory Action: Section 3.

		Risk Assessment Type: Section 3, single chemical assessment, no
aggregate

                                                             
assessment.

						

FROM:	Margarita Collantes, Biologist

Alan Levy, Ph.D., Toxicologist

Dennis McNeilly, Chemist/Risk Assessor

		Registration Action Branch II

		Health Effects Division (7509P)

THROUGH:	Christina Swartz, Chief

Richard Loranger, Ph.D., Senior Scientist

Registration Action Branch II 

		Health Effects Division (7509P)

			and

		Kelly O’Rourke, Biologist

		P. V. Shah, Ph.D., Senior Scientist

Risk Assessment Review Committee

Health Effects Division (7509P)

TO:		Cynthia Giles-Parker, Chief

		Fungicide Branch					

		Registration Division (7505P)Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc176838824 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc176838825 \h  9 

2.1	Structure and Nomenclature	  PAGEREF _Toc176838826 \h  9 

2.2	Physical and Chemical Properties	  PAGEREF _Toc176838827 \h  9 

2.3	Summary of Registered/Proposed Uses	  PAGEREF _Toc176838828 \h  10 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc176838829 \h  12 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc176838830 \h
 12 

3.1.1	Database Summary	  PAGEREF _Toc176838831 \h  12 

3.1.1.1	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc176838832 \h  12 

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc176838833 \h  12 

3.1.1.3	Sufficiency of studies/data	  PAGEREF _Toc176838834 \h  13 

3.1.2	Toxicological Effects	  PAGEREF _Toc176838835 \h  13 

3.1.3	 Dose-response	  PAGEREF _Toc176838836 \h  14 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc176838837 \h  14 

3.3	FQPA Considerations	  PAGEREF _Toc176838838 \h  14 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc176838839 \h  14 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc176838840 \h  15 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc176838841 \h  15 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc176838842 \h  15 

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc176838843 \h  15 

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc176838844 \h  15 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc176838845 \h  15 

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties	  PAGEREF
_Toc176838846 \h  15 

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc176838847 \h  16 

3.3.8	Rationale for the UFDB (when a DNT is recommended)	  PAGEREF
_Toc176838848 \h  16 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc176838849 \h 
16 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc176838850 \h  16 

3.5.1    Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc176838851 \h  16 

3.5.2	Chronic Reference Dose (cRfD)	  PAGEREF _Toc176838852 \h  17 

3.5.3	Dermal Absorption	  PAGEREF _Toc176838853 \h  17 

3.5.4	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF
_Toc176838854 \h  17 

3.5.5	Inhalation Exposure (Short-, Intermediate- and Long-Term)	 
PAGEREF _Toc176838855 \h  18 

3.5.6	Level of Concern for Margin of Exposure	  PAGEREF _Toc176838856 \h
 18 

3.5.7	Classification of Carcinogenic Potential	  PAGEREF _Toc176838857
\h  19 

3.5.8	Summary of Toxicological Doses and Endpoints for Mandipropamid for
Use in Human Risk Assessments	  PAGEREF _Toc176838858 \h  19 

3.6	Endocrine disruption	  PAGEREF _Toc176838859 \h  20 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc176838860 \h  20 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc176838861 \h 
20 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc176838862 \h  20 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc176838863 \h  21 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc176838864 \h  21 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc176838865 \h  22 

5.1.4	Analytical Methodology	  PAGEREF _Toc176838866 \h  24 

5.1.5	Environmental Degradation	  PAGEREF _Toc176838867 \h  25 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc176838868 \h  25 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc176838869 \h  26 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc176838870 \h  27 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc176838871 \h  28 

5.1.10	Food Residue Profile	  PAGEREF _Toc176838872 \h  30 

5.1.11	International Residue Limits	  PAGEREF _Toc176838873 \h  30 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc176838874 \h  30 

6.0	Residential and Other Exposures (Spray Drift, Etc.)	  PAGEREF
_Toc176838875 \h  31 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc176838876 \h  32 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc176838877
\h  32 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc176838878 \h  32 

9.1	Short-/Intermediate-/Long-Term Handler Risk	  PAGEREF _Toc176838879
\h  33 

9.2	Short-/Intermediate-/Long-Term Postapplication Risk	  PAGEREF
_Toc176838880 \h  37 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc176838881 \h  37


10.1	Toxicology	  PAGEREF _Toc176838882 \h  37 

10.2	Residue Chemistry	  PAGEREF _Toc176838883 \h  37 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc176838884 \h 
38 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc176838885 \h  39 

A.2  Toxicity Profiles	  PAGEREF _Toc176838886 \h  40 

A.3  Executive Summaries	  PAGEREF _Toc176838887 \h  45 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc176838888 \h  62 

Appendix C:  Tolerance Reassessment Summary and Table	  PAGEREF
_Toc176838889 \h  67 

Appendix D:  Review of Human Research	  PAGEREF _Toc176838890 \h  69 

Appendix E:  Mechanistic Studies	  PAGEREF _Toc176838891 \h  69 

 1.0	Executive Summary TC \l1 " 1.0	Executive Summary  

α-(2-propynyloxy)-benzeneacetamide], in/on the following raw
agricultural and processed commodities:

     Brassica, Head and Stem, Subgroup 5A	3 ppm

     Brassica, Leafy Greens, Subgroup 5B	30 ppm

     Vegetables, Cucurbit, Group 9	0.30 ppm

     Vegetables, Fruiting, Group 8	1 ppm

     Vegetables, Leafy, except Brassica, Group 4	15 ppm

     Vegetables, Tuberous and Corm, Subgroup 1C	0.01 ppm

     Grapes	2 ppm

     Grapes, raisins	4 ppm

     Onion, dry bulb	0.05 ppm

     Onion, green	4 ppm

     Tomato Paste	1.3 ppm

These petitions (6F7057 and 7F7184) reflect the first uses for the
fungicide; no U.S. uses for mandipropamid are registered and there are
no current U.S. tolerances.  The end-use product (EP) associated with
these petitions is Mandy Flowable Fungicide, 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 0.52 lb ai/acre for all crops except green onions for
which a maximum seasonal rate of 0.39 lb ai/acre is proposed.  The
proposed preharvest intervals (PHIs) range from 0 day (cucurbits) to 14
days (grapes; tuberous and corm vegetables).  No residential uses are
proposed.

TOXICITY/HAZARD

The toxicity data base for mandipropamid is adequate for risk assessment
and tolerance setting.

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); however, it is classified as a
skin sensitizer.

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.  A
90-day rat dietary study was used to select the dose and endpoint for
short- and intermediate-term inhalation exposure.  

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 were identified for acute dietary
exposure (general population including infants and children; females
13-49 years of age) or for dermal risk assessment.  Therefore, these
risk assessments are not necessary.

FQPA ASSESSMENT

HED recommends 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.  In addition, the toxicological database is complete and there
is no need for additional uncertainty factors.  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 residue of concern is the parent plus the
metabolite SYN 500003.  In drinking water, the residue of concern is the
parent plus the metabolites SYN 500003 and SYN 504851.  

A Tier I drinking water assessment for the proposed mandipropamid uses
was conducted by EFED  (I. Abdel-Saheb; D339258; April 23, 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.

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 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 ACB/BEAD for a petition method
validation.  The Analytical Chemistry Branch recommends that the
petitioner provide information for a second MS/MS ion transition to
provide a confirmation of analyte identity.  If two ion transitions are
not available, the petitioner should provide an alternate
chromatographic column and/or mobile-phase combination to add an
additional degree of specificity and further reduce the possibility of
false positive residues. A separate confirmatory method for Method
415/01 will not be required provided that two ion transitions are
monitored during MS/MS analysis for each analyte.  Alternatively, the
petitioner may submit an interference study for the method.

Although submission of a revised Section F is needed for certain
commodities, adequate crop field trial data have been submitted for: 
potato, the representative commodity of tuberous and corm vegetables
(Subgroup 1C); leaf lettuce, head lettuce, celery and spinach, the
representative commodities for Vegetables, Leafy, except Brassica, Group
4 ; dry bulb and green onions; broccoli and cabbage, the representative
commodities of head and stem Brassica (Subgroup 5A); mustard greens, the
representative commodity of leafy Brassica greens (Subgroup 5B); bell
pepper, non-bell pepper, and tomato, the representative commodities of
the fruiting vegetables (Crop Group 8); and cucumber, cantaloupe, and
summer squash, the representative commodities of the cucurbit vegetables
(Crop Group 9); and grape.  The proposed use on okra is supported by
residue data translated from fruiting vegetables.

A maximum number of uses was not specified on the labels; however, based
on the residue data, the application rate, and the seasonal maximum use
rate, the number of applications specified in Table 2.3 should be
reflected on the labels.

DIETARY EXPOSURE AND RISK ESTIMATES

The dietary analysis was conducted using DEEM-FCID.  Chronic (food and
water) dietary exposure for mandipropamid is below HED’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 22% of the cPAD for the general U.S. population. 
The chronic exposure analysis assumed 100% crop treated and
HED-recommended 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 HED’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.   
SEQ CHAPTER \h \r 1 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. 
All scenarios were assessed.  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
(53,000-460,000) at baseline level of mitigation (i.e., no respirator)
and were not of concern to HED.  Inhalation risks to pilots in enclosed
cockpits with no respirator (engineering control scenario) were not of
concern.  In this assessment, HED 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
labels for Mandy Flowable Fungicide and RevusTM Fungicide propose an REI
of 4 hours.  Mandipropamid is classified as a dermal sensitizer, and
therefore, in accordance with PR Notice 95-3 criteria for low risk
pesticides, is not a candidate for a reduced risk active ingredient REI
of 4 hours.  The REI on the proposed labels need to be increased to 12
hours in order to comply with the WPS.

ENVIRONMENTAL JUSTICE CONSIDERATIONS

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, nondietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

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, analytical methods,
reference standard, revised section F), and the occupational exposure
issue in Section 10.3 (revise label REI to indicate 12 hours),  HED
recommends for establishment of tolerances as specified in Appendix C.

Additional Data Needs.  See Section 10.

2.0	Ingredient Profile TC \l1 " 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 and tomatoes, and Pseudoperonospora cubensis in cucurbits. 
Mandipropamid is also proposed for uses on leafy vegetables to control
downy mildew (Bremia lactucae) and blue mold (Peronospora effuse).  A
summary of the proposed uses is presented in Table 2.3. 

2.1	Structure and Nomenclature TC \l2 " 2.1	Structure and Nomenclature  

Table 2.1.   Test Compound Nomenclature.

Compound

	Common name	Mandipropamid

Company experimental name	NOA 446510

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

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

CAS registry number	374726-62-2

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



Physical and Chemical Properties

 TC \l2 " 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

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 TC \l2 " 2.3	Summary of Registered/Proposed
Uses  

Table 2.3.   Details of Proposed Uses of 2.08 lb ai/gal flowable
formulation (Mandy Flowable Fungicide).

