UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 		25/MAR/2009

Subject:	Pyrimethanil

Human-Health Risk Assessment for Proposed Uses on Stone Fruits and
Citrus Fruits.

PC Code:	288201	DP Barcode:	D353181

Decision No.:	393117	Registration No.:  	43813-32-2792 and 264-788

Petition No.:	8E7353	Regulatory Action:	Amended Section 3

Risk Assessment Type: 	Single Chemical/

Aggregate Assessment	Case No.:	None

TXR No.:	None	CAS No.:	53112-28-0

MRID No.:	None	40 CFR	§180.518

From:		Debra N. Rate, Ph.D., Biologist

		Alternative Risk Integration and Assessment (ARIA)

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

		Registration Division (RD; 7505P)

Through:	William Cutchin, Acting Senior Branch Scientist

		ARIA/RIUMERB/RD (7505P)

		George F. Kramer, Ph.D., Senior Chemist

Risk Assessment Branch 1 (RAB1)

		Health Effects Division (HED; 7509P)

	Dana M. Vogel, Branch Chief

		RAB1/HED (7509P)

To:		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Susan Stanton,
Environmental Specialist

Minor Use Team

RIMUERB/RD (7505P)

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc225750617"  1.0	Executive
Summary	  PAGEREF _Toc225750617 \h  4

  HYPERLINK \l "_Toc225750618"  2.0	Ingredient Profile	  PAGEREF
_Toc225750618 \h  11

  HYPERLINK \l "_Toc225750619"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc225750619 \h  12

  HYPERLINK \l "_Toc225750620"  2.2	Structure and Nomenclature	  PAGEREF
_Toc225750620 \h  12

  HYPERLINK \l "_Toc225750621"  2.3	Physical and Chemical Properties
PAGEREF _Toc225750621 \h  13

  HYPERLINK \l "_Toc225750622"  3.0	Hazard Characterization/Assessment
PAGEREF _Toc225750622 \h  13

  HYPERLINK \l "_Toc225750623"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc225750623 \h  13

  HYPERLINK \l "_Toc225750624"  3.1.1	Adequacy of the Toxicity Database
 PAGEREF _Toc225750624 \h  15

  HYPERLINK \l "_Toc225750625"  3.1.2	Evidence of Neurotoxicity
PAGEREF _Toc225750625 \h  15

  HYPERLINK \l "_Toc225750626"  3.1.3	Recommendation for a DNT Study
PAGEREF _Toc225750626 \h  16

  HYPERLINK \l "_Toc225750627"  3.2	FQPA Considerations	  PAGEREF
_Toc225750627 \h  16

  HYPERLINK \l "_Toc225750628"  3.3	Dose-Response Assessment	  PAGEREF
_Toc225750628 \h  17

  HYPERLINK \l "_Toc225750629"  3.3.1	Acute-Population Adjusted Dose
(aPAD) - Females age 13-49	  PAGEREF _Toc225750629 \h  17

  HYPERLINK \l "_Toc225750630"  3.3.2	Acute Population Adjusted Dose
(aPAD) - General Population	  PAGEREF _Toc225750630 \h  18

  HYPERLINK \l "_Toc225750631"  3.3.3	Chronic-Population Adjusted Dose
(cPAD)	  PAGEREF _Toc225750631 \h  18

  HYPERLINK \l "_Toc225750632"  3.3.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc225750632 \h  18

  HYPERLINK \l "_Toc225750633"  3.3.5	Dermal Absorption	  PAGEREF
_Toc225750633 \h  18

  HYPERLINK \l "_Toc225750634"  3.3.6	Dermal Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc225750634 \h  19

  HYPERLINK \l "_Toc225750635"  3.3.7	Long-Term Dermal Exposure
(Long-Term)	  PAGEREF _Toc225750635 \h  19

  HYPERLINK \l "_Toc225750636"  3.3.8	Inhalation Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc225750636 \h  19

  HYPERLINK \l "_Toc225750637"  3.3.9	Long-Term Inhalation Exposure
PAGEREF _Toc225750637 \h  19

  HYPERLINK \l "_Toc225750638"  3.3.10	Level of Concern for Margin of
Exposure	  PAGEREF _Toc225750638 \h  19

  HYPERLINK \l "_Toc225750639"  3.3.11Classification of Carcinogenic
Potential	  PAGEREF _Toc225750639 \h  20

  HYPERLINK \l "_Toc225750640"  3.3.12	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc225750640 \h  20

  HYPERLINK \l "_Toc225750641"  3.3.13	Summary of Toxicological Doses
and Endpoints for Pyrimethanil for Use in Human Health Risk Assessments
 PAGEREF _Toc225750641 \h  20

  HYPERLINK \l "_Toc225750642"  3.4	Endocrine Disruption	  PAGEREF
_Toc225750642 \h  22

  HYPERLINK \l "_Toc225750643"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc225750643 \h  22

  HYPERLINK \l "_Toc225750644"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc225750644 \h  23

  HYPERLINK \l "_Toc225750645"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc225750645 \h  23

  HYPERLINK \l "_Toc225750646"  5.1.1	Metabolism in Primary Crops
PAGEREF _Toc225750646 \h  23

  HYPERLINK \l "_Toc225750647"  5.1.2	Metabolism in Rotational Crops
PAGEREF _Toc225750647 \h  23

  HYPERLINK \l "_Toc225750648"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc225750648 \h  23

  HYPERLINK \l "_Toc225750649"  5.1.4	Analytical Methodology	  PAGEREF
_Toc225750649 \h  23

  HYPERLINK \l "_Toc225750650"  5.1.5	Environmental Degradation
PAGEREF _Toc225750650 \h  24

  HYPERLINK \l "_Toc225750651"  5.1.6	Comparative Metabolic Profile
PAGEREF _Toc225750651 \h  24

  HYPERLINK \l "_Toc225750652"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc225750652 \h  25

  HYPERLINK \l "_Toc225750653"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc225750653 \h  25

  HYPERLINK \l "_Toc225750654"  5.1.9	Drinking Water Residue Profile
PAGEREF _Toc225750654 \h  25

  HYPERLINK \l "_Toc225750655"  5.1.10	Food Residue Profile	  PAGEREF
_Toc225750655 \h  26

  HYPERLINK \l "_Toc225750656"  5.1.11	International Residue Limits
PAGEREF _Toc225750656 \h  27

  HYPERLINK \l "_Toc225750657"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc225750657 \h  27

  HYPERLINK \l "_Toc225750658"  5.2.1	Acute Dietary Exposure/Risk
PAGEREF _Toc225750658 \h  27

  HYPERLINK \l "_Toc225750659"  5.2.2	Chronic Dietary Exposure/Risk
PAGEREF _Toc225750659 \h  28

  HYPERLINK \l "_Toc225750660"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc225750660 \h  29

  HYPERLINK \l "_Toc225750661"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc225750661 \h  29

  HYPERLINK \l "_Toc225750662"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc225750662 \h  29

  HYPERLINK \l "_Toc225750663"  7.0	Aggregate Risk Assessment and Risk
Characterization	  PAGEREF _Toc225750663 \h  30

  HYPERLINK \l "_Toc225750664"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc225750664 \h  30

  HYPERLINK \l "_Toc225750665"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc225750665 \h  30

  HYPERLINK \l "_Toc225750666"  7.3	Long-Term Aggregate Risk	  PAGEREF
_Toc225750666 \h  30

  HYPERLINK \l "_Toc225750667"  7.4	Cancer Risk	  PAGEREF _Toc225750667
\h  31

  HYPERLINK \l "_Toc225750668"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc225750668 \h  31

  HYPERLINK \l "_Toc225750669"  9.0	Occupational Exposure/Risk Pathway
PAGEREF _Toc225750669 \h  31

  HYPERLINK \l "_Toc225750670"  9.1	Handler Risk	  PAGEREF _Toc225750670
\h  31

  HYPERLINK \l "_Toc225750671"  9.2	Postapplication Risk	  PAGEREF
_Toc225750671 \h  34

  HYPERLINK \l "_Toc225750672"  9.3	Restricted Entry Interval (REI)
PAGEREF _Toc225750672 \h  36

  HYPERLINK \l "_Toc225750673"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc225750673 \h  36

  HYPERLINK \l "_Toc225750674"  10.1	Toxicology	  PAGEREF _Toc225750674
\h  36

  HYPERLINK \l "_Toc225750675"  10.2	Residue Chemistry	  PAGEREF
_Toc225750675 \h  37

  HYPERLINK \l "_Toc225750676"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc225750676 \h  37

  HYPERLINK \l "_Toc225750677"  11.0	References:	  PAGEREF _Toc225750677
\h  37

  HYPERLINK \l "_Toc225750678"  Appendix B:  Metabolism Assessment
PAGEREF _Toc225750678 \h  42

  HYPERLINK \l "_Toc225750679"  Appendix C:  Tolerance Reassessment
Summary and Table	  PAGEREF _Toc225750679 \h  43

  HYPERLINK \l "_Toc225750680"  Appendix D:  Review of Human Research
PAGEREF _Toc225750680 \h  44

1.0	Executive Summary

The Interregional Research Project Number 4 (IR-4) has submitted a
petition proposing uses for pyrimethanil
[4,6-dimethyl-N-phenyl-2-pyrimidinamine], formulated as Penbotec® 400SC
(EPA Reg. No. 43813-32-2792) and Scala SC (EPA Reg. No. 264-788), on
stone fruit and citrus fruit.  The petitioner has proposed the
establishment of permanent tolerances for pyrimethanil residues of 10
ppm in/on fruit, stone, group 12; 10 ppm in/on fruit, citrus (except
lemon), group 10 (postharvest); and 11 ppm in/on lemons.  The petitioner
has also requested upon establishment of the new tolerances, removal of
the current permanent tolerances: fruit, stone (except cherry), group 12
at 3.0 ppm, and fruit, citrus group 10 (postharvest) at 10 ppm.

Pyrimethanil is an amino acid synthesis inhibitor that inhibits the
secretion of fungal enzymes necessary for fungal infection.
Pyrimethanil is currently registered in the U.S. for use on almonds,
pome fruit, citrus fruit, stone fruit (except cherry), bananas, grapes,
onions, pistachios, strawberries, tomatoes and tuberous and corm
vegetables.  Permanent tolerances have been established for residues of
pyrimethanil per se in/on plant commodities at levels ranging from 0.05
ppm in/on vegetable, tuberous and corm, subgroup 1C to 150 ppm in/on
citrus oil [40 CFR §180.518(a)(1)].  Tolerances have also been
established for pyrimethanil residues and its metabolite
4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol in fat (0.01 ppm), kidney
(2.5 ppm) and byproducts (except kidney) (0.01 ppm) of cattle, goats,
horses and sheep and in milk (0.05 ppm) [40 CFR §180.518(a)(2)].

Use Profile:  Pyrimethanil is applied to the registered crops as 1-6
broadcast applications (foliar or mature fruit) per year not to exceed
the maximum seasonal rate (0.7 - 2.1 lb ai/A), depending on the crop.
Minimum preharvest intervals (PHIs) range from 0 to 7 days.  The current
action is for preharvest use on lemons (0.690 lb ai/A/season), and
postharvest applications to stone fruit (0.40 lb ai/200,000 lb fruit)
(DP# 361301, D. Rate, 05/MAR/2009).

Human Health Risk Assessment for Pyrimethanil:

Toxicity/Hazard:  The toxicity data base for pyrimethanil is adequate
for risk assessment and tolerance setting.  A hazard characterization
for pyrimethanil is provided in Section 3 of this risk assessment.

Appropriate endpoints were identified for exposures to pyrimethanil.
The identified endpoints for pyrimethanil are as follows:

The acute dietary no-observable adverse-effect level (NOAEL) for the
general population is 100 mg/kg/day.  The lowest-observable
adverse-effect level (LOAEL) is 1000 mg/kg/day based on an acute
neurotoxicity (rat) study.

The acute dietary NOAEL for females 13-49 years is 45 mg/kg/day.  The
LOAEL is 300 mg/kg/day based on a developmental toxicity (rabbit) study.

The chronic dietary NOAEL is 17 mg/kg/day.  The LOAEL is 221 mg/kg/day
based on a chronic toxicity (rat) study.

The short- and intermediate-term oral NOAELs are 23.1 mg/kg/day.  The
LOAELs are 300-600 mg/kg/day based on a reproductive toxicity (rat)
study.

The short- and intermediate-term dermal NOAELs are 23.1 mg/kg/day.  The
LOAELs are 300-600 mg/kg/day based on a reproductive toxicity (rat)
study.  (Dermal absorption rate = 51%)

The long-term dermal NOAEL is 17 mg/kg/day.  The LOAEL is 221 mg/kg/day
based on decreased body-weight gains; increased serum cholesterol and
gamma-glutamyl transferase (GGT), increased relative liver/body-weight
ratios, necropsy and histopathological findings in the liver and
thyroid.  (Dermal absorption rate = 51%)

The inhalation (short-, intermediate-term) NOAEL is 23.1 mg/kg/day.  The
LOAEL is 300-600 mg/kg/day based on a reproductive toxicity (rat) study.
 (Inhalation absorption rate = 100%)

The long-term inhalation NOAEL is 17 mg/kg/day.  The LOAEL is 221
mg/kg/day based on a reproductive toxicity (rat) study.  (Inhalation
absorption rate = 100%)

The pyrimethanil risk assessment team has evaluated the quality of the
hazard and exposure data; and, based on these data, recommended that the
Food Quality Protection Act (FQPA) safety factor (SF) be reduced to 1x.
The recommendation is based on the following:

The toxicological database is complete for FQPA assessment.  However,
data gaps remain for the mouse carcinogenicity study, and the
immunotoxicity study.  Although a mouse carcinogenicity study remains a
condition of registration, as previously requested (TXR #: 0050408, J.
Kidwell, 24/APR/2003).  EPA concluded that the FQPA factor for this data
gap is not necessary because 1) in the submitted carcinogenicity study
in mice, higher incidence of urinary bladder distension were observed at
the highest dose tested (211 mg/kg/day) in male mice at necropsy,
however, the dose response for this effects can not be determined since
tissues were not examined at the mid and low-doses, 2) the new study is
not likely to yield the POD lower than the current POD (17 mg/kg/day)
selected for the cRfD, 3) the cRfD is based on the thyroid tumors seen
in rats for which the MOE approach is utilized for both cancer and non
cancer effects.  In a 90-day oral toxicity study with rats, a slight
decreased in thymus weight was observed at 529 mg/kg/day (highest dose
tested; HDT).  There were no histopathological findings noted in the
thymus.  There were no effects on thymus in the chronic carcinogenicity
study in rats at doses up to and including 221 mg/kg/day (HDT).
Therefore, decreases in thymus weight in the 90-day study are considered
equivocal and not a trigger for immunotoxicity study.  Since an
immunotoxicity study is now a data requirement in the 40 CFR revised
Part 158, it will be required as a condition of registration.  However,
a UFDB is not warranted since the effects (decreased in thymus weight)
were seen only in the 90-day study and not in a chronic study and the
decrease in thymus weight was not associated with any histopathological
finding.  In addition, the current NOAEL of 17 mg/kg/day selected for
cPAD would be protective of any cancer or non-cancer effects as well as
potential immunotoxicity seen at a dose level of 529 mg/kg/day.

The acute dietary food exposure assessment utilizes
recommended/tolerance-level residues for all commodities; empirical or
default processing factors when appropriate; and 100% crop-treated (CT)
information for all proposed/registered uses.  By using these
screening-level assumptions, actual exposures/risks will not be
underestimated.

The chronic dietary food exposure assessment utilizes
recommended/tolerance-level residues for all commodities; empirical or
default processing factors when appropriate; and 100% CT information for
all proposed/registered uses.  By using these screening-level
assumptions, actual exposures/risks will not be underestimated.

The dietary drinking water assessment utilized modeling results which
included conservative assumptions for the parent and all degradates of
concern.  Since conservative assumptions were used in the water models
where environmental fate data are lacking, the water exposure assessment
will not underestimate the potential risks for infants and children.

There are no registered or proposed residential uses for pyrimethanil.

There is no evidence of qualitative or quantitative increased
susceptibility following prenatal or postnatal exposures, therefore,
there are no residual uncertainties for pre-/post-natal toxicity
following exposure to pyrimethanil.

Relating to the carcinogenic potential of pyrimethanil, it is classified
as “a Group C carcinogen” based on thyroid follicular cell tumors in
both sexes of the 2-year rat study.  The Agency has determined that
cancer dietary risk concerns due to long-term consumption of
pyrimethanil residues are adequately addressed by the chronic dietary
exposure analysis using the reference dose (cRfD, cPAD); therefore a
separate cancer dietary exposure analysis is not necessary.

Residue Chemistry:  The qualitative nature of the pyrimethanil residue
in plant commodities is adequately understood based on acceptable
metabolism studies in lettuce, grapes, and tomatoes.  The HED Metabolism
Assessment Review Committee (MARC) has determined that for risk
assessment and tolerance expression, parent only is the residue of
concern.

There is an adequate residue analytical method of enforcement for the
requested commodities, stone fruit and lemons.  This HPLC method has
been subjected to a successful Petition Method Validation (PMV) by the
Analytical Chemistry Branch (ACB)/Biological and Economic Analysis
Division (BEAD).  The data-collection method used for the analysis of
lemons and stone fruit for pyrimethanil is a gas chromatography with
mass selective detection (GC/MSD) method.  This method is adequate for
data collection based on acceptable method recoveries which were
generally within the acceptable range of 70-120% for all fortified
samples.

There are adequate storage stability data to support the integrity of
samples collected from the submitted field studies.  There are no
storage stability issues or corrections that need to be applied to these
residue studies.

An adequate number of field trials were conducted to support the
preharvest use of pyrimethanil on lemons.  The results of the lemon
trials show that the residues on lemons following one foliar air blast
application (0.69 lb ai/A) ranged from 0.068 ppm to 0.31 ppm.

Adequate magnitude of the residue studies were submitted for the
postharvest application of pyrimethanil to stone fruit (peach, plum,
sweet cherry, tart cherry).  The field trial studies were performed at a
2x the proposed use rate of (0.4 lb ai/A) with the exception of the tart
cherry studies which were carried out at 0.65x and 0.86x, respectively.
Due to the nature of the postharvest applications, normalization of the
residues to a 1x value was allowed.  The highest postharvest stone fruit
residues were 6.5 ppm (sweet cherry).  No additional field trial data
are required.

Dietary Exposure (Food and Drinking Water):

Drinking Water Exposure and Risk

This memorandum uses Tier 2 Estimated Drinking Water Concentrations
(EDWCs) for the combined residues of the fungicide pyrimethanil
(4,6-dimethyl-N-phenyl-2-pyrimidinamine) and its major metabolite
(2-amino-4,6-dimethylpyrimidine), for the proposed new uses.  The
Environmental Fates and Effects Division (EFED) used Pesticide Root Zone
Model (PRZM)/ and Exposure Analysis Modeling System (EXAMS) and
Screening Concentration in Ground Water (SCI-GROW) modeling in
estimating EDWCs derived from surface water and groundwater,
respectively.  For surface water, the maximum estimated peak acute
concentration of combined residues (adjusted for regional percent
cropped area) is 37.8 ppb from use of pyrimethanil on Florida
strawberries.  The chronic cancer value represents the mean annual value
over a 30-year period, while acute and non-cancer chronic values
represent ninetieth percentiles.

Acute Dietary Exposure and Risk

An acute population-adjusted dose (  SEQ CHAPTER \h \r 1 aPAD) is
established for females 13 to 50 years old based upon the developmental
toxicity study with rabbits.  In this study, the LOAEL of 300 mg/kg is
based on increases in fetuses with 13 thoracic vertebrae and 13 pairs of
ribs.  An uncertainty factor (UF) of 100x (10x for inter-species
extrapolations, 10x for intra-species variations, and a FQPA SF of 1x)
was used to calculate the aPAD.  For females 13 to 50 years old, the
aPAD for pyrimethanil is equal to 0.45 mg/kg.

An   SEQ CHAPTER \h \r 1 aPAD is established for the general population
including infants and children based upon the acute neurotoxicity study
with rats.  In this study, the LOAEL of 1000 mg/kg/day is based on
decreased motor activity, ataxia, decreased body temperature, hind limb
grip strength, and dilated pupils.  An UF of 100x (10x for inter-species
extrapolations, 10x for intra-species variations, and a FQPA SF of 1x)
was used to calculate the aPAD.  For the general U.S. population and all
population subgroups except females 13-49 years of age the aPAD for
pyrimethanil is equal to 0.10 mg/kg/day.  An aPAD of 0.45 mg/kg bw/day
was used for the population subgroup females 13-49 years of age.

DEEM-FCID™) (ver. 7.81) default processing factors (as necessary),
empirical processing factors for orange and apple juice, tolerance-level
residues, 100% CT for all commodities and EDWCs (37.8 ppb) for direct
and indirect water sources.  The resulting acute exposure estimates are
below the ARIA’s level of concern (<100% aPAD) for U.S. general
population (10% aPAD), females 13-49 years of age (13% aPAD) and all
population subgroups; the most highly exposed population subgroup is all
infants with 35% aPAD.

Chronic Dietary Exposure and Risk

A   SEQ CHAPTER \h \r 1 chronic population-adjusted dose (cPAD) is
established based upon the chronic toxicity study with rats.  In this
study, the LOAEL of 221 mg /kg/day is based on decreased body-weight
gains, increased serum cholesterol and GGT, increased relative
liver/body-weight ratios, necropsy and histopathological findings in the
liver and thyroid.  An UF of 100x (10x for inter-species extrapolations,
10x for intra-species variations, and a FQPA SF of 1x) was used to
calculate the cPAD.  The cPAD for pyrimethanil is equal to 0.17
mg/kg/day.

The chronic dietary analyses assumed DEEM( (ver. 7.81) default
processing factors (as necessary), empirical processing factors for
orange and apple juice, tolerance-level residues, 100% CT for all
commodities and EDWCs (5.1 ppb) for direct and indirect water sources.
The resulting chronic exposure estimates are below ARIA’s level of
concern (<100% cPAD) for U.S. general population (13% cPAD) and all
population subgroups; the most highly exposed population subgroup is
children 1-2 years old with 64% cPAD.

Cancer Dietary Risk

Pyrimethanil is classified as a Group C carcinogen based on thyroid
follicular cell tumors in both sexes of the 2-year rat study (NOAEL = 17
mg/kg/day).  The HED Cancer Peer Review Committee (CPRC) recommended the
margin-of-exposure (MOE) approach (i.e., threshold consideration; MOE is
equal to NOAEL divided by chronic exposure).  When assessing risk
because there appeared to be sufficient evidence for relating thyroid
tumors in the rat to a disruption of the thyroid-pituitary status (see
TXR# 0052257 for full discussion), an acceptable MOE was not defined by
the HED Hazard Identification and Review Committee (HIARC) or CPRC.
However, for threshold cancer effects where the mode of action is well
understood, like thyroid carcinogens such as pyrimethanil, the MOE that
indicates a reasonable certainty of no harm would be greater than or
equal to 100 (10x for inter-species extrapolations, 10x for
intra-species variations, and a FQPA SF of 1x).  Since the cPAD (0.17
mg/kg/day) is protective of non-cancer and cancer end points, a separate
cancer risk is not necessary.

Residential Exposure:  Currently, there are no registered/proposed uses
of pyrimethanil that result in residential exposures.  Therefore, a
residential exposure assessment was not performed.

Aggregate Risk:  The Agency conducts aggregate exposure assessments by
summing dietary (food and water) and residential exposures (residential
or other non-occupational exposures).  Since there are no
registered/proposed uses of pyrimethanil that result in residential
exposures, the acute and chronic aggregate risk assessments were equal
to the acute dietary and chronic dietary estimates (food and water
only), respectively.