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)

Brassica, Head and Stem Subgroup (Broccoli, Chinese broccoli (gai lon),
Brussels sprouts, cabbage, Chinese cabbage (napa), Chinese mustard
cabbage (gai choy), cauliflower, cavalo broccoli, and kohlrabi)

Brassica, Leafy Greens, Subgroup (Broccoli raab, Chinese cabbage,
collards, kale, mizuna, mustard greens, mustard spinach, and rape greens
– including all cultivars and/or hybrids of these)

Postemergence

Foliar spray

Ground, aerial, or

chemigation	0.13	41	0.52	1

	Use Directions and Restrictions:  For resistance management, do not
apply more than two applications of Mandy before alternation with at
least one application of a fungicide that is not in Group 40. 
Applications should begin prior to disease development and continue
throughout the season on a 7-10 day schedule of fungicides, following
the resistance management guidelines.  A silicone-based adjuvant should
be added at recommended rates.

Dry Bulb (bulb onion, garlic, and shallot)

Green Onion (green onions, leek, and Welch onion)

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	41  for dry bulb vegetables;

31 for green onions	0.52 for dry bulb vegetables;

0.39 for green onions	7

	Use Directions and Restrictions:  For resistance management, do not
apply more than two applications of Mandy before alternation with at
least one application of a fungicide that is not in Group 40. 
Applications should begin prior to disease development and continue
throughout the season on a 7-10 day schedule of fungicides, following
the resistance management guidelines.  A silicone-based adjuvant should
be added at recommended rates.

Cucurbits (cantaloupe, chayote, Chinese waxgourd, cucumber, gourds,
honeydew melons, Momordica spp. (bitter melon, balsam apple), muskmelon,
watermelon, pumpkin, squash, and zucchini – including all cultivars
and/or hybrids of these)

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	41	0.52	0

	Use Directions and Restrictions:  For resistance management, do not
apply more than One application of Mandy before alternation with at
least one application of a fungicide that is not in Group 40. 
Applications should begin prior to disease development and continue
throughout the season on a 7-10 day schedule of fungicides, following
the resistance management guidelines.  A non-ionic surfactant may be
added at recommended rates.

Fruiting Vegetables (pepper [bell, non-bell, and sweet non-bell],
eggplant, okra, groundcherry, and pepino; see below for specific
proposed use on tomatoes)

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	41	0.52	1

	Use Directions and Restrictions:  For resistance management, do not
apply more than two applications of Mandy before alternation with at
least one application of a fungicide that is not in Group 40. 
Applications should begin prior to disease development and continue
throughout the season on a 7-10 day schedule of fungicides, following
the resistance management guidelines.  When disease epidemics are
severe, tank mix Mandy with another fungicide that is efficacious for
disease control.  For Phytopthora blight control, Mandy should always be
tank mixed to provide adequate control.  A non-ionic surfactant may be
added at recommended rates.



Tomato (including tomatillo)

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	41 	0.52	1

	Use Directions and Restrictions:  For resistance management, do not
apply more than two sequential applications of Mandy or any other Group
40 (CAA) fungicide before alternation with at least two applications of
a fungicide that is not in Group 40.  Applications should begin prior to
disease development and continue throughout the season on a 7-10 day
schedule of fungicides, following the resistance management guidelines. 
A non-ionic surfactant may be added at recommended rates.

Grapes

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	41	0.52	14

	Use Directions and Restrictions:  For resistance management, do not
apply more than two applications of Mandy before alternation with at
least one application of a fungicide that is not in Group 40. 
Applications should begin prior to disease development and continue
throughout the season on a 7-10 day schedule of fungicides, following
the resistance management guidelines.  A non-ionic surfactant may be
added at recommended rates.

Vegetables, Leafy, except Brassica (amaranth, arugula, cardoon, celery
(Chinese), celtuce, chervil, chrysanthemum (edible-leaved and garland),
corn salad, cress (garden and upland), dandelion, dock, endive, fennel
(Florence), lettuce, orach, parsel, purslane (garden and winter),
radicchio (red chicory), rhubard, spinach (New Zealand and vine), Swiss
chard.)

Postemergence

Foliar spray

Ground, aerial, or

Chemigation

	            0.13	                 41	             0.52	            1

	Use Directions and Restrictions:  For resistance management, do not
apply more than two applications of Mandy before alternation with at
least one application of a fungicide that is not in Group 40. 
Applications should begin prior to disease development and continue
throughout the season on a 7-10 day schedule of fungicides, following
the resistance management guidelines.  A non-ionic surfactant may be
added at recommended rates.

Vegetables, Tuberous and Corm, Subgroup (arracacha, arrowroot, artichoke
(Chinese and Jerusalem), burdock, canna, cassava (edible, bitter, and
sweet), chayote (root), chufa, dasheen (taro), ginger, leren, potato,
sweet potato, tanier, turmeric, and yam (bean and true))

Postemergence

Foliar spray

Ground, aerial, or

Chemigation	0.13	41 	0.52	14

	Use Directions and Restrictions:  For resistance management, do not
apply more than two sequential applications of Mandy or any other Group
40 (CAA) fungicide before alternation with at least two applications of
a fungicide that is not in Group 40.  Applications should begin prior to
disease development and continue throughout the season on a 7-10 day
schedule of fungicides, following the resistance management guidelines. 
A non-ionic surfactant may be added at recommended rates.

A maximum number of uses were not specified on the labels; however,
based on the residue data, the application rate, and the seasonal
maximum use rate, the number of applications specified in this table
should be reflected on the labels.

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered (animal, human, general
literature)  TC \l4 "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 new chemical, and no
general literature search was conducted.

3.1.1.2	 Mode of action  TC \l4 "3.1.1.2	Mode of action, metabolism,
toxicokinetic data 

Mandipropamid is a mandelamide and belongs to the chemical family of the
carboxylic acid amides (CAA), or more specifically, the mandelic acid
amides.  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  TC \l4 "3.1.1.3	Sufficiency of
studies/data 

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

3.1.2	Toxicological Effects  TC \l3 "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 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  TC \l3 "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)  TC \l2 "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  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Database  TC \l3 "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.

3.3.2	Evidence of Neurotoxicity  TC \l3 "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  TC \l3 "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  TC \l3 "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   TC \l3 "3.3.5
Additional Information from Literature Sources 

This is a new active ingredient and no literature search was performed.

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.6.1	Determination of Susceptibility  TC \l4 "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  TC \l4 "3.3.6.2	Degree of Concern
Analysis and Residual Uncertainties 

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 HED 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).

3.3.7	Recommendation for a Developmental Neurotoxicity Study  TC \l3
"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.

3.3.8	Rationale for the UFDB (when a DNT is recommended)  TC \l3 "3.3.8
Rationale for the UFDB (when a DNT is recommended) 

Not applicable.

3.4	FQPA Safety Factor for Infants and Children  TC \l2 "3.4	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 complete.

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 HED-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  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.5.1    Acute Reference Dose (aRfD) - Females age 13-49 & General
Population   TC \l3 "3.5.1    Acute Reference Dose (aRfD) - Females age
13-49 

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

3.5.2	Chronic Reference Dose (cRfD)   TC \l3 "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  TC \l3 "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)   TC \l3 "3.5.4
Dermal Exposure (Short-, Intermediate- and Long-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)   TC \l3 "3.5.5
Inhalation Exposure (Short-, Intermediate- and Long-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  TC \l3 "3.5.6	Level of
Concern for Margin of Exposure 

Table 3.5.6.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term (1 - 30 Days)	Intermediate-Term   (1 - 6 Months)
Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	N/A	N/A	N/A

Inhalation	100	100	N/A

Residential Exposure

There are no proposed or registered residential uses for mandipropamid. 

Note: Two uncertainty factors are used:  UFA = extrapolation from animal
to human (interspecies) and

UFH = potential variation in sensitivity among members of the human
population (intraspecies).

3.5.7	Classification of Carcinogenic Potential  TC \l3 "3.5.7
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.”  

Summary of Toxicological Doses and Endpoints for Mandipropamid for Use
in

            Human Risk Assessments  TC \l3 "3.5.8	Summary of
Toxicological Doses and Endpoints for Mandipropamid for Use in Human
Risk Assessments 

Table 3.5.8a  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.  A cancer risk assessment was not conducted,
the chronic risk assessment would be protective of any cancer effects.

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 3.5.8b  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

	Residential 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.  A cancer risk assessment was
not conducted, the chronic risk assessment would be protective of any
cancer effects.

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  TC \l2 "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 TC \l1 " 4.0
Public Health and Pesticide Epidemiology Data  

This section is not applicable for a new chemical registration.

5.0	Dietary Exposure/Risk Characterization TC \l1 " 5.0	Dietary
Exposure/Risk Characterization  

Pesticide Metabolism and Environmental Degradation TC \l2 " 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.

Metabolism in Primary Crops

 TC \l3 " 5.1.1	Metabolism in Primary Crops  

DER Reference List     46800127.der.doc (Lettuce)

  		         46800129.der.doc (Tomato)

		         46800130.der.doc (Grape)

		         46800131.der.doc (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 residues in lettuce, 54-80% of the Total
Radioactive Residue (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.

Metabolism in Rotational Crops TC \l3 " 5.1.2	Metabolism in Rotational
Crops  

DER Reference List 46800145.der.doc (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.

 (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.

Metabolism in Livestock TC \l3 " 5.1.3	Metabolism in Livestock  

DER Reference List     46800128.der.doc

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.

Conclusions:  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.

Analytical Methodology TC \l3 " 5.1.4	Analytical Methodology  

DER Reference List	46800132.der.doc (Includes MRIDs 46800127 & 46800133)

			46800134.der.doc (Includes MRID 46800135)

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 limit of
quantitation (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 has been forwarded
to ACB/BEAD for a petition method validation.

For the purpose of tolerance enforcement, HED 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.  

The Analytical Chemistry Branch recommends that the petitioner provide
information for a second MS/MS ion transition to provide a confirmation
of analyte identity.  If two ion transitions are not available, the
petitioner should provide an alternate chromatographic column and/or
mobile-phase combination to add an additional degree of specificity and
further reduce the possibility of false positive residues. A separate
confirmatory method for Method 415/01 will not be required provided that
two ion transitions are monitored during MS/MS analysis for each
analyte.  Alternatively, the petitioner may submit an interference study
for the method.

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.

Environmental Degradation TC \l3 " 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 the 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.

Comparative Metabolic Profile TC \l3 " 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 TC \l3 "
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 notes that SYN 500003 still possesses a propargyl side chain like
those found in the parent.  Loss of this side chain could produce the
reactive compound propiolaldehyde.  The latter is believed to be the
source of the liver toxicity of propargyl alcohol, for which the
petitioner has submitted a 14-day repeat exposure study with rats
showing similar hepatotoxicity as seen with mandipropamid.  Therefore,
HED concludes that metabolites and degradates still having a propargyl
side should be considered comparably as toxic as the parent fungicide.

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

5.1.8    Pesticide Metabolites and Degradates of Concern TC \l3 " 5.1.8
Pesticide Metabolites and Degradates of Concern   

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
requested 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 in 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 concludes 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.

Drinking Water Residue Profile TC \l3 " 5.1.9	Drinking Water Residue
Profile  

A Tier I drinking water assessment for the proposed mandipropamid uses
was performed by EFED  (I. Abdel-Saheb; D339258; April 23, 2007) for the
dietary drinking water component.  The drinking water assessment for
mandipropamid includes the major aquatic degradates (SYN 500003 and SYN
504851).

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 following drinking water EEC’s are
shown in the Table 5.1.9.

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 TC \l3 " 5.1.10	Food Residue Profile  

DER Reference List    46800137.der.doc (Grape)

                                    46800138.der.doc (Dry Bulb and Green
Onions)

                                    46800139.der.doc (Vegetable,
Tuberous and Corm, Subgroup 1C)

                                    46800140.der.doc (Cucurbit
Vegetables, Group 9)

                                    46800141.der.doc (Brassica,
Vegetables, Group 5)

                                    46800142.der.doc (Fruiting
Vegetables, Group 8)

                                    47061902.der.doc (Vegetable, Leafy,
Except Brassica, Group 4)

			In addition, see Mandipropamid.  Request to Register New Food/Feed
Uses on Head and Stem Brassica, Brassica Leafy 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.  Dennis McNeilly; Aug 28, 2007; D328534.

			Crop Field Trials:  The registration requirements for magnitude of
the residue in plants have been evaluated and deemed fulfilled for the
following raw agricultural commodities (RACs): Head and Stem Brassica,
Brassica Leafy Greens, Cucurbit Vegetables, Fruiting Vegetables, Leafy
Vegetables, except Brassica; Tuberous and Corm Vegetables, Grapes, and
Onions (Dry Bulb and Green).

			Processed food:  The registration requirements for magnitude of the
residue in the processed food/feed commodities are fulfilled for:
Fruiting Vegetables, Tuberous and Corm Vegetables, and Grapes.  The
other crop groups in these petitions do not trigger data requirements
for processed foods.

5.1.10  International Residue Limits TC \l3 " 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 TC \l2 " 5.2	Dietary Exposure and Risk  

HED, D328534; Aug 28, 2007; D.McNeilly.

valuation 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 the Environmental Fate and Effect Division
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 22% 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	0.011076	22	N/A	N/A

All Infants (< 1 year old)	0.007927	16



Children 1-2 years old	0.015104	30



Children 3-5 years old	0.014557	29



Children 6-12 years old	0.010923	22



Youth 13-19 years old	0.009067	18



Adults 20-49 years old	0.010843	22



Adults 50+ years old	0.011376	23



Females 13-49 years old	0.010998	22



	1  -  This analysis includes food and drinking water.

6.0      Residential and Other Exposures (Spray Drift, etc.) TC \l1 "
6.0	Residential and Other Exposures (Spray Drift, Etc.) 

Residential exposures were not assessed because the 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.

Aggregate Risk Assessments and Risk Characterization TC \l1 " 7.0
Aggregate Risk Assessments and Risk Characterization  

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

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 HED’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 mandipropamid is not likely to be carcinogenic.

8.0	Cumulative Risk Characterization/Assessment TC \l1 " 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 TC \l1 " 9.0	Occupational
Exposure/Risk Pathway  

Exposure to pesticide handlers is likely during the occupational use of
mandipropamid in a variety of occupational environments.  The
anticipated use patterns and current labeling indicate several
occupational exposure scenarios based on the types of equipment and
techniques that can potentially be used for mandipropamid applications. 

The quantitative exposure/risk assessment developed for occupational
handlers is based on the following scenarios.  Occupational exposure is
expected to be short- and intermediate-term.  HED does not expect long
term exposure, due to the limited number of applications and the fact
that there are no residential uses.

Mixer/Loaders:

Mixing/loading liquids to support aerial applications;

Mixing/loading liquids to support chemigation applications;

Mixing/loading liquids to support groundboom applications;

Mixing/loading liquids to support airblast applications.

	Applicators:

(5) Applying liquids with aerial equipment;

(6) Applying liquids with groundboom equipment;

(7) Applying liquids with airblast equipment;

Flaggers:

	(8) Flagging for aerial spray applications.

 

Short-/Intermediate-Term Occupational Handler Risk TC \l2 " 9.1
Short-/Intermediate-/Long-Term 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) Version 1.1 (August 1998).

*	The toxicological endpoint of concern for inhalation risks is not
sex-specific; therefore,

the average body weight of an adult handler (i.e., 70 kg) is used to
complete the

inhalation risk assessments.

*	An inhalation absorption factor of 100% was assumed.

*	For noncancer risk assessments, HED assumes the maximum application
rates allowed by

	labels. 

*	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. 

Margins of Exposure:  Noncancer 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 (HED’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:  Mandipropamid Handler Exposure and Risk



Exposure Scenario	Crop or Target	

Mitigation Level	

Inhalation Unit Exposurea (mg/kg/day)	Application Rateb

lb ai/acre	Area Treated Dailyc (Acres)	

Daily Dose 

(mg/kg/day)	MOEd



Mixer/loader



Mixing/Loading Liquid Concentrates for Aerial Applications	Grapes;
Brassica vegetables; Dry bulb vegetables; Bulb Vegetables-green onion;
Cucurbits; Tomato; Fruiting vegetables; Leafy greens; Leafy Vegetables;
Tuberous and Corm vegetables	

Baseline	

0.0012	

0.13 

	350 	

0.00078	53,000

Mixing/Loading Liquid Concentrates for Chemigation Applications	Grapes;
Brassica vegetables; Dry bulb vegetables; Bulb Vegetables-green onion;
Cucurbits; Tomato; Fruiting vegetables; Leafy greens; Leafy Vegetables;
Tuberous and Corm vegetables

	0.13 	350 	

0.00078	53,000

Mixing/Loading Liquids Concentrates for Groundboom Applications	Brassica
vegetables; Dry bulb vegetables; Bulb Vegetables-green onion; Cucurbits;
Tomato; Fruiting vegetables; Leafy greens; Leafy Vegetables; Tuberous
and Corm vegetables

	0.13  	80 	

0.00018	230,000

Mixing/Loading Liquids Concentrates for Airblast Applications	Grapes

	0.13	40 	

0.000089	460,000



Applicator

Applying Sprays via Aerial Equipment	Grapes; Brassica vegetables; Dry
bulb vegetables; Bulb Vegetables-green onion; Cucurbits; Tomato;
Fruiting vegetables; Leafy greens; Leafy Vegetables; Tuberous and Corm
vegetables	

Engineering Controls	

0.000068	0.13 	350 	

0.000044	930,000

Applying Sprays via Groundboom Equipment	Brassica vegetables; Dry bulb
vegetables; Bulb Vegetables-green onion; Cucurbits; Tomato; Fruiting
vegetables; Leafy greens; Leafy Vegetables; Tuberous and Corm vegetables


Baseline	

0.00074	0.13  	80 	

0.00011	370,000

Applying Sprays via Airblast Equipment	Grapes



0.0045	0.13 	40 	

0.00033	120,000

Flagger

Flagging for Aerial Sprays Applications	Grapes; Brassica vegetables; Dry
bulb vegetables; Bulb Vegetables-green onion; Cucurbits; Tomato;
Fruiting vegetables; Leafy greens; Leafy Vegetables; Tuberous and Corm
vegetables	

Baseline	

0.00035	0.13 	350 	

0.00023	180,000

Footnotes

a.  Inhalation daily dose (mg/kg/day) = daily unit exposure (μg/lb ai) 
x application rate x amount handled per day  x conversion factor
(1mg/1,000 μg) / body weight (70 kg).

b.  Application rates are the maximum application rates determined from
proposed labels for mandipropamid.

c.  Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 “Standard Values for Daily Acres
Treated in Agriculture.” 

d.  Inhalation MOE = NOAEL (41mg/kg/day) / inhalation daily dose
(mg/kg/day).



9.2	Short-/Intermediate-Term Occupational Postapplication Risk TC \l2 "
9.2	Short-/Intermediate-/Long-Term 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 labels does
not comply with the Worker Protection Standard (WPS).  A 12-hour REI is
appropriate as mandipropamid is classified as a dermal sensitizer and
would not be a candidate for the reduced 4-hour REI. 

Data Needs and Label Recommendations TC \l1 " 10.0	Data Needs and Label
Recommendations  

10.1	Toxicology TC \l2 " 10.1	Toxicology  

None.

      Residue Chemistry TC \l2 " 10.2	Residue Chemistry  

Directions for use  -  Burdock should be removed from the label as it is
a member of Subgroup 1B (vegetable, root, except sugar beet) and not
Subgroup 1C (vegetable, tuberous and corm) unless the petitioner wishes
to support a separate tolerance for burdock and submit the appropriate
supporting residue data.  Okra is listed in the submitted label as a
member of the Fruiting Vegetable Group.  The 10/18/06 ChemSAC meeting
recommended the inclusion of okra in Crop Group 8 (Vegetable, Fruiting).
 However, a separate tolerance for okra must be listed in the 40 CFR
180.xxx, until the new crop group regulation is published.

The maximum number of applications were not specified on the draft
labels.  Based on the submitted mandipropamid residue data, proposed
application rates, and proposed seasonal maximum use rate, the number of
applications specified in Table 2.3 should be reflected on the labels.

Analytical methods  -  .  The method was forwarded to ACB/BEAD for a
petition method validation.  The Analytical Chemistry Branch recommends
that the petitioner provide information for a second MS/MS ion
transition to provide a confirmation of analyte identity.  If two ion
transitions are not available, the petitioner should provide an
alternate chromatographic column and/or mobile-phase combination to add
an additional degree of specificity and further reduce the possibility
of false positive residues. A separate confirmatory method for Method
415/01 will not be required provided that two ion transitions are
monitored during MS/MS analysis for each analyte.  Alternatively, the
petitioner may submit an interference study for the method.  (Note: The
registrant has indicated they will officially submit the German S-19
method as a confirmatory method for mandipropamid.  HED’s preliminary
review of an advance copy, indicates adequate recovery of mandipropamid
using that method).    

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 required.   .   

Revised section F  -  The petitioner is required to submit a revised
Section F to:  (i) amend the proposed tolerance for leafy Brassica
greens (Subgroup 5B) from 30 to 25 ppm; (ii) amend the proposed
tolerance for cucurbit vegetables (Crop Group 9) from 0.30 to 0.60 ppm.;
(iii) amend the proposed tolerance for grape from 2.0 to 1.4 ppm; (iv)
amend the proposed tolerance for leafy vegetables (Crop Group 4) from
15.0 to 20.0 ppm; (v) amend the proposed tolerance for grape raisin from
4.0 to 3.0 ppm; (vi) propose a tolerance of 1.0 ppm for okra; (vii)
propose a tolerance of 0.03 ppm for potato wet peel; and (viii) remove
the proposed tolerance for tomato paste because HED-recommended
tolerance for the RAC will cover any expected residues in tomato paste
and puree.

10.3	Occupational and Residential Exposure TC \l2 " 10.3	Occupational
and Residential Exposure  

Revise REI on the labels to 12 hours in order to comply with the Worker
Protection Standard.