Occupational Exposure/Risk:

Handler Risk:  Based on the proposed new uses, the most highly exposed
occupational pesticide handlers are expected to be mixer/loaders using
open-pour loading of liquid formulations, applicators using open-cab,
airblast sprayers and aerial applicators.  It is anticipated that most
ground applications will be applied by the grower.  It is unlikely that
pesticide handlers would be exposed continuously for 30 days or more
(short-term duration exposures).  In this case, the short-term and
intermediate-term (1 – 6 months) duration exposures (dermal and
inhalation) have the same toxicological endpoints.  Therefore, in the
event that intermediate-term exposure were to occur, the risks estimated
for short-term exposure are adequate to describe those for
intermediate-term exposures as well.  A handler assessment was performed
and is considered to result in a conservative estimate of worker risk.
A MOE of 100 is adequate to protect occupational pesticide handlers from
short-term exposures to pyrimethanil.  The combined MOE for dermal and
inhalation exposure (510, 450, and 2,500 for mixer/loaders, airblast
sprayers and aerial applicators, respectively) is not of concern, if
workers wear gloves as directed on the label.

Postapplication Risk:  The petitioner has requested the use of
pyrimethanil for post-harvest treatment of stone fruit by including
pyrimethanil in fruit dips, washes, drenches, line sprays, and wax line
sprays.  Therefore, it is possible that fruit packers and sorters be
exposed to pyrimethanil residues as a result of the post-harvest, fruit
treatment.  ARIA/HED believes packers would typically experience
short-term exposures, although, intermediate-term duration exposures
might also occur.  However, since the toxicological endpoints are the
same, the conservative estimate of risk for short-term exposure is
adequate to protect workers who might experience intermediate-term
exposures.

The Agency has no data addressing the sorting/culling/packing of
post-harvest treated fruit.  Therefore, Jaquith used the “hands
only” data from the worker reentry study of citrus harvesting to
derive a TC.  HED/ARIA believes that exposure from packing, sorting or
culling will not be greater than what is measured during harvest.

A MOE ( 100 is adequate to protect workers.  Since the estimated MOEs >
100 (MOE = 1300), the proposed uses do not exceed the ARIA‘s level of
concern.  These estimates are considered conservative in that they
assume workers hands are not protected by gloves and that 100% of the
active ingredient is biologically available from the surface of the
fruit and that dermal absorption is 51%.

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://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.
pdf_"
http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.p
df ).

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

Review of Human Research:  This risk assessment relies in part on data
from studies in which adult human subjects were intentionally exposed to
a pesticide or other chemical.  These studies (listed in Appendix D)
have been determined to require a review of their ethical conduct.  They
are also subject to review by the Human Studies Review Board.  The
listed studies have received the appropriate review.

Regulatory Recommendations and Data Deficiencies:

Recommendations

The tolerances proposed by the registrant in the current petitions are
listed in Table 1.0, along with ARIA’s recommended tolerance levels.
SEQ CHAPTER \h \r 1

Pending submission of a revised label and Section B (see requirements
under Directions for Use), the submission of analytical standards for
the regulated metabolites (see requirements under Submittal of
Analytical Reference Standards), and a revised Section F (see
requirements under Proposed Tolerances), the residue chemistry,
toxicology and occupational exposure databases support conditional
registration and establishment of permanent tolerances as summarized in
Table 1.0.  For an unconditional registration, the petitioner is
instructed to resolve all deficiencies associated with the toxicological
requirements (see Toxicology).

Table 1.0.  Tolerance Summary for Pyrimethanil.

Commodity	Proposed / Established Tolerance (ppm)	Recommended Tolerance
(ppm)	Comments; Correct Commodity Definition

40 CFR §180.518 (a)(1)

Stone Fruits (Crop Group 12) 	10	10	Fruit, stone, group 12

Citrus Fruits (Crop Group 10) 	10	11	Fruit, citrus, group 10

Fruit, stone (except cherry), group 12	3.0	Remove

	Fruit, citrus, group 10 (postharvest)	10	Remove

Data Deficiencies/Requirements

Toxicology:

Mouse carcinogenicity study was previously requested (TRX# 0050408, J.
Kidwell, 24/APR/2003) and this requirement has not been fulfilled.

Immunotoxicity study (required as a result of the revisions of 40 CFR
§158).

Residue Chemistry:

The petitioner should submit a revised Section F to reflect the
appropriate crop commodity definitions and tolerance recommendations as
listed in Table 1.0 and Appendix C.

The petitioner should amend the label to prohibit the use of adjuvants
on the preharvest use on lemons.

The petitioner should amend the Section B to reflect the label and
requested proposed use patterns.

The petitioner should submit new analytical standards for pyrimethanil,
to replace the expired samples.

2.0	Ingredient Profile

  SEQ CHAPTER \h \r 1 Pyrimethanil is an anilinopyrimidine fungicide
that inhibits the secretion of fungal enzymes which are required during
the infection process.  Pyrimethanil blocks the ability of the fungus to
degrade and digest the plant tissues, thus stopping penetration and
development of the disease.  The precise mechanism of inhibition of
enzyme secretion has not been fully established.  Protein synthesis is
not inhibited, and evidence suggests that extracellular enzymes
accumulate inside the fungus, their release being blocked in the
presence of the fungicide.  Pyrimethanil penetrates rapidly into the
plant tissues, where it stops the development of the disease, providing
a significant curative action.  In vitro, germ tube extension and
mycelial growth are inhibited.

Pyrimethanil does not exhibit cross-resistance to sterol-inhibitors,
dicarboximides, benzimidazoles, quinone outside inhibitors, or
phenylamides, but may exhibit cross-resistance in certain plant
pathogenic fungi including anilinopyridine (AP) compounds such as
cyprodinil and mepanipyrim.

2.1	Summary of Proposed Uses

Table 2.1.  Summary of Section B Directions for Use of Pyrimethanil.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate	Max. No. Applic. per Season	Max. Seasonal
Applic. Rate	PHI

(days)	Use Directions and Limitations

Stone Fruit, Crop Group 12

High-Volume Spray, Drench or Dip

	PENBOTEC 400SC

[43813-32]

	16 fl.oz/100 gal water with water or wax/oil emulsion to treat 200,000
lbs. fruit

	1

	16 fl.oz/100 gal water/200,000 lbs. fruit

(0.0255 lb ai/oz)	NA

	Do not make more than one postharvest application.  May be applied the
same day as sold or eaten.

Low-Volume Spray

	PENBOTEC 400SC

[43813-32]

	64 fl.oz/100 gal water with water or wax/oil emulsion.  Apply 10-25 gal
to treat 200,000 lbs. fruit	1

	64 fl.oz/100 gal water Apply 10-25 gal to 200,000 lbs. fruit

	NA

	Do not make more than one postharvest application.  May be applied the
same day as sold or eaten.  Do not use this method of application on
cherry.

Lemon

Foliar air blast

	SCALA SC

[264-788]

	18 fl oz/A (0.690 lb ai/A)

	1

	18 fl oz/A/season (0.690 lb ai/A/season)	7

	Do not apply with in 7 days of harvest (7-day PHI).  Do not apply more
than 18 fl oz /A/year in the field.

Text in bold-type is present on the label but is missing from the
Section B.

Conclusions  The submitted label for PENBOTEC 400SC states that stone
fruit can be treated by high-volume spray, drench or dip; however, only
stone fruit (except cherries) may be treated with low-volume spray.  The
Section B should be revised and submitted to match the label for this
condition.

The submitted label for SCALA SC does not include use directions for
lemon.  No adjuvants were used in the lemon studies.  The label should
be revised to include the proposed use for lemons, and to prohibit the
use of adjuvants in the preharvest treatment of lemons.

2.2	Structure and Nomenclature

Table 2.2.  Test Compound Nomenclature.

Chemical structure

Common name	Pyrimethanil

Company experimental name	NR*

IUPAC name	N-(4,6-dimethylpyrimidin-2yl)aniline

CAS name	4,6-dimethyl-N-phenyl-2-pyrimidinamine

CAS #	53112-28-0

End-use product/(EP)	Penbotec® 400SC and Scala SC

*NR = Not Reported

2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of the Technical Grade Test
Compound.

Parameter	Value	References

Melting point	96oC	The Pest Manual.  British Crop Protection Council.
Twelfth Edition, Editor: C.D.S. Tomlin.

pH (water solution at 25oC)	6.1

	Specific gravity at 20oC	1.15

	Water solubility (g/l at 25oC)	0.121

	Solvent solubility (g/l at 20oC)	 acetone – 389, ethyl acetate –
617, methanol – 176, methylene chloride – 1000, n-hexane – 23.7,
toluene – 412

	Vapor pressure at 25oC	2.2 mPa

	Octanol/water partition coefficient log (KOW)  	2.84

	UV/visible absorption spectrum	No UV absorption above 290 nm	Pest
Management Regulatory Agency Health, Canada, 2006.

3.0	Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization

References:

Memo, 11/15/2004, Dana M. Vogel, et. al. D284866

PYRIMETHANIL - Second Report of the Hazard Identification Assessment
Review Committee, TXR #: 0052257, P.V. Shah, 12/2/03.

Cancer Peer Review of Pyrimethanil, TXR: 0050189, Y. Yang and E. Rinde,
2/11/97.

Pyrimethanil: Report of the Dose Adequacy Review Team (DART), TXR #:
0050408, J. Kidwell, 24/APR/2003.

Pyrimethanil is of low acute toxicity by the oral (toxicity category
III), inhalation (toxicity category III), and dermal (toxicity category
III) routes.  It is slightly irritating to the eyes and non-irritating
to the skin in rabbit studies.  Pyrimethanil is not a dermal sensitizer.
 Subchronic and chronic repeated oral toxicity studies in rats, mice,
and dogs primarily resulted in decreased body weight and body-weight
gains, often accompanied by decreased food consumption.  The major
target organs in rats and mice were the liver and thyroid.  In
subchronic studies in rats and mice, liver toxicity was manifested as
increased absolute and relative body weights.  Histopathological changes
in the liver were primarily associated with increased evidence of
hypertrophy in centrilobular hepatocytes.  In a subchronic toxicity
study in mice, increases in absolute thyroid weight were observed,
associated with exfoliative necrosis and pigmentation of follicular
cells.  In a subchronic toxicity study in rats, thyroid effects were
manifested as an increased incidence and severity of follicular
epithelial hypertrophy and follicular epithelial brown pigment.

The HIARC (TXR# 0052257, P. Shah, 03/DEC/2003) concluded that there is a
potential concern for neurotoxicity resulting from acute exposures at
1000 mg/kg in the acute neurotoxicity study in rats based on ataxia,
decreased motor activity, decreased body temperature, decreased hind
limb grip strength in males, and dilated pupils in females.

No signs of neurotoxicity were evident at doses up to 392 mg/kg/day in
the subchronic neurotoxicity study in rats.  This study was classified
as unacceptable because it was not conducted at doses up to 1000
mg/kg/day (limit dose).  However, the HIARC did not require a new study
because the results of a repeat study are not likely to impact the
current endpoints used for risk assessment.  No evidence of
neuropathology was seen in neurotoxicity studies, subchronic or chronic
studies in mice, rats, and dogs.

There was no quantitative or qualitative evidence of increased
susceptibility following prenatal exposure (in rats and rabbits), or
postnatal exposure (in rats).  There were no effects on fertility or
reproduction in the two-generation reproduction study in rats.

In a carcinogenicity study in mice, there was no increase in the
incidence of any tumor types in either sex.  However, the mouse
carcinogenicity study was considered as inadequate for assessing the
carcinogenic potential of pyrimethanil by DART (TRX# 0050408, J.
Kidwell, 24/APR/2003) because the high dose in the existing study was
judged to be inadequate.  In a carcinogenicity study in rats, the
thyroid was the only tissue showing a higher incidence of tumors than
those seen in the control group.  In this study, benign follicular cell
adenomas were seen in both sexes.  A pair-wise comparison of the
incidence in the high-dose treated males was not statistically
significant when compared to the control group, while the high-dose
females were determined to be statistically significant.  The CPRC (TRX#
0050189, Y. Yang and E. Rinde, 11/FEB/1997) classified pyrimethanil as a
Group C- possible human carcinogen and recommended that a threshold or
MOE approach be used to estimate cancer risk to humans.  The threshold
approach was recommended because the thyroid tumors associated with
administration of pyrimethanil in Sprague-Dawley rats may be due to a
disruption in the thyroid-pituitary status.  The HIARC concluded that
there is no concern for mutagenicity resulting from exposures to
pyrimethanil.

In a 90-day oral toxicity study with rats, a slight decrease in thymus
weight was observed at 529 mg/kg/day (Highest-Dose Tested; HDT).  There
were no histopathological findings noted in the thymus.  There were no
effects on the thymus in the chronic carcinogenicity study in rats at
doses up to and including 221 mg/kg/day (HDT).  Therefore, decreases in
thymus weight in the 90-day study are considered equivocal and not a
trigger for immunotoxicity study.  Since an immunotoxicity study is now
a data requirement in the 40 CFR revised Part 158, it will be required
as a condition of registration.  However, a database uncertainty factor
is not warranted at this time since the effects (decreased in thymus
weight) were seen only in the 90-day study and not in a chronic study
and the decrease in thymus weight was not associated with any
histopathological finding.  In addition, the current NOAEL of 17
mg/kg/day selected for cPAD would be protective of any potential
immunotoxicity seen at a dose level of 529 mg/kg/day.

3.1.1	Adequacy of the Toxicity Database

The HIARC concluded that the toxicology database for pyrimethanil is
complete with the exception of the following data gaps:

A mouse carcinogenicity study is requested by the DART (TRX# 0050408, J.
Kidwell, 24/APR/2003) because the high dose in the existing study was
judged to be inadequate for assessing the carcinogenic potential of
pyrimethanil.

Immunotoxicity study (required as a result of the revisions of 40 CFR
§158).

3.1.2	Evidence of Neurotoxicity

The HIARC (TXR# 0052257, P. Shah, 03/DEC/2003) concluded there is a
concern for neurotoxicity resulting from exposure to pyrimethanil.  This
is based on observations of ataxia, decreased motor activity, decreased
body temperature, decreased hind limb grip strength in males, and
dilated pupils in females in the acute neurotoxicity study in rats (1000
mg/kg).

No evidence of neuropathology was seen in the neurotoxicity studies or
the subchronic or chronic toxicity studies in rats, dogs, and mice,
although the high doses in the subchronic neurotoxicity study and the
mouse oncogenicity study are considered inadequate.

An acceptable acute neurotoxicity study in rats is available.  A
subchronic neurotoxicity study was judged to be unacceptable/guideline,
based on the inadequacy of the high dose.  HIARC concluded that a repeat
subchronic neurotoxicity study (conducted at higher dose levels) is not
required since these results would not impact regulatory endpoints.

<IP_ADDRESS>	Determination of Susceptibility

Based on the results in developmental toxicity studies in rats and
rabbits, there is no quantitative or qualitative evidence of increased
susceptibility of rat or rabbit fetuses to in utero exposure to
pyrimethanil.  There is no evidence of qualitative or quantitative
increased susceptibility following pre-/post-natal exposure tp
pyrimethanil in two generation reproduction study.  There were no
effects on fertility or reproduction in the two-generation reproduction
study in rats.

<IP_ADDRESS>	Degree of Concern Analysis

There are no concerns or residual uncertainties for pre- and/or
postnatal toxicity following exposure to pyrimethanil.

3.1.3	Recommendation for a DNT Study

Based on the weight-of-evidence presented, HIARC concluded that a
developmental neurotoxicity (DNT) study is not required for pyrimethanil
since there is no evidence of neuropathology and no neurotoxic signs up
to 392 mg/kg/day in a subchronic neurotoxicity study in rats; the only
evidence of neurotoxicity occurs after an acute dose level (1000 mg/kg)
much higher than those used to establish endpoints for risk assessment
(100 mg/kg for acute exposures; approximately 20 mg/kg/day for repeated
exposures), the 1000 mg/kg/day dose is also higher than the doses tested
or than those used in the reproduction study, which had a high dose of
343 mg/kg/day.

HIARC noted, as seen in the CPRC report, that the effects on the
thyroid-pituitary status were associated with the large increase in
uridine diphosphate glucuronosyl transferases (UDPGT) seen in the 14-day
dietary rat study.  The effects seen in the thyroid and the liver, while
treatment-related, are not severe in nature; in each of these studies
there is a wide dose spread (~10-fold difference between NOAELs and
LOAELs) which provides a measure of protection for any potential effects
reflecting increased sensitivity or susceptibility in offspring.
Additionally, the endpoints selected for risk assessment will cover any
concern for thyroid or liver effects seen at higher doses.

3.2	FQPA Considerations

On April 24, 2003, the HED HIARC evaluated the potential for increased
susceptibility of infants and children from exposure to pyrimethanil
according to the February 2002 OPP 10X Guidance Document.  The HIARC
concluded that the toxicology database was complete for FQPA purposes
and that there are no residual uncertainties for pre-/postnatal
toxicity.  Since a mouse carcinogenicity study is still unfulfilled and
an immunotoxicity study is now a data requirement in the 40 CFR revised
Part 158, they will be required as a condition of registration.
However, a database uncertainty factor is not warranted at this time
since the effects (decreased in thymus weight) were seen only in the
90-day study and not in a chronic study and the decrease in thymus
weight was not associated with any histopathological finding.  In
addition, the current NOAEL of 17 mg/kg/day selected for cPAD would be
protective of any potential cancer/non-cancer effects and/or
immunotoxicity seen at a dose level of 529 mg/kg/day.  EPA concluded
that the FQPA factor for the new carcinogenicity study in mice is not
necessary because 1) in the submitted carcinogenicity study in mice,
higher incidence of urinary bladder distension were observed at the
highest dose tested (211 mg/kg/day) in male mice at necropsy, however,
the dose response for this effects can not be determined since tissues
were not examined at the mid and low-doses, 2) the new study is not
likely to yield the POD lower than the current POD (17 mg/kg/day)
selected for the cRfD, 3) the cRfD is based on the thyroid tumors seen
in rats for which the MOE approach is utilized for both cancer and non
cancer effects.  Thus, no additional SFs will be added for database
uncertainties, at this time.  Based on the HIARC conclusions and the
pyrimethanil risk assessment team’s evaluation of the hazard and
exposure data, the FQPA SF will remain at 1x.  The recommendation is
based on the following:

The toxicology database is complete for the evaluation of the FQPA
safety factor.

There are no residual uncertainties concerning pre- and postnatal
toxicity.

There are no residual uncertainties with respect to exposure data.

The dietary food exposure assessment utilizes tolerance-level residues
(established or recommended) and 100% CT for all proposed/established
commodities.  By using these assumptions, the acute and chronic
exposures/risks will not be underestimated.

The dietary drinking water assessment utilizes water concentration
values generated by models and associated modeling parameters which are
designed to provide conservative, health-protective, high-end estimates
of water concentrations which will not likely be exceeded.

There are no residential uses.

The FQPA SF recommended by the pyrimethanil review team assumes that the
exposure databases (dietary food, drinking water, and residential) are
complete and that the risk assessment for each potential exposure
scenario includes all metabolites and/or degradates of concern and does
not underestimate the potential risk for infants and children.

3.3	Dose-Response Assessment

3.3.1	Acute-Population Adjusted Dose (aPAD) - Females age 13-49

The developmental toxicity study in rabbits was used to select the
endpoint for establishing the aPAD for females 13-49 years of age.  An
UF of 100x (10x for inter-species extrapolations, 10x for intra-species
variations, and a FQPA SF of 1x) and the NOAEL (45 mg/kg/day) were used
to calculate the aPAD.  The aPAD of 0.45 mg/kg is (developmental LOAEL
of 300 mg/kg/day) based upon increase in fetuses with 13 thoracic
vertebrae and 13 pairs of ribs at 300 mg/kg.

3.3.2	Acute Population Adjusted Dose (aPAD) - General Population

An   SEQ CHAPTER \h \r 1 aPAD of 1 mg/kg is established for the general
population including infants and children based upon functional
observational battery (FOB) and motor activity effects noted in the
dosed rats.  In this study, the LOAEL of 1000 mg/kg/day is based on
decreased motor activity, ataxia, decreased body temperature, hind limb
grip strength, and dilated pupils.  An UF of 100x (10x for inter-species
extrapolations, 10x for intra-species variations, and a FQPA SF of 1x)
and the NOAEL (100 mg/kg/day) were used to calculate the aPAD.  For the
general population including infants and children, the aPAD for
pyrimethanil is equal to 1 mg/kg.

3.3.3	Chronic-Population Adjusted Dose (cPAD)

A   SEQ CHAPTER \h \r 1 cPAD is established based upon the chronic
toxicity study with rats.  In this study, the LOAEL of 221 mg /kg/day is
based on decreased body-weight gains, increased serum cholesterol and
gamma-glutamyl transferase (GGT), increased relative liver/body-weight
ratios, necropsy and histopathological findings in the liver and
thyroid.  An UF of 100x (10x for inter-species extrapolations, 10x for
intra-species variations, and a FQPA SF of 1x) and the NOAEL (17
mg/kg/day) were used to calculate the cPAD.  The cPAD for pyrimethanil
is equal to 0.17 mg/kg/day.

3.3.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Both the short- and intermediate-term incident oral exposure endpoints
were selected (23.1 mg/kg/day (NOAEL)), based upon the reproductive
toxicity study in the rat.  The NOAEL was chosen based on decreased pup
body weights throughout lactation in both generations (18%, F1; 16% F2;
PND 21).  The endpoint of concern is appropriate for the populations of
concern (infants and children).  This dose would address any concerns
for thyroid toxicity.

3.3.5	Dermal Absorption

A dermal absorption study was submitted (MRID No. 46630101) and reviewed
(DP# 322065, P.V. Shah, 23/FEB/2009).  A dermal absorption factor of 51%
was chosen based on actual in vivo dermal absorption study in rats.
Previously, HED used a dermal absorption factor of 37.2% (DP# 322065, K.
Lowe, 04/JAN/2007).  This dermal absorption factor was based on
preliminary review of the MRID 46630101; however, subsequent to a
detailed review HED concluded that the dermal factor of 51% is more
appropriate for this dermal exposure assessment.

3.3.6	Dermal Exposure (Short- and Intermediate-Term)

The short- and intermediate term dermal and inhalation endpoints for use
in risk assessment are established for pyrimethanil.  The effects seen
were decreased mean body weights and body-weight gains in the
reproduction study with rats.  The NOAEL is 23.1 mg/kg/day.  The level
of concern (LOC) for occupational dermal exposure is a MOE of 100 or
greater.

3.3.7	Long-Term Dermal Exposure (Long-Term)

The long term dermal exposure endpoints for use in risk assessment have
been chosen for pyrimethanil based on the combined
chronic/carcinogenicity study in rats.  The effects seen were decreased
body weight gains, increased serum cholesterol, increased relative
liver/body weight ratios, necropsy and histopathological findings in the
liver and thyroid at a LOAEL of 221 mg/kg/day and a NOAEL of 17
mg/kg/day.

3.3.8	Inhalation Exposure (Short- and Intermediate-Term)

No inhalation exposure study was submitted.  The short- and
intermediate-term inhalation exposures for use in risk assessment have
been chosen for pyrimethanil based on the reproduction study in rats.
The effects seen were decreased mean body weights and body weight gains
at 5000 ppm (294 mg/kg/day, male; 343 mg/kg/day, female) in the
reproduction study.  The Agency has assumed that oral exposure is
complete and equivalent to inhalation absorption.

3.3.9	Long-Term Inhalation Exposure

No inhalation exposure study was submitted.  The long-term inhalation
exposure for use in risk assessment has been chosen for pyrimethanil
based on the combined chronic/carcinogenicity study in rats.  The
effects seen were decreased body weight gains, increased serum
cholesterol, increased relative liver/body weight ratios, necropsy and
histopathological findings in the liver and thyroid at a LOAEL of 221
mg/kg/day and a NOAEL of 17 mg/kg/day.  The Agency has assumed that oral
exposure is complete and equivalent to inhalation absorption.

3.3.10	Level of Concern for Margin of Exposure

The target MOEs for occupational and non-dietary residential exposure
risk assessments are as follows:

Table 3.3.10.  Summary of Levels of Concern for Risk Assessment.

Route	Duration

	Short-Term

(1-30 days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	NA	NA	NA

Inhalation	100	100	100

Residential (Non-Dietary) Exposure

Oral	100	100	NA

Dermal	NA	NA	NA

Inhalation	100	100	100

3.3.11Classification of Carcinogenic Potential

Pyrimethanil was classified as a Group C carcinogen based on thyroid
follicular cell tumors in both sexes of the 2-year rat study (NOAEL = 17
mg/kg/day); the CPRC recommended the MOE approach (i.e., threshold
consideration).  Since the cPAD is considered protective of non-cancer
and cancer end points, a separate cancer risk is not necessary.