References:

Mandipropamid: Occupational and Residential Exposure Assessment;
Margarita Collantes; Aug 7, 2007; D340958.

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.  Dennis McNeilly. 
Aug 28, 2007

Mandipropamid: Chronic Dietary (Food and Drinking Water) Exposure and
Risk Assessment for Mandipropamid to Support Section 3 Registration for
Use on the following Raw Agricultural Commodities:  Brassica, Head and
Stem, Subgroup 5A; Brassica, Leafy Greens, Subgroup 5B; Vegetables,
Cucurbit, Group 9; Vegetables, Fruiting, Group 8; Vegetables, Leafy,
except Brassica,Group 4; Vegetables, Tuberous and Corm, Subgroup 1C;
Grapes; Onion, dry bulb; and Onion, green.  PC Code:  036602.  DP
Barcode: D333121.  Dennis McNeilly.  Aug 28, 2007.

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

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

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

“-“ = Indicates not applicable 

A.2  Toxicity Profiles TC \l2 "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	Sensitizer	N/A

870.2600	Skin sensitization mouse	46800212	Not acceptable	N/A

	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.



A.3  	Executive Summaries TC \l2 "A.3  Executive Summaries 

A.3.1	Subchronic Toxicity

90-Day Oral Toxicity – Rat

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRIDs 46800216
and 46800214), NOA 446510 (Mandipropamid; 96.5% a.i.; Batch No.
SEZ2BP007) was administered in the diet to Alpk:APfSD rats (10/sex/dose)
at dose levels of 0, 100, 500, 3000, or 5000 ppm (equivalent to 0/0,
8/9, 41/45, 260/260, and 435/444 mg/kg bw/day in males/females) for 90
days. 

No adverse treatment-related effects were observed on mortality,
clinical signs, neurological evaluation, food consumption,
ophthalmoscopic examinations, hematology, urinalysis, or gross
pathology.

Decreased (p<= 0.05) body weights were observed in the males at 3000 ppm
during Weeks 2-14 (decr 1-10%) and at 5000 ppm during Weeks 2-5, 11, and
13-14 (decr 2-7%).  Differences (p<=0.05) in cumulative body weight
gains generally paralleled the differences in body weights.  Decreases
of 11-28% in body weight gain (calculated by the reviewers) were noted
in the >=3000 ppm males during Weeks 1-7, 7-14, and overall (1-14). 
Decreased (p<=0.05) food utilization was noted in the >=3000 ppm males
during Weeks 1-4, 5-8, 9-13, and 1-13 (decr 9-29%), except in the 5000
ppm males during Weeks 5-8.

Indications of slight hepatotoxicity were observed.  Plasma
gamma-glutamyl transferase was increased (p<= 0.01) in the >=3000 ppm
males (incr 58-105%).  Absolute and adjusted for body weight liver
weights were increased (p<=0.05) by 14-36% in both sexes at >=3000 ppm. 
Minimal to slight eosinophilia in the liver was noted in the 5000 ppm
males (8/10) and the >=3000 ppm females (10/10 each treated) vs 0/10 in
the controls and other dose groups.  

The LOAEL is 3000 ppm (equivalent to 260 mg/kg/day in both sexes), based
on decreased body weights, body weight gains, and food utilization in
males, and indication of slight hepatotoxicity in both sexes.  The NOAEL
is 500 ppm (equivalent to 41/45 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral
toxicity study in the rat.

90-Day Oral Toxicity – Mouse

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRIDs 46800213
and 46800217), NOA 446510 (Mandipropamid; 96.5% a.i.; Batch No.
SEZ2BP007) was administered in the diet to C57BL/10JfCD-1 mice
(10/sex/dose) at dose levels of 0, 300, 800, 2000, or 5000 ppm
(equivalent to 0/0, 37/47, 98/129, 248/316 and 624/800 mg/kg bw/day in
males/females) for 90 days. 

No adverse treatment-related effects were observed on mortality,
clinical signs, food consumption, food utilization, hematology, or on
gross pathology.

In the 5000 ppm females, initial transient losses (p<=0.01) were
observed in body weight gains on Days 2-3 contributing to a decreased
(p<=0.01) overall (Weeks 1-14) body weight gain of 23%.  Decreased
(p<=0.05) body weight was noted on Days 2 and 3 (decr 1-2%) and at Week
14 (decr 4%).

In the 5000 ppm females (n=10), slight periportal eosinophilia was noted
in 2 mice (and minimal eosinophilia in 7 mice) vs 0 controls.  Adjusted
liver weight increased by 31%.  Together these findings were considered
possibly indicative of slight hepatotoxicity.  

The LOAEL is 5000 ppm (equivalent to 624/800 mg/kg/day in
males/females), based on decreased body weight gain in males and females
as well as the suggestion of effects on the liver (increased weights in
males and females as well as microscopic pathology).  The NOAEL is 2000
ppm (equivalent to 248/316 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral
toxicity study in the mouse.



 90-Day Oral Toxicity – Dog

EXECUTIVE SUMMARY: :  In a 90-day oral toxicity study (MRID 46800218),
NOA446510 (Mandipropamid; 96.5% w/w, Batch # SEZ2BP007) was administered
daily in capsules to 4 beagle dogs/sex/dose for 13 weeks at doses of 0,
5, 25, 100, or 400 mg/kg/day.

There were no mortalities and no adverse effects of treatment on
clinical observations, food consumption, ophthalmoscopy, hematology,
urinalysis, or gross pathology.  There were no treatment-related effects
on any parameter at 5 or 25 mg/kg/day.

Body weights were decreased in the 100 mg/kg/day females beginning at
Week 8 and in the 400 mg/kg/day animals beginning at Week 3, resulting
in decreased body weight gains; however, these decreases were not
considered adverse because they were minimal (body weights were only
decreased by 2-5% and body weight gains by 9-15%).  Note that similar
decreases (<=12%) in body weights were observed throughout the chronic
toxicity study at 400 mg/kg/day; but were associated with more
substantial decreases of 23-56% in body weight gains for Weeks 1-13
compared to the subchronic study.

The liver was a target organ for toxicity.  At 400 mg/kg/day, increases
over controls (p<=0.05, unless otherwise noted) in cholesterol (incr.
27-49%), alkaline phosphatase activity (incr. 37-113%), and alanine
aminotransferase (ALT) activity (incr. 43-238%, not significant at Week
4) were observed in both sexes throughout the study.  Differences in
these parameters were also noted at 100 mg/kg/day, but the increases
over controls were of a lesser magnitude and therefore attained
significance less frequently than at 400 mg/kg/day and were not
consistently observed throughout the study.

Increases (incr. 10-19%) in absolute, relative to body weight, and
adjusted for terminal body weight liver weights were observed in both
sexes at >=100 mg/kg/day, with the adjusted liver weight attaining
significance (p<=0.05) in the males at both doses and in the females at
400 mg/kg/day.  

At 100 mg/kg/day, minimal pigmentation of the hepatocytes and of the
Kupffer cells was observed in 1/4 males and 2/4 females, compared to 0
controls.  At 400 mg/kg/day, the incidence of this finding increased to
all dogs (4/4 per sex), and the severity increased from minimal at 100
mg/kg/day to minimal to slight at 400 mg/kg/day.  It was stated that
this brown pigment had a predominantly centrilobular distribution and
was negative for hemosiderin and lipofuscin.  It was bi-refringent when
viewed under polarized light and appeared to be consistent with
porphyrin.  Minimal centrilobular hepatocyte vacuolation was noted in
the 100 mg/kg/day (1/4) and 400 mg/kg/day (3/4) females as compared to
0/4 controls.

The data indicate that there are treatment-related effects on the liver
both at 100 and 400 mg/kg/day.  However, the changes at 100 mg/kg/day do
not constitute an adverse effect of toxicity, but are more indicative of
an effect of exposure that, at that dose, cannot be considered adverse. 
Examination of the weight of evidence at 100 mg/kg/day shows that there
were: increased liver weights; minimal pigmentation in the hepatocytes
and Kupffer cells in 1/4 males and 2/4 females; and minimal
centrilobular hepatocyte vacuolation in 1/4 females.  Increased liver
weights (and even hepatocellular hypertrophy) are only considered
adverse if accompanied by adverse macroscopic findings, microscopic
findings, and/or substantial changes in at least two clinical chemistry
parameters indicative of hepatotoxicity (HED Guidance Document #G0201). 
At 100 mg/kg/day, cholesterol and alkaline phosphatase were only
increased by 22-53% and were not consistently observed throughout the
study.  ALT, the most definitive indicator of liver toxicity, was only
increased by 35-37% (not significant) at Week 13.  Furthermore, the
microscopic findings at this dose were minimally increased in severity
and/or incidence over controls.  The presence of pigment consistent with
porphyrin was minimal in severity at this dose (compared to minimal to
slight at 400 mg/kg/day); and minimal centrilobular hepatocyte
vacuolation was only observed in 1/4 females at this dose (compared to
3/4 females at 400 mg/kg/day).

The LOAEL is 400 mg/kg/day based on evidence of liver toxicity
(increased cholesterol, alkaline phosphatase activity, ALT activity,
liver weights, and microscopic pigment in the hepatocytes and Kupffer
cells in both sexes and centrilobular hepatocyte vacuolation in the
females).  The NOAEL is 100 mg/kg/day. 

This study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.3150, OECD 409) for a subchronic oral
toxicity study in dogs.

21/28-Day Dermal Toxicity – Rat

EXECUTIVE SUMMARY:  In a 28-day dermal toxicity study (MRID 46800222),
NOA446510 (Mandipropamid; 96.5% a.i., Batch # SEZ2BP007) was applied to
the shaved skin of 10 Wistar rats/sex/dose at dose levels of 0, 250,
500, or 1000 mg/kg/day (limit dose), 6 hours/day for 5-6 days/week (21
total doses) during a 28-day period.

No compound-related effects were observed in mortality, clinical signs
of toxicity, body weight, body weight gain, food consumption, FOB, motor
activity, ophthalmoscopic exams, hematology, clinical chemistry,
urinalysis, absolute or relative organ weights, or gross or microscopic
pathology in either sex.  There was an increased incidence of slight
dermal irritation (erythema, edema, and desquamation of the application
site) at 250 mg/kg/day and above.  The erythema and edema were generally
observed throughout the study and the desquamation was observed between
Days 3-15 in the treated animals.  The LOAEL was not observed.  The
NOAEL is 1000 mg/kg/day (limit dose).

This study is classified as acceptable/guideline and satisfies the
guideline requirement for a 28-day dermal toxicity study (OPPTS
870.3200; OECD 410) in rats. 

90-Day Inhalation – Rat

There are no inhalation studies available.



A.3.2	Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity – Rat

EXECUTIVE SUMMARY: In a developmental toxicity study (MRIDs 46800224,
46800223, and 46800228), NOA446510 (Mandipropamid, 96.5% a.i.; Batch #
SEZ2BP007) in 0.5% aqueous carboxymethylcellulose was administered daily
via oral gavage to 24 time-mated A1pk:APfSD (Wistar-derived) rats/group
at a dose volume of 1 mL/100 g at dose levels of 0, 50, 200, or 1000
mg/kg/day from gestation day (GD) 5 through 21.  All dams were killed on
GD 22; their fetuses were removed by cesarean section and examined.  