3.3.12	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  An aggregated
exposure risk assessment is not required since there are no residential
uses for pyrimethanil at this time.

3.3.13	Summary of Toxicological Doses and Endpoints for Pyrimethanil for
Use in Human Health Risk Assessments

The strengths and weaknesses of the pyrimethanil toxicology database
were considered during the process of toxicity endpoint and dose
selection.  The selected toxicity endpoints are summarized in Tables
3.3.13.a and 3.3.13.b.

Table 3.3.13.a  Summary of Toxicological Doses and Endpoints for
Pyrimethanil 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 	Study and Toxicological Effects

Acute Dietary

(Females 13-49 years of age)	NOAEL= 45 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Acute RfD = 0.45 mg/kg/day

aPAD =0.45 mg/kg/day	Developmental Toxicity - Rabbit:

LOAEL = 300 mg/kg/day based on increases in fetuses with 13 thoracic
vertebrae and 13 pairs of ribs.

Acute Dietary (General Population, including Infants and Children)
NOAEL = 100 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Acute RfD = 1 mg/kg/day	Acute Neurotoxicity- Rat:  LOAEL = 1000
mg/kg/day based on decreased motor activity, ataxia, decreased body
temperature, hind limb grip strength, and dilated pupils.

Chronic Dietary (All Populations)	NOAEL= 17 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Chronic RfD = 0.17 mg/kg/day

cPAD = 0.17 mg/kg/day	Chronic Toxicity - Rat:

LOAEL = 221 mg/kg/day based on decreased body weight gains; increased
serum cholesterol and GGT, increased relative liver/body weight ratios,
necropsy and histopathological findings in the liver and thyroid.

Cancer (oral, dermal, inhalation)   	Pyrimethanil was classified as a
Group C carcinogen based on thyroid follicular cell tumors in both sexes
of the 2-year rat study (NOAEL = 17 mg/kg/day); the CPRC recommended the
MOE approach (i.e., threshold consideration).  Since the cPAD is
protective of non-cancer and cancer end points, a separate cancer risk
is not necessary.

Table 3.3.13.b  Summary of Toxicological Doses and Endpoints for
Pyrimethanil for Use in Occupational Human-Health Risk Assessments.

Exposure

Scenario	Dose Used in Risk Assessment, UF 	FQPA SF* and LOC for Risk
Assessment	Study and Toxicological Effects

Short-Term Dermal (1 to 30 days)	Oral ( Parental) NOAEL=

23.1 mg/kg/day

(dermal absorption rate = 100%)	Occupational LOC for MOE = 100
Reproductive Toxicity - Rat

LOAEL = 300-600 mg/kg/day based on based on decreased pup body weights
throughout lactation in both generations (17% on lactation day 21).

Intermediate-Term

Dermal (1 to 6 months)	Oral (Parental) NOAEL = 23.1 mg/kg/day

(dermal-absorption rate = 51%	Occupational LOC for MOE = 100
Reproductive Toxicity - Rat

LOAEL = 300-600 mg/kg/day based on decreased mean body weights and
body-weight gains in the reproduction study.

Long-Term Dermal (>6 months)

	Oral study NOAEL= 17 mg/kg/day

(dermal-absorption rate = 51%) 	Occupational LOC for MOE = 100 	Chronic
Toxicity -Rat

LOAEL = 221 mg/kg/day based on decreased body-weight gains; increased
serum cholesterol and GGT, increased relative liver/body-weight ratios,
necropsy and histopathological findings in the liver and thyroid.

Short-Term Inhalation (1 to 30 days)

	Oral study Parental NOAEL= 23.1 mg/kg/day

(inhalation absorption rate = 100%)	Occupational LOC for MOE = 100
Reproductive Toxicity - Rat

LOAEL = 300-600 mg/kg/day based on decreased mean body weights  and
body-weight gains in the reproduction study.

Intermediate-Term Inhalation (1 to 6 months)	Oral study Parental NOAEL =
23.1 mg/kg/day

(inhalation absorption rate = 100%)	Occupational LOC for MOE = 100
Reproductive Toxicity - Rat

LOAEL = 300-600 mg/kg/day based on decreased mean body weights and
body-weight gains in the reproduction study.

Long-Term Inhalation (>6 months)

	Oral study NOAEL= 17 mg/kg/day

(inhalation absorption rate = 100%)	Occupational LOC for MOE = 100
Chronic Toxicity - Rat

LOAEL = 221 mg/kg/day based on  decreased body-weight gains, increased
serum cholesterol and GGT, increased relative liver/body-weight ratios,
necropsy and histopathological findings in the liver and thyroid.

Cancer (oral, dermal, inhalation)	Group C with a MOE approach for
quantification of human cancer risk.  Since the cPAD is protective of
non-cancer and cancer end points, a separate cancer risk is not
necessary (see above).

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level.
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  FQPA SF = FQPA Safety Factor.  PAD =
population-adjusted dose (a = acute, c = chronic).  RfD = reference
dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not
applicable.

3.4	Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (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 the
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 has 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).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, pyrimethanil may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data

Based on the usage patterns and the lack of residential use sites, no
incident reports are expected at this time.

5.0	Dietary Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

  SEQ CHAPTER \h \r 1 The qualitative nature of the pyrimethanil residue
in plant commodities is adequately understood based on acceptable
metabolism studies in lettuce, grapes, and tomatoes.  The HED MARC has
determined that for risk assessment and tolerance expression, parent
only is the residue of concern.  Future new uses on root crops whose
tops are significant food/feed items will require the analysis of
samples for metabolite AEC614278.

5.1.2	Metabolism in Rotational Crops

Stone fruits and citrus fruits are typically not rotated.  Therefore,
residue data pertaining to confined and field accumulation in rotational
crops are not germane to this tolerance petition.

5.1.3	Metabolism in Livestock

The crop uses proposed in this petition include dried citrus pulp (i.e.,
proposed preharvest use on lemons) which is a regulated livestock
feedstuff; however, citrus pulp was addressed in a previous Agency
memorandum (DP# 284001, J. Morales and G. Kramer, 12/JAN/2004) and the
addition of this lemon use will not change previously calculated
livestock tolerances.  Therefore, issues pertaining to livestock
metabolism, analytical methods and storage stability data for and
residues in livestock commodities are not addressed in the current
petition.

5.1.4	Analytical Methodology

DP# 284866, D. Vogel, et al., 15/NOV/2004.

A residue analytical method entitled “Analytical Method for the
Determination of Residues of ZK 100309 in Vines, Strawberries, and
Apples by HPLC” was submitted in conjunction with an earlier
pyrimethanil petition, PP#4E4384, for the establishment of a tolerance
on imported wine grapes.  The method has been subjected to a successful
validation by ACB/BEAD (DP# 288256, E. Kolbe, 07/JUL/2004).  This method
is adequate for enforcement of the proposed tolerances.

5.1.5	Environmental Degradation

EFED studies indicated that pyrimethanil is expected to be moderately
persistent in the environment.  Aerobic metabolism is expected to be the
major route of degradation for pyrimethanil in the environment.  The
only major degradate is 2-amino-4,6-dimethylpyrimidine (degradate 1).
Although it may be less toxic than the parent, degradate 1 is expected
to be more mobile and more persistent in the environment than the
parent.  MARC recommended that parent and degradate 1 are the residues
of concern for drinking water.

5.1.6	Comparative Metabolic Profile

The major route of dissipation for pyrimethanil is expected to be
aerobic metabolism for both aqueous and terrestrial environments.
Pyrimethanil partitions into the sediment, but is stable to anaerobic
(total system) degradation in both soil and sediment systems.
Pyrimethanil is stable to both hydrolysis and aqueous photolysis at
environmental pHs, but is susceptible to photolysis in soil.

In plants, pyrimethanil is the only significant residue ranging from
essentially all of the Total Radioactive Residues (TRR) in carrots and
tomatoes to 44% in lettuce.  Limited metabolism of pyrimethanil occurs
with minor amounts (less than 10%) of the phenyl and pyrimidyl
hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE
C621312) being released after acid hydrolysis.  Analysis of the foliage
from apples and carrots confirmed that the metabolism of pyrimethanil in
plants proceeded primarily via hydroxylation of the aromatic ring
structures as well as the methyl groups.

In livestock, pyrimethanil is rapidly metabolized and excreted from
lactating dairy cows.  The observed total radioactive residues in edible
tissues and milk were as follows: milk maximum residue of 0.069 ppm;
liver - 0.363 ppm; kidney 0.249 ppm, and muscle 0.017 ppm.  The
metabolic pathway is similar to that of plants involving hydroxylation
of the phenyl and pyrimidine rings as well as hydroxylation of the
methyl substituents.  Further metabolic reactions occur including
cleavage of the phenyl ring to produce substituted pyrimidines.  The
major metabolite was AE C614276 (46% of the kidney residues, 63% of the
milk residues resulting from hydroxylation of the phenyl ring.
Hydroxylation of the pyrimidinyl ring of pyrimethanil resulted in
formation of minor amounts of AE C614277.  Hydroxylation of the methyl
groups of pyrimethanil resulted in formation of minor amounts of AE
C614278.  Hydroxylation of the methyl groups of AE C614276 resulted in
formation of minor amounts of AE C614800.

In rats, when pyrimethanil was administered orally, it was absorbed
rapidly and eliminated within 24 hours.  The major routes of elimination
were the urine (approximately 72% of the administered dose), and the
feces (17-18% of the administered dose).  The main pathways of
metabolism involved oxidation to phenols in either or both aromatic
rings.  The minor pathways of metabolism involved oxidation of the
methyl group to the corresponding alcohol.

5.1.7	Toxicity Profile of Major Metabolites and Degradates

The primary residue of concern in both crop and animal commodities is
pyrimethanil.  In the animal metabolism, since major metabolites are
produced following the oral administration of pyrimethanil, toxicology
data for metabolites are completely supported by data obtained for
pyrimethanil.

Pesticide Metabolites and Degradates of Concern

The residues which are regulated in plant commodities are pyrimethanil,
per se (40 CFR §180.518).  For risk assessment purposes, the residues
of concern are 1) pyrimethanil for plant commodities; 2) in livestock,
pyrimethanil + metabolite AEC614276 for ruminant muscle, fat and
byproducts; 3) pyrimethanil + metabolite AEC614277 for milk.  In
drinking water, residues of concern are pyrimethanil + Degradate 1
(2-amino-4,6-dimethylpyrimidine).

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	Pyrimethanil, per se 	Pyrimethanil, per se

	Rotational Crop	Pyrimethanil, per se 	Pyrimethanil, per se

Livestock

	Ruminant	Pyrimethanil + AEC614276 for muscle, fat and byproducts.  For
milk, pyrimethanil + AEC614277.	Pyrimethanil + AEC614276 for muscle, fat
and byproducts.

Pyrimethanil + AEC614277 for milk.

	Poultry	Not Applicable	Not Applicable

Drinking Water

	Parent (Pyrimethanil) + Degradate 1 (2-amino-4,6-dimethylpyrimidine)
Not Applicable

5.1.9	Drinking Water Residue Profile

DP# 353180, M. Corbin, 08/JAN/2009

EFED provided EDWCs for the combined residues of the fungicide
pyrimethanil (4,6-dimethyl-N-phenyl-2-pyrimidinamine) and its major
metabolite (2-amino-4,6-dimethylpyrimidine), for the proposed new uses,
based on a maximum annual application rate of 0.75 lbs. ai/acre.  The
models, PRZM/EXAMS and SCI-GROW were used in estimating EDWCs derived
from surface water and groundwater, respectively.  Table 5.1.9 shows the
highest combined residues of pyrimethanil and its major metabolite based
on the registered seasonal application rate of 2.1 lb ai/A on strawberry
in Florida.

Table 5.1.9  Estimated Drinking Water Concentrations for Combined Total
Residues, Parent (Pyrimethanil) Plus Its Major Degradate
(2-amino-4,6-dimethylpyrimidine).

Chemical	Acute (peak) Surface Water Concentration (ppb)	Annual-Average
Surface Water Concentration (ppb)	Ground Water Concentration (ppb)

Pyrimethanil plus

2-amino-4,6-dimethylpyrimidine.	37.8	5.1	4.8

In this assessment, the annual-average surface water concentration (5.1
ppb) and the acute peak surface water concentrations (37.8 ppb) were
used for chronic and acute dietary exposure assessments, respectively.

5.1.10	Food Residue Profile

47425604.der.doc, D. Rate, 03/NOV/2008 (Lemon)

47425601.der.doc, D. Rate, 03/NOV/2008 (Peach)

47425602.der.doc, D. Rate, 03/NOV/2008 (Plum)

47425603.der.doc, D. Rate, 03/NOV/2008 (Sweet Cherry)

47425605.der.doc, D. Rate, 03/NOV/2008 (Cherry)

DP# 361301, D. Rate, 05/MAR/2009.

Crop Field Trials:

In combination with previously reviewed data and the established
tolerance of 10 ppm for postharvest treatment of citrus fruit, ARIA
recommends for a tolerance in/on fruit, citrus, group 10 at 11 ppm which
will include the labeled preharvest and postharvest applications of
pyrimethanil to lemons and the postharvest applications to the remainder
of the citrus fruit group.  ARIA also recommends for the removal of the
current tolerance of 10 ppm on fruit, citrus, group 10.

The petitioner requested a tolerance of 10 ppm on stone fruit.
Preharvest uses currently have an established tolerance of 3 ppm on
stone fruit (except cherry).  The data submitted with this petition are
for the postharvest application to representative crops of peaches,
plums and cherries.  The field trial studies were performed at 2x the
proposed application rate for all commodities except the tart cherries
for which the two submitted studies were performed at 0.65x and 0.86x
the proposed use rate.  Due to the nature of the postharvest
applications, the Agency will allow on a case-by-case basis for the
residues to be normalized to the proposed 1x application rate.
Following a normalization process for all submitted data and
commodities, the highest postharvest application residues would likely
occur at a level of 6.5 ppm on sweet cherries.  The highest postharvest
application residues (6.5 ppm) + the established tolerance for
preharvest uses on stone fruit (except cherry) (3 ppm) are not expected
to exceed the requested tolerance of 10 ppm.

The submitted data in conjunction with previously reviewed data support
a tolerance of 10 ppm on the proposed/labeled pre- and postharvest uses
of stone fruit.  Thus, ARIA recommends for the following tolerances: 10
ppm in/on fruit, stone.  ARIA also recommends for the removal of the
current tolerance of 3.0 ppm on fruit, stone (except cherry)
(postharvest).

Processed Food:

Processing studies for citrus fruit and plum were previously reviewed
(DP# 284001 & 284870, J. Morales, 12/JAN/2004) and while pyrimethanil
residues were found not to concentrate in prunes, following an
exaggerated (5x) study, pyrimethanil residues concentrated 16x in citrus
oil.  No additional processed food and feed studies were necessary or
submitted for the proposed uses and requested tolerances of the current
petition.

5.1.11	International Residue Limits

Codex maximum residue limits (MRLs) have been established for
pyrimethanil per se in/on plant commodities.  Codex MRLs are listed for
citrus fruit at 7 ppm (postharvest); cherry (postharvest), peach and
nectarine at 4 ppm; apricot at 3 ppm; and plum at 2 ppm.  Presumably due
to differences in application and use patterns, harmonization is not
feasible at this time.

A Canadian MRL for citrus fruit (Calamondins, citrus citron, citrus
hybrids, grapefruits, kumquats, lemons, limes, oranges, pummelos,
satsuma mandarins, tangerines) is established at 10 ppm and for stone
fruit (apricots,  nectarines, peaches, plumcots, plums, prune plums)
established at 3 ppm.  There are no Mexican MRLs established for
residues of pyrimethanil in commodities associated with this review.

International Residue Limit (IRL) form is attached in Appendix C.

5.2	Dietary Exposure and Risk

 DEEM-FCID™, Version 2.03 which use food consumption data from the
U.S. Department of Agriculture’s CSFII from 1994-1996 and 1998.  The
analyses were performed to support Section 3 requests for the proposed
new uses/tolerances of pyrimethanil in/on lemons (preharvest) and
postharvest uses on stone fruits.

5.2.1	Acute Dietary Exposure/Risk

The unrefined acute assessment assumed that pyrimethanil residues are
present in all commodities at tolerance levels and that 100% of all
crops are treated.  DEEM-FCID™ Version 7.81 default processing factors
were used as necessary when empirical processing factors were not
available.  Drinking water was incorporated directly into the dietary
assessment using the EDWCs generated by the PRZM/EXAMS and SCI-GROW
water models.

The resulting acute food exposure estimates are not of concern to ARIA
(<100% aPAD) at the 95th percentile of the exposure distribution for the

The resulting acute dietary exposure estimates for food and water
combined are well below ARIA’s level of concern (i.e., <100% of the
aPAD) for the general U.S. population and all population subgroups at
the 95th percentile of the exposure distribution.  Using the
DEEM-FCID™ software, dietary exposure is estimated at 0.097656
mg/kg/day for the general U.S. population (10% of the aPAD), 0.349407
mg/kg/day (35% of the aPAD) for all infants <1 years old, the population
subgroup with the highest estimated acute dietary exposure to
pyrimethanil and 0.057646 mg/kg/day for the females 13-49 years of age
population (13% of the aPAD).  Therefore, the acute dietary risk
assessment shows that for all included commodities plus drinking water,
the acute dietary risk estimates are below ARIA’s level of concern for
the general population subgroups and females 13-49 years of age (i.e.,
<100% aPAD).

5.2.2	Chronic Dietary Exposure/Risk

The unrefined acute and chronic assessments assumed that pyrimethanil
residues are present in all commodities at tolerance levels and that
100% of all crops are treated.  DEEM™ Version 7.81 default processing
factors were used to estimate residues in all commodities as appropriate
when empirical processing factors are not available.  As in the acute
scenario, drinking water was incorporated directly into the chronic
dietary assessment using the EDWC values generated by the PRZM/EXAMS and
SCI-GROW ground water models.

The resulting chronic dietary exposure estimates for food and water
combined are well below ARIA’s level of concern (i.e., <100% of the
cPAD) for the overall U.S. population and all population subgroups.
Using the DEEM-FCID™ software, dietary exposure is estimated at
0.022477 mg/kg/day for the general U.S. population (13% of the cPAD) and
0.106869 mg/kg/day (63% of the cPAD) for children 1 to 2 years old, the
population subgroup with the highest estimated chronic dietary exposure
to pyrimethanil.  The chronic dietary risk assessment shows that for all
included commodities plus drinking water, the chronic dietary risk
estimates are below ARIA’s level of concern (i.e., <100% cPAD).

Table 5.2.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for Pyrimethanil.

Population

Subgroup	Acute Dietary1

95th Percentile	Chronic Dietary1

	aPAD (mg/kg/day)	Dietary Exposure

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

(mg/kg/day)	% cPAD

U.S. Population (total)	1.0 mg/kg bw/day	0.097656	10	0.17 mg/kg bw/day
0.022477	13

All Infants (< 1 year old)

0.349407	35

0.090130	53

Children 1-2 years old

0.336523	34

0.106869	63

Children 3-5 years old

0.245654	25

0.073678	43

Children 6-12 years old

0.128346	13

0.033439	20

Youth 13-19 years old

0.060097	6

0.013225	8

Adults 20-49 years old

0.053444	5

0.011950	7

Adults 50+ years old

0.064689	7

0.016453	10

Females 13-49 years old	0.45 mg/kg bw/day	0.057646	13

0.013112	8

1 Population subgroups with the highest exposure and risk are in bold
type.  %aPAD and %cPAD are shown to nearest whole number.

5.2.3	Cancer Dietary Risk

Relating to the carcinogenic potential of pyrimethanil, it is classified
as “a Group C carcinogen” based on thyroid follicular cell tumors in
both sexes of the 2-year rat study.  The Agency has determined that
cancer dietary risk concerns due to long-term consumption of
pyrimethanil residues are adequately addressed by the chronic dietary
exposure analysis using the reference dose; therefore, a separate cancer
dietary exposure analysis was not performed.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Currently, there are no registered/proposed uses of pyrimethanil that
result in residential exposures.  Therefore, a residential exposure
assessment was not performed.

6.1	Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby
to 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
pyrimethanil.  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 should be
placed on product labels/labeling.  The Agency has completed its
evaluation of the new database submitted by the Spray Drift Task Force,
a membership of U.S. pesticide registrants, and is developing a policy
on how to appropriately apply the data and the AgDRIFT® computer model
to its risk assessments for pesticides applied by air, orchard airblast
and ground hydraulic methods.  After the policy is in place, the Agency
may impose further refinements in spray drift management practices to
reduce off-target drift with specific products with significant risks
associated with drift.

7.0	Aggregate Risk Assessment and Risk Characterization

The Agency conducts aggregate exposure assessments by summing dietary
(food and water) and residential exposures (residential or other
non-occupational exposures).  Since there are no registered/proposed
uses of pyrimethanil that result in residential exposures, the acute and
chronic aggregate risk assessments are equal to the acute dietary and
chronic dietary estimates (food and water only), respectively.

7.1	Acute Aggregate Risk

No acute residential/recreational exposures are expected.  In the case
of pyrimethanil, the acute aggregate risk is composed of exposures to
pyrimethanil residues in food and drinking water and is equivalent to
the acute dietary risk discussed in Section 5.2.  As shown in Table 5.2,
the acute risk estimates do not exceed the Agency’s level of concern
for the general U.S. population and all population subgroups.

7.2	Short- and Intermediate-Term Aggregate Risk

Pyrimethanil is not registered for residential uses.  Therefore, short-
and intermediate term residential exposures are not expected.

7.3	Long-Term Aggregate Risk

A long-term aggregate risk assessment was not performed, because
long-term residential exposure to pyrimethanil (i.e., >6 months) is
unlikely to occur based upon the use patterns.  Specifically, in the
case of pyrimethanil, the chronic aggregate risk is composed of
exposures to pyrimethanil residues in food and drinking water and is
equivalent to the chronic dietary risk discussed in Section 5.2.  As
shown in Table 5.2, the chronic risk estimates do not exceed the
Agency’s level of concern for the general U.S. population and all
population subgroups.

7.4	Cancer Risk

Pyrimethanil is classified as a Group C carcinogen based on thyroid
follicular cell tumors in both sexes of the 2-year rat study (NOAEL = 17
mg/kg/day); the CPRC recommended the MOE approach (i.e., threshold
consideration; MOE = NOAEL ( chronic exposure) when assessing risk
because there appeared to be sufficient evidence for relating thyroid
tumors in the rat to a disruption of the thyroid-pituitary status (see
TXR No. 0052257 for full discussion).  A threshold cancer effects where
the mode of action is well understood for thyroid tumors, the MOE that
indicates a reasonable certainty of no harm would be 100 or greater
(representing 2 factors of 10 for inter-species and intra-species
extrapolation).

A separate cancer dietary assessment was not conducted for pyrimethanil
as the chronic assessment is considered protective for carcinogenic
effects.

8.0	Cumulative Risk Characterization/Assessment

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

9.0	Occupational Exposure/Risk Pathway

DP# 362617, M. Dow, 10/MAR/2009

The proposed new uses were evaluated in the cited memorandum and the
resulting occupational exposure/risks were reviewed by the HED Science
Advisory Council for Exposure (ExpoSAC).

9.1	Handler Risk

Based on the proposed new uses, the most highly exposed occupational
pesticide handlers are expected to be mixer/loaders using open-pour
loading of liquid formulations, applicators using open-cab, airblast
sprayers and aerial applicators.  It is anticipated that most ground
applications will be applied by the grower.  It is unlikely that
pesticide handlers would be exposed continuously for 30 days or more
(short-term duration exposures).  In this case, the short-term and
intermediate-term (1 – 6 months) duration exposures (dermal and
inhalation) have the same toxicological endpoints.  Therefore, in the
event that intermediate-term exposure were to occur, the risks estimated
for short-term exposure are adequate to describe those for
intermediate-term exposures as well.