All females survived to scheduled sacrifice, and there were no clinical
signs of toxicity.  There were no treatment-related, adverse effects on
body weight, body weight gains, food consumption, clinical chemistry,
liver weights, or gross pathology at any dose.  The maternal LOAEL was
not observed.  The maternal NOAEL is 1000 mg/kg/day, the limit dose.

There were no abortions, premature deliveries, or complete litter
resorptions and no effects of treatment on the numbers of litters, live
fetuses, dead fetuses, resorptions (early or late) or on fetal sex
ratio, or post-implantation loss, fetal body weights, gravid uterine
weights, or skeletal ossification in the fetuses.  Also, there was no
treatment-related effect on the ossification scores of the paws.  There
were no treatment-related external, visceral, or incidences of skeletal
variations or malformations.  

The developmental LOAEL was not observed.  The developmental NOAEL is
1000 mg/kg/day (limit dose).

This study is classified acceptable/guideline (OPPTS 870.3700a) and
satisfies the guideline requirements for a developmental study in the
rat.   

870.3700b Prenatal Developmental Toxicity – Rabbit

EXECUTIVE SUMMARY: :  In a developmental toxicity study (MRIDs 46800227,
46800225, 46800226, and 46800229), NOA446510 (Mandipropamid, 96.5% a.i.;
Batch # SEZ2BP007) in 0.5% aqueous carboxymethylcellulose was
administered daily via oral gavage to 24 time-mated female New Zealand
White rabbits/group at a dose volume of 4 mL/kg at dose levels of 0, 50,
250, or 1000 mg/kg/day from gestation day (GD) 5 through 29.  All
surviving rabbits were killed on GD 30; their fetuses were removed by
cesarean section and examined.  

There were no treatment-related mortalities and no adverse clinical
signs of toxicity.  There were no treatment-related, adverse effects on
body weight, body weight gains, food consumption, or gross pathology at
any dose.

The maternal LOAEL was not observed.  The maternal NOAEL is 1000
mg/kg/day, the limit dose.

At 250 mg/kg/day, one female aborted; otherwise, there were no premature
deliveries or complete litter resorptions and no effects of treatment on
the numbers of litters, live fetuses, dead fetuses, resorptions (early
or late) or on fetal body weights, sex ratio, or post-implantation loss,
fetal body weights, gravid uterine weights, or skeletal ossification in
the fetuses.  There were no treatment-related external, visceral, or
skeletal variations or malformations.  Also, there was no
treatment-related effect on the ossification scores of the paws.

The developmental LOAEL was not observed.  The developmental NOAEL is
1000 mg/kg/day.

This study is classified acceptable/guideline (OPPTS 870.3700a) and
satisfies the guideline requirements for a developmental study in the
rabbit.  

A.3.3	Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

EXECUTIVE SUMMARY:  In a two-generation reproduction toxicity study
(MRID 46800230), Mandipropamid (96.5%; Batch # SEZ2BP007) was
administered in the diet to 26 Alpk:APfSD (Wistar-derived) rats/sex/dose
group at dose levels of 0, 50, 250, or 1500 ppm (mg/kg/day mean of F0
and F1 premating M/F = 0/0, 4.7/5.0, 22.9/24.5 and 146.3/148.2).  The P
generation animals were fed the test diets for 10 weeks prior to mating
to produce the F1 litters. Upon weaning, F1 parents were fed the test
diets for 10 weeks prior to mating to produce the F2a litters.  Because
of equivocal differences in live birth index, whole litter losses, and
live litter size between the control and 1500 ppm groups, the F1 parents
were mated a second time to produce the F2b litters.

There were no effects of treatment on parental mortality, clinical
signs, estrous cycle duration or periodicity; sperm parameters, or gross
pathology.  Additionally, there were no treatment-related effects on
body weights, body weight gains, food consumption, or food utilization
during gestation or lactation.

During pre-mating in the P generation, food consumption was increased by
5-10% (p<=0.05) in the 1500 ppm males during Weeks 1-4, while body
weights were comparable to controls.  Because these animals were eating
more food to maintain the same body weight, food utilization was
decreased (p<=0.05) by 8% during Weeks 1-4, resulting in decreased
(decr. 4%; p<=0.01) food utilization for the overall (Weeks 1-10)
pre-mating period.

At 1500 ppm in the F1 generation, body weights were decreased by 2-8% in
the males throughout pre-mating, attaining significance (p<=0.05) in 7
of 11 weeks.  Weekly cumulative body weight gains in these animals were
decreased by 6-9% (p<=0.05) throughout pre-mating, resulting in a
decrease of 6% in body weight gain for the overall (Weeks 1-11)
pre-mating period. Food consumption in these males was decreased by 5%
during Weeks 9-10, and food utilization was decreased by 8% (p<=0.01)
during Weeks 1-4 and by 6% (p<=0.05) during Weeks 5-8, resulting in a
decrease of 4% (p<=0.01) for overall (Weeks 1-10) food utilization.

In the 1500 ppm F1 females, food utilization was comparable to controls
during pre-mating.  Thus, the increases in body weights and body weight
gains observed in these dams were not considered adverse and may have
been due to the increased food consumption.

At 1500 ppm, absolute and adjusted liver weights were increased in the P
males (incr.17-19%) and females (incr.7-8%) and in the F1 males and
females (incr.11-17%).  These increases attained significance (p<=0.05)
except for the absolute liver weight in the P females.  Because there
were no microscopic findings in the liver and clinical chemistry
analyses were not performed, the increased liver weights were considered
equivocal in this study.  Similar findings in the liver were noted in
the subchronic (MRID 46800216) and combined chronic/oncogenicity (MRID
46800234) studies in rats, submitted concurrently.

Absolute and adjusted adrenal weights were increased by 13-23% (p<=0.05)
at 1500 ppm compared to controls in the P males and F1 males and
females.  Absolute adrenal weights were also increased (incr.11%;
p<=0.05) in the 250 ppm F1 females.  An increased severity of vascular
ectasia was observed in the 1500 ppm females (8 dams with minimal to
moderate severity) compared to controls (7 dams of minimal severity). 
However, vascular ectasia was only observed in 0-4 animals per group at
1500 ppm in the P generation male and females and in the F1 generation
males.  The Sponsor stated that vascular ectasia in the adrenal is a
common spontaneous age-related lesion seen predominantly in female rats.
 It was also stated that the severity and incidence observed in the 1500
ppm F1 dams is within the historical control maximum for 1 year interim
sacrifice.  Although data were not available, it was stated that the
incidence of this finding can be as high as 90% at one year and varies
widely, along with severity.  Therefore, the findings in the adrenal
gland were considered to be equivocal.

The LOAEL for parental toxicity is 1500 ppm (equivalent to 146.3/148.2
mg/kg/day in males/females) based on decreased body weights, body weight
gains, food consumption, and food utilization in the males.  The NOAEL
is 250 ppm (equivalent to 22.9/24.5 mg/kg/day in males/females).

There were no treatment-related effects on viability, clinical signs, or
anogenital distance.  In the F2a litter, the live birth index was lower
at 1500 ppm (86.8%) compared to controls (97.7%), and the litter size on
PND 1 was decreased by 22% (p<=0.01) at 1500 ppm compared to controls. 
However, when the numbers of whole litter losses were excluded, these
effects were not evident.

At 1500 ppm, adjusted pup weights were decreased (p<=0.05) by 7-14% in
the F1 and F2b pups of both sexes.  In the F2a litter, pup weights of
the treated males and females were comparable to controls.  There were
no effects of treatment on total litter weight.

In the F1 parental males, the time until preputial separation was longer
(p<=0.05) at 1500 ppm (44.8 days) compared to controls (43.7 days),
indicating a slight delay in sexual maturation likely related to the
decreased pup body weights beginning on PND 15.  However, the time to
vaginal opening was unaffected by treatment.

At 1500 ppm, adjusted (for terminal body weight) liver weights were
increased by 9-17% in the F1, F2a, and F2b pups.  Additionally at this
dose, absolute liver weights were increased by 14% in the F2a females. 
However, because no clinical chemistry or histopathology analyses were
performed, the increased liver weights could not be considered to be an
adverse effect.

 

The LOAEL for offspring toxicity 1500 ppm (equivalent to 146.3/148.2
mg/kg/day in males/females) based on decreased pup body weights in both
sexes.  The NOAEL is 250 ppm (equivalent to 22.9/24.5 mg/kg/day in
males/females).

There were no effects of treatment on the pre-coital interval, number of
females pregnant, number of complete litter resorptions, mating success,
post-implantation loss, or gestation duration in either generation. 
There were no effects of treatment on whole litter losses in the P
generation.  However, in the F1 generation, the number of whole litter
losses was increased in the F2a litter at 1500 ppm compared to controls.
 Therefore, the F1 dams were mated a second time to produce the F2b
litters, and there was no effect on the number of whole litter losses,
indicating that the finding in the F2a litter was incidental.

The LOAEL for reproductive toxicity was not observed.  The NOAEL is 1500
ppm (equivalent to 146.3/148.2 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3800; OECD 416) for a two-generation
reproduction study in the rat.

A.3.4	Chronic Toxicity

870.4100b Chronic Toxicity – Dog

EXECUTIVE SUMMARY: In a chronic toxicity study (MRID 46800232), NOA
446510 (Mandipropamid; 96.5% w/w, Batch #: SEZ2BP007) was administered
daily in capsules to 4 beagle dogs/sex/dose for 52 weeks at doses of 0,
5, 40, or 400 mg/kg/day.

There were no mortalities and no effects of treatment on ophthalmoscopy,
hematology, urinalysis, or gross pathology.  There were no
treatment-related effects on any parameter at 5 mg/kg/day.

One 40 mg/kg/day female was slightly thin beginning at Week 6, and one
400 mg/kg/day female was slightly to moderately thin beginning at Week
-2.  Additionally at 400 mg/kg/day, two females exhibited slight to
moderate salivation during dosing (83 incidences beginning at Week 3)
and at non-dosing observations (96 occasions beginning at Week 1). 
These clinical findings continued until study termination.

At 400 mg/kg/day, minor decreases of 1-12% in body weights were observed
in both sexes throughout the study.  Body weight gains for Weeks 1-13
were decreased by 23% compared to controls in the males and by 30% in
the females.  Body weight gains for the overall (Weeks 1-53) study
remained decreased at this dose in the males (decr. 15%) and females
(decr. 45%).  Additionally in the 400 mg/kg/day females, minor (<=7%
compared to controls) but consistent (43 out of 52 weeks) decreases in
food consumption were observed.

The liver was the target organ of toxicity.  At >=40 mg/kg/day, alkaline
phosphatase activity was increased throughout the study in the males
(incr. 57-174%) and females (incr. 27-273%).  These increases attained
significance (p<=0.05), except in 40 mg/kg/day females at Week 13. 
Additionally in the males, alanine aminotransferase (ALT) activity was
increased throughout the study at 40 mg/kg/day (incr. 89-150%; not
significant) and 400 mg/kg/day (incr. 315-445%; p<=0.05).  Additionally
at 400 mg/kg/day, ALT was increased throughout the study in the females
(incr. 182-352%), attaining significance (p<=0.05) at Week 52.

Increases in absolute (incr. 7-15%), relative to body weight (incr.
20-27%), and adjusted for terminal body weight (incr. 16-19%) liver
weights were observed in the 400 mg/kg/day males and females, with the
adjusted liver weight in the males attaining significance (p<=0.01).

At 40 mg/kg/day, minimal increased pigment in the liver was observed in
2/4 males and 1/4 females, compared to 0/4 controls.  At 400 mg/kg/day,
the incidence of this finding increased to 3/4 males and 3/4 females,
and the severity was minimal to moderate in the males and minimal to
slight in the females.  It was stated that this pigment appeared to be
consistent with porphyrin.     

The LOAEL is 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 and increased alanine
aminotransferase activity in males).  The NOAEL is 5 mg/kg/day. 

This study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.4100b, OECD 452) for a chronic oral
toxicity study in dogs.

A.3.5	Carcinogenicity

870.4200a Combined Chronic/Carcinogenicity – Rat

EXECUTIVE SUMMARY: In a combined chronic toxicity/carcinogenicity study
(MRID 46800234), NOA 446510 (Mandipropamid; 96.5% a.i.; Batch No.
SEZ2BP007) was administered in the diet to Alpk:APfSD rats (52/sex/dose)
at doses of 0, 50, 250, or 1000 ppm (equivalent to 0, 3.0/3.5,
15.2/17.6, and 61.3/69.7 mg/kg bw/day in males/females) for up to 2
years.  Additionally, 12 rats/sex/dose were treated similarly and
terminated after 1 year.

No treatment-related effects were observed on mortality, clinical signs,
neurological evaluation, food consumption, ophthalmoscopic examination,
hematology, clinical chemistry, urinalysis, or organ weights.  No
treatment-related pathological findings were noted at 12 months.

In the 1000 ppm males, decreased (p<=0.05) body weights were generally
observed during Weeks 2-15 and 67-103 (decr 1-6%).  A similar effect was
observed on cumulative body weight gain (decr 3-7%; p<=0.05).  Overall
(Weeks 1-105) body weight gain was decreased by 6% (not statistically
significant).  Food utilization was decreased during Weeks 1-4, 5-8,
9-13, and 1-13 by 5-7% (p<=0.01; except not statistically significant at
Weeks 9-13).

In the kidney of the 1000 ppm males, an increased incidence of a
roughened surface was observed (13/64 treated vs 5/64 controls). 
Severity of chronic progressive nephropathy was increased, with an
increased incidence of moderate to marked severity of 53% treated vs 38%
controls.  Associated increases in the incidences of minimal to marked
renal osteodystrophia fibrosa (19% treated vs 8% controls) and minimal
to marked parathyroid hyperplasia (28% treated vs 17% controls) were
also noted.  

The LOAEL is 1000 ppm (equivalent to 61.3/69.7 mg/kg/day in
males/females), based on decreased body weight gain and food utilization
and increased nephrotoxicity in the males. The NOAEL is 250 ppm
(equivalent to 15.2/17.6 in males/females).

At the doses tested, there was not a treatment-related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on decreased body weight gain and food utilization and increased
nephrotoxicity in the males.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.4300; OECD 453) for a combined chronic
toxicity/carcinogenicity study in rats.

870.4200b Carcinogenicity – Mouse

EXECUTIVE SUMMARY:  In a carcinogenicity study (MRID 46800233), NOA
446510 (Mandipropamid; 96.5% a.i.; Batch No. SEZ2BP007) was administered
in the diet to C57BL/10JfCD-1 mice (50/sex/dose) at dose levels of 0,
100, 500, or 2000 ppm (equivalent to 0/0, 10.6/13.2, 55.2/67.8, and
222.7/284.6 mg/kg bw/day in males/females) for up to 80 weeks. 

No adverse treatment-related effects were observed on mortality, food
consumption, hematology (i.e., leukocyte differential), gross pathology,
or histopathology.

An increased frequency of circling behavior was observed in the females
at 500 and 2000 ppm.  However, this behavior was only slightly increased
in incidence at 2000 ppm compared to controls.  Dose-related increases
in the number of mice with their left ear being torn were observed in
both sexes at 500 and 2000 ppm.  The number of mice with the right ear
torn was minimal in incidence (<=1 mouse/dose group) and did not show a
pattern with dose.  It was stated that the animals were identified by
ear tags, and it is likely that these identification tags were placed in
the left ear.  The mice were housed together in groups and could have
removed the tags (and selectively torn the left ear) of their cage-mates
via fighting or other interactions.  However, this would not explain why
the incidence of this finding was dose-related.  The possibility that
the test substance increased fighting or some other behavior that led to
the left ear being torn cannot be ruled out.  However, because there
were no dose-related incidences in scabs or other signs of fighting and
because there were no clinical signs of neurotoxicity in this study or
in the acute or subchronic neurotoxicity studies in rats (MRID 46800240
through 46800242), the toxicological importance of this finding is
considered equivocal.

al significance (p≤0.05) throughout the study, except at Week 81 in
the males and at Week 79 in the females.  Food utilization was decreased
(p≤0.05) in the males for Weeks 9-13 (decr. 20%) and Weeks 1-13 (decr.
5%) and in the females for Weeks 1-4 (decr. 12%) and reflected the
decrease in body weights at this dose.  The decreases in body weights
were not considered to be of biological or toxicological significance.

Absolute, relative to body weight, and adjusted for initial body weight
liver weights were increased in the males at 500 ppm and in both sexes
at 2000 ppm.  These increases were significant (p<=0.05) except for
absolute weights in the 2000 ppm males (relative liver weights were not
examined statistically).  In the absence of any microscopic findings in
the liver, the relatively small increases in liver weights were not
considered adverse but were likely an adaptive response to the presence
of the test substance.

At the doses tested, there were no effects of treatment on the incidence
or time to onset of any tumor types.  Therefore, there was no evidence
of a carcinogenic effect.  Dosing was considered adequate based on
decreased body weight and body weight gain. 

The LOAEL is 2000 ppm (equivalent to 223/285 mg/kg/day in
males/females), based on decreased body weight gain in both sexes and
decreased food utilization in males.  The NOAEL is 500 ppm (equivalent
to 55/68 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity
study in mice.

A.3.6	Mutagenicity

870.5100 Bacterial Reverse Mutation Test 

 derived from the livers of male Sprague-Dawley rats induced with
phenobarbital/β-naphthoflavone.  The standard plate incorporation
method was used in all trials except for Trial 2 (+S9), where a
pre-incubation step was added.  Standard strain-specific mutagens served
as positive controls.

NOA446510 was tested up to the limit dose (5000 µg/plate). 
Precipitation of the test material was observed at 2500 µg/plate and
above in Trial 1 (+/-S9) and at 1000 µg/plate and above in Trial 2
(-S9) and Trial 3 (+S9).  No precipitation was noted at any
concentration in the pre-incubation assay (Trial 2 (+S9).  No evidence
of cytotoxicity (thinning of background lawn/reduced number of
revertants) was observed in any strain in the presence or absence of S9.
 There were no treatment-related increases in the mean number of
revertants/plate in any strain.  The positive controls induced marked
increases in revertant colonies compared to controls in all strains in
the presence and absence of S9-activation.  There was no evidence of
induced mutant colonies over background.

The study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.5100; OECD 471) for in vitro
mutagenicity (bacterial reverse gene mutation) data.

870.5300 In Vitro Mammalian Cell Gene Mutation Test 

EXECUTIVE SUMMARY: In three independent trials of a mammalian cell gene
mutation assay at the TK +/- locus (MRID 46800236), L5178Y mouse
lymphoma cells cultured in vitro were exposed to NOA446510
(Mandipropamid; 96.5% a.i., Batch # SEZ2BP007) in DMSO at concentrations
of 0, 257, 515, 1030, 2060, or 4119 µg/mL (Trials 1 and 2, +/-S9) or 0,
1, 10, 50, 100, 250, or 500 µg/mL (Trial 3, +/-S9) for 4 hours.  The S9
fraction was derived from the livers of male Sprague-Dawley rats induced
with phenobarbital and β-naphthoflavone.  Ethylmethane-sulphonate (EMS)
and Benzo(α)pyrene (BP) served as positive controls in the absence and
presence of S9, respectively.

NOA446510 was tested up to the limit dose (4119 (g/mL, approximately 10
mM).  Cytotoxicity (decreased mean relative survival) was observed at
all doses in the presence and absence of S9 in Trials 1 and 2.  No
statistically significant (p≤0.05) or biologically relevant increases
in mutant frequency were observed in the absence of S9.  However, in the
presence of S9, statistically significant increases (p≤ 0.05) in
mutant frequency were noted at 2060 g/mL in Trial 1 and 1030 g/mL
in Trial 2.  These findings were less than twice the negative control
values and were not dose-dependent; thus the findings were not
considered biologically significant or treatment related.  The positive
controls induced the appropriate response both in the presence and
absence of S9.  There was no evidence of induced mutant colonies over
background in the presence or absence of S9-activation.

The study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.5300, OECD 476) for in vitro
mutagenicity (mammalian forward gene mutation) data.

870.5375 In Vitro Mammalian Chromosome Aberration Test 

EXECUTIVE SUMMARY: In two independent trials of a mammalian cell
cytogenetics assay (chromosome aberration; MRID 46800237), lymphocyte
cultures were prepared from human peripheral blood and exposed to
NOA446510 (Mandipropamid; 96.5% a.i., Batch # SEZ2BP007) in DMSO at
concentrations of 0, 10, 50, 100, 250, 500, 1000, 2000, 3000, or 4119
µg/mL (+/-S9) for 3 hours followed by a 17 hour recovery period (Trial
1); 0, 1, 2.5, 5, 10, 25, 50, 100, or 250 µg/mL for 3 hours with a 17
hour recovery period (+S9, Trial 2); or 0, 1, 2.5, 5, 10, 25, 50, 100,
or 250 µg/mL for 20 hours with no recovery period (-S9, Trial 2).

NOA446510 was tested up to cytotoxic concentrations.  Excessive
cytotoxicity was observed at 250 µg/mL and above (+/-S9, Trial 1), 100
µg/mL and above (+S9, Trial 2), and 50 µg/mL and above (-S9, Trial 2).
 Therefore, the following concentrations were selected for evaluation of
chromosomal aberrations: (i) 10, 50, and 100 µg/mL (+/-S9, Trial 1);
(ii) 2.5, 10, and 25 µg/mL (-S9, Trial 2); and (iii) 5, 25, and 50
µg/mL (+S9, Trial 2).  No significant increases in the mean percentage
of aberrant cells were observed in either trial in the presence or
absence of S9.  The positive controls induced increases (p<0.001) in the
number of aberrant cells in the presence and absence of S9 in both
trials.  There was no evidence of chromosome aberrations induced over
background in the presence or absence of S9-activation.