Particularly for ground applications, private (i.e., grower) applicators
may perform all functions, that is, mix, load and apply the material.
The HED ExpoSAC standard practice directs that although the same
individual may perform all those tasks, they shall be assessed
separately.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998).  HED/ARIA has adopted a methodology to
present the exposure and risk estimates separately for the job functions
in some scenarios and to present them as combined in other cases.  Most
exposure scenarios for hand-held equipment (such as hand wands, backpack
sprayers, and push-type granular spreaders) are assessed as a combined
job function.  With these types of hand-held operations, all handling
activities are assumed to be conducted by the same individual.  The
available monitoring data support this and HED/ARIA presents them in
this way.  Conversely, for equipment types such as fixed-wing aircraft,
groundboom tractors, or air-blast sprayers, the applicator exposures are
assessed and presented separately from those of the mixers and loaders.
By separating the two job functions, HED/ARIA determines the most
appropriate levels of personal protective equipment (PPE) for each
aspect of the job without requiring an applicator to wear unnecessary
PPE that might be required for a mixer/loader (e.g., chemical resistant
gloves may only be necessary during the pouring of a liquid
formulation).

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  For pesticide handlers, it is HED/ARIA standard practice to
present estimates of dermal exposure for “baseline” that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves as well as for “baseline” and the use of protective gloves or
other PPE as might be necessary.  The proposed labels direct applicators
and other handlers to wear long-sleeved shirt, long pants, shoes plus
socks and chemical-resistant gloves.

The toxicological parameters used in this risk assessment are taken from
the HED Toxicological Endpoint Selection (TES) Module (dedicated
database) 14 JUNE 2008.  The short-term dermal toxicological endpoint is
identified from a rat reproduction study were the toxic effects
identified were decreases in pup weight during lactation.  The NOAEL is
23.1 mg ai/kg bw/day.  The level of concern is for MOE < 100.

A dermal absorption factor of 51% was identified from an in vivo dermal
absorption study in the rat (MRID 46630101) (Pers. Comm. P.V. Shah, 10
MAR 2009).  Previously, the HED had used a dermal absorption factor of
37.2% (Memo, K. Lowe, 04 JAN 2007, DP Code 322065) based on a
preliminary review of MRID 46630101.  However, upon subsequent review,
HED concluded that 51% is the appropriate dermal factor for use in risk
assessment.

The short-term inhalation toxicological endpoint is identified from the
same study as the dermal endpoint.  The NOAEL is 23.1 mg ai/kg bw/day
and the toxic effects are the same as those identified for the dermal
endpoint.  HED/ARIA assumes 100% absorption via the inhalation route of
exposure.  The level of concern for inhalation exposure is a MOE < 100.

Pyrimethanil is classified as a Group “C” – possible human
carcinogen.  A MOE method was recommended for use in risk assessment.
Since chronic or long-term exposures are not expected (in view of the
MOE approach for assessment) for the proposed uses, a cancer risk
assessment is not necessary.  Short-term exposures are not likely to
result in cancer risk.  See Table 9.1 for a summary of estimated
exposures and risks to occupational pesticide handlers.

Table 9.1.  Estimated Handler Exposure and Risk from the Proposed Use of
Pyrimethanil on Lemon.

Unit Exposure1

mg ai/lb handled

Applic. Rate2

Units Treated3

Per Day

Average Daily

Dose4

mg ai/kg bw/day

NOAEL5

mg ai/kg bw/day

MOE6

SHORT-TERM

Mixer/Loader - Liquid - Open-pour

Dermal:

SLNoGlove  2.9 SLWGloves  0.023

Inhal              0.0012

0.7 lb ai/A

350 A/day

SLNoGlove 5.17

SLWGlove 0.041

Inhal           0.0042

23.1	SLNoGlove

4

SLWGlove

510

Applicator - Airblast - Open Cab

Dermal:

SLNoGlove   0.36

SLWGloves   0.24

Inhal              0.0045

0.7 lb ai/A

40 A/day

SLNoGlove 0.073

SLWGlove  0.049

Inhal          0.0018

23.1	SLNoGlove

310

SLWGlove

450

Applicator - Fixed-wing - Aerial (Pilots not required to wear gloves)

Dermal:

SLNoGlove  0.0050

Inhal           0.000068

0.7 lb ai/A

350 A/day

SLNoGlove 0.0089

Inhal        0.00024

23.1

SLNoGlove

2,500

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Dermal:  SLNoGlove = Single layer
work clothing (long pants, long-sleeved shirt, shoes plus socks) No
gloves;  SLWGloves = single layer work clothing WITH  the use of
protective gloves;   Inhal. = Inhalation.  Units = mg a.i./pound of
active ingredient handled.

2.  Applic. Rate. = Taken from Section B of the IR-4 submission.

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

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated *
absorption factor  (51 % dermal absorption;  100 % inhalation
absorption) ( Body Weight (70 kg).

5.  NOAEL = No Observable Adverse Effect Level  23.1 mg a.i./kg bw/day
for short-term  dermal and short-term inhalation exposures

6.  MOE = Margin of Exposure = NOAEL  ( ADD.

A MOE of 100 is adequate to protect occupational pesticide handlers from
short-term exposures to pyrimethanil.  Provided mixer/loaders wear
protective gloves as directed on the product labels, the proposed use
patterns do not exceed the HED/ARIA’s level of concern regarding
short-term duration exposures.

9.2	Postapplication Risk

The Science Advisory Council for Exposure (ExpoSAC) and the Agricultural
Reentry Task Force (ARTF) have identified numerous post-application,
agricultural activities which can result in worker exposure to
dislodgeable foliar pesticide residues (Standard Operating Procedure
(SOP) 003.1, Rev. 7 Aug. 2000, Regarding Agricultural Transfer
Coefficients; Amended ExpoSAC Meeting notes - 13 Sept 01).

In addition to identifying the post-application agricultural activities,
the ExpoSAC SOP (No 003.1 Rev. 7 Aug 2000) also identifies Transfer
Coefficients (TC) expressed as cm²/hr for each of the post-application,
agricultural activities.  The TCs are derived from data in surrogate
exposure studies conducted during the various activities listed.  The
highest TC for the proposed use on lemons is 1,500 cm2/hr.

The TCs used in this assessment are taken from an interim TC SOP
developed by HED’s ExpoSAC using proprietary data from ARTF database
(SOP # 3.1).  It is the intention of HED’s ExpoSAC that this SOP will
be periodically updated to incorporate additional information about
agricultural practices in crops and new data on TCs.  Much of this
information will originate from exposure studies currently being
conducted by the ARTF, from further analysis of studies already
submitted to the Agency, and from studies in the published scientific
literature.

Lacking chemical-specific dislodgeable foliar residue (DFR) data, HED
assumes 20% of the application rate is available as DFR on day zero
after application.  This is adapted from the ExpoSAC SOP No. 003 (7 May
1998 - Revised 7 August 2000).

The following convention may be used to estimate post-application
exposure.

Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw

 and where:

Surrogate DFR = application rate * 20% available as dislodgeable residue
* (1-D)t * 4.54 x 108 µg/lb * 2.47 x 10-8 A/cm2 .

0.7 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm² =
1.57 µg/cm2, therefore,

1.57 µg/cm2 * 1,500 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.51 (51% dermal
absorption) ( 70 kg bw = 0.137 mg/kg bw/day.

MOE = NOAEL ( ADD then 23.1 mg/kg bw/day ( 0.137 mg/kg bw/day = 170.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOE is > 100, the
proposed use does not exceed ARIA/HED’s level of concern.

Stone Fruit Post-Harvest Use - Fruit Packing

The IR-4 and Janssen Pharmaceutica, Inc. have requested the use of
pyrimethanil for post-harvest treatment of stone fruit by including
pyrimethanil in fruit dips, washes, drenches, line sprays, and wax line
sprays.  Therefore, it is possible that fruit packers and sorters be
exposed to pyrimethanil residues as a result of the post-harvest, fruit
treatment.  ARIA/HED believes packers would typically experience
short-term exposures, although, intermediate-term duration exposures
might also occur.  However, since the toxicological endpoints are the
same, the conservative estimate of risk for short-term exposure is
adequate to protect workers who might experience intermediate-term
exposures.  The assessment assumes workers do not wear protective
gloves.

To estimate possible packer exposure, ARIA/HED assumes all residues
occur on the surface of the fruit.  It also assumes that residues occur
at the recommended tolerance level of 10 ppm (DP# 361301, D. Rate,
05/MAR/2009).  Therefore there would be 10 µg pyrimethanil residue per
gram of fruit.  All surface residues are assumed to be
“bioavailable” for transfer.

For stone fruit, ARIA/ HED assumes a typical peach is 2.75” in
diameter and weighs 300 g (  HYPERLINK "http://www.ars.usda.gov"
www.ars.usda.gov ;    HYPERLINK "http://www.ext.vt.edu"  www.ext.vt.edu
).

A packing work shift is assumed to be 8 hr.  A TC of 750 cm²/hr is
taken from D. Jaquith (Memo, 14 SEP 2000, DP# 267084) who cites a study
by Nigg, H.N., J.H. Stamper, and R.M. Queen (1984) “The Development
and Use of a Universal Model to Predict Tree Crop Harvester Pesticide
Exposure” (J. Am. Ind. Hyg. Assoc.; 45:182-186).

The Agency has no data addressing the sorting/culling/packing of
post-harvest treated fruit.  Therefore, Jaquith used the “hands
only” data from the worker reentry study of citrus harvesting to
derive a TC.  HED/ARIA believes that exposure from packing, sorting or
culling will not be greater than what is measured during harvest.

The Residue Value of a single fruit = 10 µg ai/g fruit * 300 g fruit =
3000 µg ai/fruit.

The surface area is assumed to be 4πr2.  A 2.75 in. diameter fruit =
1.375 in. radius.   1.375 in. * 2.54 cm/in = 3.4925 cm.

Therefore, 4πr2 = 4 * 3.14 * (3.4925 cm)2 = 153 cm².

3000 µg ai/fruit ( 153 cm²/fruit = 19.6 µg ai/cm²

( 19.6 µg ai/cm² * 750 cm²/hr * 8 hr/day * 0.001 mg/µg = 117.6 mg
ai/day.

117.6 mg ai/day * 0.51 (51% dermal absorption) ( 70 kg bw = 0.86 mg
ai/kg bw/day.

In a study by Brouwer, H., R. Kroese and J. Van Hemmen, 1999 (Transfer
of Contaminants from Surface to Hands: Experimental Assessment of
Linearity of the Exposure Process, Adherence to the Skin, and Area
Exposed During Fixed Pressure and Repeated Contact with Surfaces
Contaminated with a Powder in Appl. Occupat. and Environm. Hyg. 14:
231-239) it was determined that repeated hand contacts with contaminated
surfaces resulted in a transfer efficiency of about 2%.

D. Jaquith (Memo, DP# 280908, “Revision to Occupational and
Residential Exposure Assessment for Thiabendazole use for Post Harvest
Treatment,” 07/FEB/2002) utilized the data from Brouwer, et al.  In a
similar manner, the estimated exposure for packing/handling stone fruit
is adjusted according to the data presented by Brouwer, et al.

0.86 mg ai/kg bw/day * 0.02 = 0.0172 mg ai/kg bw/day

MOE = NOAEL ( ADD ( 23.1 mg ai/kg bw/day ( 0.0172 mg ai/kg bw/day =
1300.

A MOE ( 100 is adequate to protect workers.  Since the estimated MOEs >
100, the proposed uses do not exceed the HED/ARIA‘s level of concern.
These estimates are considered conservative in that they assume workers
hands are not protected by gloves and that 100% of the active ingredient
is biologically available from the surface of the fruit and that dermal
absorption is 51%.  The estimates are considered conservative.

9.3	Restricted Entry Interval (REI)

The Interim Worker Protection Standard (WPS) REI of 12 hours is adequate
to protect agricultural workers re-entering the proposed crop use sites.
 For the uses covered by the WPS, the label REI is 12 hours.

10.0	Data Needs and Label Recommendations

10.1	Toxicology

1) Mouse carcinogenicity study was requested by the DART (TRX# 0050408,
J. Kidwell, 24/APR/2003) because the high dose in the existing study was
judged to be inadequate for assessing the carcinogenic potential of
pyrimethanil.  This requirement has not been fulfilled.

2) Immunotoxicity study (required as a result of the revisions of 40 CFR
§158).