This study is classified as acceptable/guideline and satisfies the
Guideline requirement (OPPTS 870.5375, OECD 473) for in vitro
mutagenicity (chromosome aberration) data.

870.5395 Bacterial Mutation Assay

EXECUTIVE SUMMARY: In a bone marrow micronucleus assay (MRID 46800238),
6-7 week old, male Wistar rats (5/dose/harvest time) were treated once
via gavage (10 mL/kg) with NOA446510 (Mandipropamid; 96.5% a.i., Batch #
SEZ2BP007) in aqueous 0.5% methylcellulose at doses of 0 or 2000 mg/kg
(limit dose).  Bone marrow cells were harvested at 24 and 48 hours after
dosing.

NOA446510 was tested at the limit dose (2000 mg/kg).  No
compound-related mortalities or clinical signs of toxicity were
observed.  A small decrease (p<0.05) in the percentage of polychromatic
erythrocytes (PCE) was observed at 48 hours post-dosing, indicating that
NOA446510 was slightly toxic to the bone marrow.  No treatment-related
increases in the micronucleated polychromatic erythrocyte (MPCE)
frequency were observed in the treated animals at either sacrifice time
compared to controls.  The positive control induced the appropriate
response.

This study is classified as acceptable/guideline and satisfies the
guideline requirement for Test Guideline OPPTS 870.5395; OECD 474 for in
vivo cytogenetic mutagenicity data.

870.5550 Unscheduled DNA Synthesis

EXECUTIVE SUMMARY: In an in vivo/in vitro unscheduled DNA synthesis
assay (MRID 46800239), rat hepatocyte cultures were prepared from 2-3
male Wistar rats/dose that were orally dosed (gavage, 10 mL/kg) once
with NOA446510 (Mandipropamid; 96.5% a.i., Batch # SEZ2BP007) in 0.5%
carboxymethylcellulose at doses of 0 or 2000 mg/kg.  Hepatocytes were
harvested at 2 or 16 hours post-dosing.   

NOA446510 was tested up to the limit dose (2000 mg/kg).  The net nuclear
grain (NNG) counts in the treated animals (–4.8 to –4.7) were well
below the threshold of 0 or more NNG required for a positive response,
and the mean percent of cells in repair (>5 NNG/cell) in the treated
animals was only 1% in both trials.  The positive controls induced the
appropriate response in both trials.  There was no evidence that
unscheduled DNA synthesis, as determined by radioactive tracer
procedures [nuclear silver grain counts] was induced.

The study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.5550; OECD 482/486) for other
genotoxic mutagenicity data.

A.3.7	Neurotoxicity

870.6200a Acute Neurotoxicity Screening Battery

EXECUTIVE SUMMARY: In an acute neurotoxicity study (MRIDs 46800242 and
46800241), groups of fasted, >=42-day old Alpk:APfSD (Wistar-derived)
rats (10/sex/dose) were given a single gavage dose (10 mL/kg) of NOA
446510 (Mandipropamid; 96.5% a.i., Batch No. SEZ2BP007) in 0.5%
carboxymethylcellulose at doses of 0, 200, 600, or 2000 mg/kg (limit
dose) and were sacrificed on Day 15.  Functional observational battery
(FOB) and motor activity testing were performed on all animals during
pre-exposure, Days 1 (at 2-4 hours post-dosing), 8, and 15.  At study
termination, 5 animals/sex/dose group were anesthetized and perfused in
situ for neuropathological examination.  The brain and peripheral
nervous system tissues collected from the perfused animals in the
control and 2000 mg/kg/day groups were subjected to histopathological
evaluation.  

No treatment-related effects were observed on mortality, clinical signs,
body weight, body weight gains, food consumption, functional
observational battery parameters, motor activity, or neuropathology.

The LOAEL was not observed.  The NOAEL is 2000 mg/kg (limit dose).

This neurotoxicity study is classified as acceptable/guideline and
satisfies the guideline requirement for an acute neurotoxicity study in
rats (870.6200a; OECD 424).

870.6200b Chronic Neurotoxicity Screening Battery

EXECUTIVE SUMMARY: In a subchronic neurotoxicity study (MRID 46800240)
NOA 446510 (Mandipropamid; 96.5% a.i., Batch No. SEZ2BP007) was
administered in the diet to 12 Alpk:APfSD rats/sex/group at dose levels
of 0, 100, 500, or 2500 ppm (equivalent to 0/0, 7.4/8.4, 37.3/41.0, and
192.5/206.7 mg/kg bw/day in males/females) for at least 90 consecutive
days.  Neurobehavioral assessment (functional observational battery
[FOB] and motor activity testing) was performed in 12 rats/sex/group at
Weeks -1, 2, 5, 9, and 14.  At study termination, 5 rats/sex/group were
anesthetized and perfused in situ for neuropathological examination. 
The tissues from the perfused animals in the control and 2500 ppm groups
were subjected to histopathological evaluation of brain and peripheral
nervous system tissues.  

No adverse, treatment-related effects were observed on mortality,
clinical signs, food consumption, functional observational battery
parameters, motor activity, brain weights, or neuropathology.

In the 2500 ppm males, body weights were decreased (not statistically
significant [NS]) by 3% initially at Week 1 and 2-7% throughout the
study, and decreased (p<=0.05) cumulative body weight was observed from
Week 10 until termination (decr 10-11%).  Decreased (p<=0.05) food
utilization was noted during Weeks 5-8 (decr 16%).  Decreases (NS) were
also observed during Weeks 1-4 (decr 6%) and 9-13 (decr 12%), leading to
a decreased (NS) overall (Weeks 1-13) food utilization (decr 9%).  The
effect on food utilization was of a similar magnitude to that observed
on body weight and body weight gain.  There were no effects on body
weight, body weight gain, food consumption or food utilization in
females.

Slight increases (p<=0.05) of 13-26% were observed in liver weight at
2500 ppm in the following groups: female adjusted liver weight
post-perfusion, and absolute and adjusted liver weights (without
perfusion) in both sexes.  The effect on the liver was considered
equivocal in the absence of any other evidence supporting
hepatotoxicity. 

No neurological effects were observed at any dose in either sex.

The LOAEL is 2500 ppm (equivalent to 192/207 mg/kg bw/day in
males/females) based on slightly decreased body weight, body weight
gain, and food utilization in males.  The NOAEL is 500 ppm (equivalent
to 37/41 mg/kg bw/day in males/females).

The study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.6200b) for a subchronic neurotoxicity
study in rats.

A.3.8	Metabolism

Metabolism – Rat

EXECUTIVE SUMMARY: In rat metabolism studies (MRIDs 46800243, 46800244,
46800245, and 46800246), [14C]-NOA 446510 (Mandipropamid; 95.2-96.8%
radiochemical purity) in 1% w/v aqueous carboxymethylcellulose was
administered to Alpk:APfSD (Wistar-derived) rats/sex/dose as a single
oral gavage dose at 3 or 300 mg/kg body weight.  Group size was 3-4
rats/sex/dose (per time interval, where applicable).  Results were
evaluated following treatment with [methoxyphenyl-U-14C]-NOA 446510 and
[chlorophenyl-U-14C]- NOA 446510.  Bile duct-cannulation and tissue time
course studies were also performed.

Absorption was 67-74% of dose in the animals treated at 3 mg/kg and
30-45% of dose in the animals treated at 300 mg/kg, based on the sum of
the radioactive residues found 48 hours after dose administration in the
rat urine, bile, and carcass and in the cage wash.  There was no clear
difference in compound absorption between the sexes.  Absorption was
decreased at the high dose, suggesting a saturation of the absorption
kinetics.  The Tmax in blood at the low dose was 8.5 hours in males and
4.5 hours in females and at the high dose was 24 hours in males and 10
hours in females.  These data suggest that the rate of absorption is
greater in females while the extent of the absorption is similar between
the sexes, and that the extent and rate of absorption is greater in the
low dose than the high dose. 

Total recoveries at 168 hours post-dose were 88-99% of the administered
dose.  The administered dose was mostly eliminated within 48 hours. 
Excluding the 3 mg/kg females, most of the dose was excreted in the
feces regardless of the radiolabel position.  In the 3 mg/kg females,
the amount excreted in the feces was similar to that excreted in the
urine.  Regardless of sex, radiolabel position, or dose, the amount of
administered radioactivity isolated from the exhaled air was 0.16% dose
or less, and the amount of the dose remaining in the body after 168
hours was <1.1% dose.  In the multiple dose study (methoxyphenyl label
only), the excretion profile on Day 2 after a single dose was similar to
that on Day 15 after 14 doses, indicating that pre-exposure did not
influence the excretion profile.  Elimination after 48 hours in the bile
was high at 3 mg/kg (55-73% dose), but was only 22-28% dose at 300 mg/kg
(which had corresponding increases of residues found in the feces of
males and urine of females).

The liver had the highest concentration of radioactivity at the initial
measurement and all following measurements.  At 8 hours post-dose,
concentrations were 0.64-1.25 µg eq./g (0.89 µg eq./g on Day 4 in the
multiple dose study) at 3 mg/kg and 27-46 µg eq./g at 300 mg/kg;
concentrations in males were approximately double those in females.  The
second highest levels were usually found in kidneys.  More radioactivity
was isolated in the plasma than whole blood.  Thus, the profile of
tissue distribution was generally similar regardless of dose, radiolabel
position, or sex; however, there were quantitative differences.  Tissue
concentrations did not increase proportionally with dose.  A 100-fold
increase in the dose resulted in a 17-56 fold increase in concentrations
in the liver.  Results from the multiple dose study indicated that
bioaccumulation did not occur in any sampled tissue.  Half-life values
for the elimination of radioactivity from the blood were 18.4-20.2 hours
at 3 mg/kg and 24.8-32.7 hours at 300 mg/kg.

Identified compounds accounted for 65.7-93.5% of the administered dose
in each group; however 6-14% of the administered dose was unaccounted
for in the rats after 168 hours of sample collection.  Differences in
the metabolite
profi敬眠牥⁥潦湵⁤慢敳⁤湯猠硥‬潤敳‬湡⁤慲楤汯
扡汥瀠獯瑩潩⁮獡搠獥牣扩摥戠汥睯മ

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 quantity of
each metabolite isolated in males and females at 3 mg/kg after sampling
for 168 hours differed.  The amount of NOA 458422 glucuronide in females
was almost 3-fold more than in males, while lesser amounts of parent and
NOA 458422 were isolated in females.  Increasing the dose resulted in
increasing amounts of radioactivity isolated as parent.  In the animals
treated with [chlorophenyl-U-14C]-NOA 446510, only the parent was
isolated at >5% dose but other compounds were also isolated in animals
treated with [methoxyphenyl-U-14C]-NOA 446510.  Thus, there were
differences in the metabolite profile due to sex, dose, and radiolabel
position.  Each isolated unknown accounted for <5% dose.  The Sponsor
stated that repeated dosing had no effect on metabolism in the male
(only sex tested) with similar metabolic profiles obtained in samples
taken 24 hours after the first and final dose of a 14-day repeat dose
study; however, data were not reported.  The major metabolic
transformations involve loss of one or both of the molecule’s
propargyl groups followed by glucuronidation and O-demethylation.