10.2	Residue Chemistry

1) The petitioner should submit a revised Section F to reflect the
appropriate crop commodity definitions and tolerance recommendations as
listed in Appendix C.

2) The petitioner should amend the label to prohibit the use of
adjuvants in the preharvest use on lemons.

3) The petitioner should amend the Section B to reflect the label and
requested proposed use patterns. (i.e., the submitted label for PENBOTEC
400SC states that stone fruit can be treated by high-volume spray,
drench or dip; however, only stone fruit (except cherries) may be
treated with low-volume spray.)

4) The petitioner should submit new analytical standards for
pyrimethanil, to replace the expired samples.

10.3	Occupational and Residential Exposure

None

11.0	References:

DP# 361301, D. Rate, 05/MAR/2009

DP# 284866, D. Vogel, et al., 15/NOV/2004

TXR#: 0052257, P.V. Shah, 02/DEC/2003

TXR #: 0050408, J. Kidwell, 24/APR/2003

TXR: 0050189, Y. Yang and E. Rinde, 11/FEB/1997

DP# 322065, P.V. Shah, 23/FEB/2009

DP# 284001, J. Morales and G. Kramer, 12/JAN/2004

DP# 288256, E. Kolbe, 07/JUL/2004

DP# 353180, M. Corbin, 08/JAN/2009

47425604.der.doc, D. Rate, 03/NOV/2008 (Lemon)

47425601.der.doc, D. Rate, 03/NOV/2008 (Peach)

47425602.der.doc, D. Rate, 03/NOV/2008 (Plum)

47425603.der.doc, D. Rate, 03/NOV/2008 (Sweet Cherry)

47425605.der.doc, D. Rate, 03/NOV/2008 (Cherry)

DP# 353181, D. Rate, 23/JAN/2009

DP# 362617, M. Dow, 10/MAR/2009

Appendix A:  Toxicity Profile Tables

Table A.1.  Acute Toxicity Profile – Pyrimethanil.

Guideline No./Study Type	MRID No. 	Results	Toxicity Category

870.1100/Acute oral toxicity	43345002	LD50 = 4149 mg/kg, M 5971 mg/kg, F
III

870.1200/Acute dermal toxicity	43345003	LD50 >5000 mg/kg	IV

870.1300/Acute inhalation toxicity	43301604	LC50 >1.98 mg/L	III

870.2400/Primary eye irritation	43345004	slight eye irritant	IV

870.2500/Primary dermal irritation	43345005	non irritant	IV

870.2600/Dermal sensitization	43301605	not a sensitizer

Table A.2.  Toxicity Profile for Pyrimethanil.

Guideline No./Study Type	MRID, (year)/

Classification/Doses	Results

870.3100(a)

90-Day Oral Toxicity (rat) 	43345006

43301608 (1990, 1992)/

acceptable/guideline

0, 80, 800, 8000 ppm

0/0, 5.4/6.8, 54.5/66.7, 529.1/625.9 mg/kg/day [M/F]	NOAEL = 54.5
mg/kg/day [M], 66.7 mg/kg/day [F]

LOAEL = 529.1 mg/kg/day [M], 625.9 mg/kg/day [F] based on ( body weights
(20%), body-weight gain(30%), food consumption, brown urine, ( urinary
protein; ( abs.  heart, adrenal, spleen, thymus wts; ( rel. liver
kidney, gonad wts, liver, thyroid hypertrophy.

870.3100(b)

90-Day Oral Toxicity (mouse)

	43301606 (1991)

acceptable/guideline

0, 80, 900, 10,000 ppm

0/0, 12/18, 139/203, 1864/2545 mg/kg/day [M/F]	 NOAEL = 139 [M]
mg/kg/day, 203 [F] mg/kg/day

LOAEL = 1864 [M] and 2545 [F] mg/kg/day based on ( body-weight gain
(7-12%),(cholesterol, bilirubin [F/M], dark thyroids, (rel. liver
weights, kidney, thyroid, bladder histopathology.

870.3150

90-Day Oral Toxicity (dog)

	43301610 (1991)

acceptable/guideline

0, 6, 80, 1000/800 mg/kg/day [M/F]	NOAEL = 80 mg/kg/day

LOAEL = 1000/800 mg/kg/day based on ( water consumption, vomiting,
diarrhea, salivation, hypoactivity.

870.3700(a)

Developmental Toxicity (rat)

	43301617

43345018

43301619 (1991)

acceptable/guideline

0, 7, 85,1000 mg/kg/day	 NOAEL = Maternal: 85 mg/kg/day

Developmental: 85 mg/kg/day

LOAEL = Maternal: 1000 mg/kg/day based on ( body weight, and body-weight
gain.

Developmental:  LOAEL = 1000 mg/kg/day based on ( in mean litter weight
and mean fetal weight.

870.3700(b)

Developmental Toxicity (rabbit)

	43301620

43301621

43301622 (1991)

acceptable/guideline

0, 7, 45, 300 mg/kg/day	NOAEL = Maternal: 45 mg/kg/day

Developmental NOAEL:  45 mg/kg/day

LOAEL = Maternal: 300 mg/kg/day based on deaths, ( body wt, body wt
gain, food consumption, production and size of fecal pellets.

Developmental: 300 mg/kg/day based on deaths, ( body wt, body wt gain,
food consumption, production and size of fecal pellets( fetal weight, (
fetal runts, retarded ossification, 13 thoracic vertebrae and pairs of
ribs.

870.3800

Two-Generation Reproduction and Fertility Effects (rat)

	43301623 (1993)

acceptable/guideline

0, 32, 400,or 5000 ppm

0/0,1.9/2.2,23.1/27.4, 294/343 mg/kg/day [M/F]	NOAEL = Systemic: 23.1
[M] mg/kg/day, 27.4 mg/kg/day [F]

Repro: 294/343 mg/kg/day

Offspring: 23.1 mg/kg/day [M], 27.4 mg/kg/day [F]

LOAEL = Systemic: 294 mg/kg/day [M], 343 mg/kg/day [F] based on ( body
weight(11-13%), and body-weight gain (11-17%)

Repro: > 294/343 mg/kg/day

Offspring:  294 mg/kg/day based on ( pup body weights on PND 21.

870.4100b

Chronic Toxicity (dog)

	43345007

43301614 (1992)

acceptable/guideline

0, 2, 30, 400/250 mg/kg/day	NOAEL = 30mg/kg/day

LOAEL = 250 mg/kg/day based on ( body weight, food & water consumption,
food efficiency, (neutrophils, ( clotting time.

870.4200b

Carcinogenicity (mouse)

	43301615 (1992)

unacceptable/guideline

0, 16, 160, 1600 ppm

0/0, 2/2.5, 20/24.9, 210.9/253 mg/kg/day

[M/F]	NOAEL = 210.9 mg/kg/day [M],  253.8 mg/kg/day [F]

No toxicologically significant effects were found.

870.4300

Combined Chronic/Carcinogenicity (rat)

	43301612-3 (1993)/

acceptable/guideline

0, 32, 400, 5000 ppm

0/0, 1.3/1.8, 17/22, 221/291 mg/kg/day

[M/F]	NOAEL = 17 mg/kg/day [M], 22 mg/kg/day [F]

LOAEL = 221 mg/kg/day [M], 291 mg/kg/day [F] based on ( body-weight gain
(5-15% [M]; 15-45% [F])

[10-15%@ 6 mos],( serum cholesterol, GGT, rel. liver weights.; liver,
thyroid histopathology [( thyroid adenomas].

870.6200a

Acute-Neurotoxicity Screening Battery (rat)	45657221

45657220 (2001)

acceptable/guideline

0, 30, 100, 1000 mg/kg/day	NOAEL =  100  mg/kg/day [M], 100 mg/kg/day
[F]

LOAEL = 1000 mg/kg/day [M], 1000 mg/kg/day [F] based on ( motor
activity, ataxia, and (body temperature  in both sexes, ( hindlimb grip
strength in males, and ( dilated pupils in females on Day 1.

870.6200b

Subchronic-Neurotoxicity Screening Battery (rat)	45657222 (1998)
unacceptable/

guideline

0, 60, 600, 6000 ppm

0/0, 4/4.6, 38.7/44.3, 391.9/429.9 mg/kg/day [M/F]

NOAEL = 44.3 mg/kg/day [F]

LOAEL = 429.9 mg/kg/day [F],> 391.9 mg/kg/day [M] based on ( body wt
(8%), body wt gain (21%), food consumption (9-15%) [F].  No effects in
males.

870.5100

Gene Mutation	43301624 (1990);

0, 15, 50, 150, 500 or 1500 μg/plate in the presence and absence of
mammalian metabolic activation (S9-mix)

Acceptable/Guideline

There was no evidence  of induced mutant colonies over background.

870.5300

Gene Mutation	43301625 (1991);

0, 15, 50, 150, 500 or 1500 μg/plate in the presence and absence of
mammalian metabolic activation (S9-mix)

Acceptable/Guideline

There was no clear evidence of biologically significant induction of
mutant colonies over background.

870.5375

Chromosome aberration	43301627 (1990);

0, 7.8, 31.3, or 62.5 μg/mL without metabolic activation (S9-mix) and
to concentrations of 0, 31.3, 125 or 250, μg/mL with S9-mix.

Acceptable/Guideline

There was no evidence of chromosome aberrations induced over background.

870.5395

Mammalian erythrocyte micronucleus test in mice	43301626 (1991);

0, 225, 450 or 900 mg/kg body weight

Acceptable/Guideline

There was no statistically significant increase in the frequency of
micronucleated polychromatic erythrocytes in mouse bone marrow at any
dose or harvest time.

870.5550

Unscheduled DNA synthesis in mammalian culture	43301628 (1991)

0, 100, 300 or 1000 mg/kg body weight

Acceptable/Guideline

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Appendix B:  Metabolism Assessment

Table B.1.  Pyrimethanil Metabolites of Concern.

Common name/

Appendix C:  Tolerance Reassessment Summary and Table

Table C.1.  Tolerance Summary for Pyrimethanil.

Commodity	Proposed / Established Tolerance (ppm)	Recommended Tolerance
(ppm)	Comments; Correct Commodity Definition

40 CFR §180.518 (a)(1)

Stone Fruits (Crop Group 12) 	10	10	Fruit, stone, group 12

Citrus Fruits (Crop Group 10) 	10	11	Fruit, citrus, group 10

	Fruit, stone (except cherry), group 12	3.0	Remove

	Fruit, citrus, group 10 (postharvest)	10	Remove

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:

4,6-Dimethyl-N-phenyl-2-pyrimidinamine	Common Name:

Pyrimethanil

√ Proposed/Recommended Tolerance

( Reevaluated tolerance

( Other	Date:  01/13/2008

Codex Status (Maximum Residue Limits)	U. S. Tolerances

( No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#  8E7353

DP#:  361301

Other Identifier:

Residue definition (step 8/CXL): pyrimethanil for plant commodities.
For compliance with MRLs and estimation of dietary intake for plant
commodities: pyrimethanil

For compliance with MRLs for milk: the sum of pyrimethanil and
2-anilino-4,6-dimethylpyrimidin-5-ol, expressed as pyrimethanil, and for
livestock tissues (excluding poultry) is the sum of pyrimethanil and
2-(4-hydroxyanilino)-4,6-dimethylpyrimidine, expressed as pyrimethanil.

	Reviewer/Branch:  D. Rate/ARIA/RIMUERB

	Residue definition:

Plants  - Parent only

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

Citrus fruit (post harvest)	7	Citrus Fruit (Crop Group 10), 	11

Cherry (post harvest)	4	Stone Fruit (Crop Group 12) 	10

Apricot	3

Peach	4

Nectarine	4

Plum	2

Limits for Canada	Limits for Mexico

( No Limits

( No Limits for the crops requested	( No Limits

√ No Limits for the crops requested

Residue definition:

4,6-dimethyl-N-phenyl-2-pyrimidinamine

	Residue definition:  pyrimethanil

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

Calamondins, citrus citron, citrus

hybrids, grapefruits, kumquats,

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peaches, plumcots, plums, prune plums

	3

	Notes/Special Instructions:  Mexico defers to US tolerances.

S. Funk, 01/13/2009.

Appendix D:  Review of Human Research

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

Pyrimethanil	Human-Health Risk Assessment	DP# 353181

PC Code: 288201

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