This metabolism study in the rat is classified acceptable/guideline and
satisfies the guideline requirement for a metabolism study [OPPTS
870.7485, OECD 417] in rats.



Dermal Absorption – Rat

EXECUTIVE SUMMARY:  In a dermal penetration study (MRID 46800248),
[Ethyl-1-14C]-NOA 446510 (Mandipropamide; >97.9% radiochemical purity;
Batch No. ILA-163.6A-1) 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.  A12946B is a
commercial formulation 250 g/L suspension concentrate containing 23.7%
(w/w) NOA 446510.  The highest dose mimicked a formulation concentrate,
and was included 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.  The exposure duration was 6 hours,
after which 4 males for each dose level were sacrificed.  The remaining
were sacrificed at 24, 72, or 120 hours post-application (4
males/dose/time interval). 

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, was
observed (<0.17 to 3.44% of applied dose).  The majority of the
administered dose was recovered from the 6-hour skin wash (91-105%). 
0.03-0.47% of the applied dose was retained at the application site, and
0.02-0.77% dose was found in the stratum corneum.

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 LOD in
all 4 animals (<0.11%) with an additional 0.53% isolated in the stratum
corneum.  

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.



Appendix B:  Metabolism Assessment  TC \l1 "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

Rotated lettuce(14.2%, 29-Day PBI), radish roots(29.8%, 29-Day PBI) and
tops (13.8%, 58-Day PBI), and wheat forage (12.1%, 58-Day PBI), grain &
straw.

Rat (79.0%.)	benzeneacetamide,
4-chloro-N-[2-[3-metho祸㐭⠭ⴲ牰灯湹汹硯⥹

phenyl]ethyl]-α-(2-propynyloxy)	

NOA 458422

Goat kidney(17.7%) & liver;

Grape fruit & leaves;

Lettuce;

Potato leaves; 

Tomato fruit & leaves; and 

Rat (29.2%).
2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-2-prop-2-yny
loxy-acetamide	

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.

Rat.
2-(4-chlorophenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-et
hyl]-acetamide	

CGA 380775

Goat kidney & liver;

Grape fruit & leaves;

Lettuce;

Potato tuber 2 & leaves; and

Tomato fruit & leaves.
2-(4-chlorophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-ac
etamide	

CGA 155705

Grape fruit & leaves; and

Potato tuber.	4-chlorobenzoic acid	

SYN 500003

Potato tuber (12.7%, 7-DAT).	(4-chlorophenyl)-prop-2-ynyloxy-acetic acid


SYN 505503

Goat kidney & liver.

 Rat.
2-(4-chlorophenyl)-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-2-prop-2-ynyloxy-a
cetamide	

SYN 505503 glucuron

Rat.	Glucuron conjugate of
2-(4-chlorophenyl)-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-2-prop-2-ynyloxy-a
cetamide	                             

                     Not available

SYN 505504 

Potato tuber. 2.
2-(4-chlorophenyl)-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-2-hydroxy-acetamid
e	

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

Tomato fruit & leaves.	malonyl-O-glycoside of NOA 458422	

SYN 508792; 

O-glycoside of NOA 458422

Grape fruit & leaves; and

Tomato fruit & leaves.	O-glycoside of NOA 458422	

SYN 518495

Goat kidney & liver.

	2-(4-chlorophenyl)-2-hydroxy-N-[2-(3-hydroxy-4-prop-2-ynyloxy-phenyl)-e
thyl]-acetamide	

SYN 521195

Goat kidney & liver;

Grape fruit;

Lettuce; and

Potato tuber 2.
2-(4-chlorophenyl)-N-[2-(3-hydroxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-pro
p-2-ynyloxy-acetamide	

SYN 524193 

Grape fruit & leaves.

	(4-{2-[2-(chlorophenyl)-2-prop-2-ynyloxy-acetylamino]-ethyl}-2-methoxy-
phenoxy)-acetic acid	

SYN 524194

Grape fruit & leaves.
{(4-chlorophenyl)-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethylcarbamoyl]
-methoxy}-acetic acid	

SYN 524196

Grape fruit & leaves.	4-chlorobenzoic acid carboxymethyl ester	

SYN 524197

Grape fruit & leaves.
3-[2-(4-chlorophenyl)-2-prop-2-ynyloxy-acetylamino]-propionic acid	

SYN 524198

Grape fruit & leaves.

	3-[2-(4-chlorophenyl)-2-hydroxy-acetylamino]-propionic acid	

SYN 524195

Grape fruit & leaves.	2-(4-chlorophenyl)-2-hydroxy-acetamide	

SYN 524199

Grape fruit & leaves; and

Potato tuber.	(4-chlorophenyl)-(3,4,5-trihydroxy-6-h
ydroxy-methyl-tetrahydropyran-2-yloxy)- acetic acid	

SYN 524200 

Grape fruit & leaves.
2-(4-chlorobenzyloxy)-6-(3,4,5-trihydroxy-6-methyl-tetrahydro-pyran-2-yl
oxymethyl)-tetrahydro-pyran-3,4,5-triol	

SYN 524201

Grape fruit & leaves.	4-chlorobenzoic acid
3,4,5-trihydroxy-6-(3,4,5-trihydroxy-6-methyl-tetrahydro-pyran-2-yloxyme
thyl)-tetrahydro-pyran-2-yl ester	

NOA 458422

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eat grain.
2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-2-prop-2-yny
loxy-acetamide	

NOA 459119 

Tomato fruit & leaves.	(4-chlorophenyl)-hydroxy-acetic acid	

SYN 504851

Water (29%, aerobic aquatic metabolism study).

	Allyloxy-(4-chloro-phenyl)-acetic acid	

SYN 534133 

Rat (10%).

	Glucuron conjugate of CGA 380775	

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 TC \l1 "Appendix C:
 Tolerance Reassessment Summary and Table 

Appendix C. 	Tolerance Summary for Mandipropamid.

Commodity	Proposed 

Tolerance (ppm)	Recommended 

Tolerance (ppm)	Comments; Correct Commodity Definition

Proposed Tolerances

Brassica, Head and Stem, Subgroup 5A	3	3	The representative commodities
of Subgroup 5A are broccoli (or cauliflower) and cabbage.  Because the
cabbage (with wrapper) field trials yielded higher residue than the
broccoli, the cabbage field trials were entered into the NAFTA tolerance
spreadsheet for tolerance calculations.  

[Brassica, head and stem, subgroup 5A]

Brassica, Leafy Greens, Subgroup 5B	30	25	The residue data for mustard
greens, the representative commodity of Subgroup 5B, were entered into
the NAFTA tolerance spreadsheet for tolerance calculations.  

[Brassica leafy greens, subgroup 5B]

Vegetables, Cucurbit, Group 9	0.30	0.6	The representative commodities of
crop group 09 are cantaloupe, summer squash, and cucumber.  The residue
data for cantaloupe and summer squash were separately entered into the
NAFTA tolerance spreadsheet for tolerance calculations.  The data for
cucumber were not entered into the NAFTA tolerance spreadsheet because
greater than 15% of the reported residues were below the LOQ of 0.01
ppm.  If individual tolerances were to be established, the recommended
tolerances would be 0.60 ppm for cantaloupe and 0.15 ppm for summer
squash.  Since these individual values are reasonably consistent and do
not differ by a factor of 5x, HED recommends that the highest value of
0.60 ppm be used to establish a tolerance for cucurbit vegetables.

[Vegetable, cucurbit, group 9]

Vegetables, Leafy, except Brassica, Group 4	15	20	The residue data for
leaf lettuce, head lettuce, celery, and spinach, the representative
commodities of Crop Group 4,were separately entered into the NAFTA
tolerance spreadsheet for tolerance calculations.  If individual
tolerances were to be established, the recommended tolerances would be
12  ppm for leaf lettuce, 17 ppm for head lettuce, 20 ppm for celery,
and 15 ppm for spinach.  Since these individual values are reasonably
consistent and do not differ by a factor of 5x, HED recommends that the
highest value of 20 ppm be used to establish a tolerance for Vegetables,
leafy except Brassica, Group 4.

[Vegetable ,leafy,except Brassica, group 4]

Vegetables, Fruiting, Group 8	1	1.0	The residue data for bell pepper,
non-bell pepper, and tomato, the representative commodities of Crop
Group 8 were separately entered into the NAFTA tolerance spreadsheet for
tolerance calculations.  If individual tolerances were to be
established, the recommended tolerances would be 0.60 ppm for bell
pepper, 1.0 ppm for non-bell pepper, and 0.25 ppm for tomatoes.  Since
these individual values are reasonably consistent and do not differ by a
factor of 5x, HED recommends that the highest value of 1.0 ppm be used
to establish a tolerance for Fruiting Vegetables.

[Vegetable, fruiting, group 8]

Vegetables, Tuberous and Corm, Subgroup 1C	0.01	0.01	Residues were below
the method LOQ (<0.01 ppm) in/on all samples treated at 1x. 

[Vegetable, tuberous and corm, subgroup 1C]

Grapes	2	1.4	The residue data for grapes were entered into the NAFTA
tolerance spreadsheet for tolerance calculations.  

[Grape]

Grapes, raisins	4	3.0	The maximum expected residue in raisin resulting
from the proposed use is 3.0 ppm which was calculated by multiplying the
HAFT of 0.67 ppm by the average concentration factor of 4.5x.

[Grape, raisin]

Onion, dry bulb	0.05	0.05	The maximum residues in/on dry bulb onions
treated at 1x were 0.04 ppm.

Onion, green	4	4.0	Field trial data for green onions were entered into
the NAFTA tolerance spreadsheet for tolerance calculations.

Tomato Paste	1.3 	Remove	The maximum expected residue in tomato paste
and puree resulting from the proposed use will be covered by the
recommended tolerance for crop group 8.

Tolerances That Need to be Proposed

Okra	None	1.0	Okra is listed in the proposed label as a member of the
fruiting vegetables.  The ChemSAC (meeting of 10/18/06) has recommended
the inclusion of okra in crop group 8 (vegetable, fruiting).  However, a
separate tolerance for okra should be listed in the appropriate section
of the CFR entry until the new crop group regulation is published.

Potato, wet peel	None	0.03	The maximum expected residue in potato wet
peel resulting from the proposed use is 0.03 ppm which was calculated by
multiplying the HAFT of <0.01 ppm by the observed concentration factor
of >3x.  



Appendix D:  Review of Human Research TC \l1 " 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 TC \l1 " Appendix E:  Mechanistic
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; D343579).

Mandipropamid	Human Health Risk Assessment	D340784/D341460

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DRAFT Confidential, Internal, and Deliberative Material

Mandipropamid	Risk Assessment Document	Barcode: D340784

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