Document ID: EPA-HQ-OPP-2008-0609-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-10-29T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

 

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 		07/17/2008

™ A for Postharvest Use on Pome Fruits by Thermafog Application. 
Human-Health Risk Assessment.

PC Code:	288201	DP No.:	352814

Decision No.:	382439	Registration No.:  	64864-xx

Petition No.:	7F7250	Regulatory Action:	Amended Section 3 

Risk Assessment Type: 	Single Chemical/

Aggregate Assessment	Case No.:	NA

TXR No.:	NA	CAS No.:	53112-28-0

MRID No.:	NA	40 CFR	§180.518

From:		William D. Wassell, Risk Assessor

  SEQ CHAPTER \h \r 1 George F. Kramer, Ph.D., Senior Chemist

Kelly M. Lowe, Environmental Scientist

William Greear, Ph.D., Toxicologist

Registration Action Branch (RAB1)

		Health Effects Division (HED) (7509P)

		P.V. Shah, Ph.D., Acting Branch Chief

		Inerts Assessment Branch/Registration Division (IAB/RD, 7505P)

Through:	Dana M. Vogel, Branch Chief

		RAB1/HED (7509P)

To:		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Tamue Gibson/Mary
Waller, Risk Manager 21

		RD (7505P)

Pace International LLC has submitted a Section 3 registration
application for Xedathane™ A (EPA File Symbol No. 64864-xx), an
aqueous suspension-concentrate (SC) formulation containing 16%
pyrimethanil as the active ingredient (ai).  Xedathane™ A is proposed
for postharvest use on pome fruits as an aerosol via thermal fogging to
control blue and gray mold.  The proposal to register Xedathane™ A
will supplement the available pyrimethanil end-use products (EPs)
currently registered for preharvest and postharvest uses on pome fruits.

Pyrimethanil tolerances are currently established in 40 CFR §180.518
and are expressed in terms of:  (i) parent only for plant commodities;
(ii) parent + metabolite AEC614276
(4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol) for ruminant tissues; and
(iii) parent + metabolite AEC614277
(4,6-dimethyl-2-(phenylamino)-5-pyrimidinol) for milk.

™ A on pome fruits, Pace International LLC, has proposed to amend 40
CFR §180.518 (a)(1) to increase the established tolerances for residues
of the fungicide 4,6-dimethyl-N-phenyl-2-pyrimidinamine, expressed as
pyrimethanil, in/on:

Pome Fruits (Crop Group 11)	from 3 ppm to 14.0 ppm

Pome Fruit – Wet Pomace	from 12 ppm to 56.0 ppm

The petitioner also proposes to amend 40 CFR §180.518 (a)(2) to
increase the tolerance for the combined residues of the fungicide
4,6-dimethyl-N-phenyl-2-pyrimidinamine, expressed as pyrimethanil, and
its metabolite 4-[4,6-dimethyl-2-pyrimidinyl) amino]phenol in:

Kidney of cattle, goat, horse, and sheep	from 0.30 ppm to 0.6 ppm

Finally, the petitioner proposes to amend 40 CFR §180.518 (a)(3) to
increase the tolerance for the combined residues of the fungicide
4,6-dimethyl-N-phenyl-2-pyrimidinamine, expressed as pyrimethanil, and
its metabolite 4,6-dimethyl-2-(phenylamino)-5-pyrimidinol in:

Milk	from 0.03 ppm to 0.06 ppm

HED of the Office of Pesticide Programs (OPP) is charged with estimating
the risk to human-health from exposure to pesticides.  The RD of OPP has
requested that HED evaluate hazard and exposure data and conduct
dietary, occupational, residential, and aggregate exposure assessments,
as needed, to estimate the risk to human-health that will result from
the proposed and registered uses of pyrimethanil.

A summary of the findings and an assessment of human-health risk
resulting from the proposed and registered uses of pyrimethanil are
provided in this document.  The hazard characterization was provided by
William Greear (RAB1) and P.V. Shah (IAB/RD); the residue chemistry
review by George F. Kramer (RAB1); dietary exposure assessment and
aggregate exposure and risk assessment were provided by William Wassell
(RAB1); the occupational/residential exposure assessment was provided by
Kelly M. Lowe (RAB1) and the drinking water assessment was provided by
Lucy Shanaman of the Environmental Fate and Effects Division (EFED). 

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc203988555"  1.0  Executive
Summary	  PAGEREF _Toc203988555 \h  4  

  HYPERLINK \l "_Toc203988557"  2.0  Ingredient Profile	  PAGEREF
_Toc203988557 \h  11  

  HYPERLINK \l "_Toc203988558"  2.1  Summary of Proposed Uses	  PAGEREF
_Toc203988558 \h  11  

  HYPERLINK \l "_Toc203988559"  2.2  Structure and Nomenclature	 
PAGEREF _Toc203988559 \h  13  

  HYPERLINK \l "_Toc203988560"  2.3  Physical and Chemical Properties	 
PAGEREF _Toc203988560 \h  13  

  HYPERLINK \l "_Toc203988561"  3.0  Hazard Characterization/Assessment	
 PAGEREF _Toc203988561 \h  13  

  HYPERLINK \l "_Toc203988562"  3.1  FQPA Considerations	  PAGEREF
_Toc203988562 \h  15  

  HYPERLINK \l "_Toc203988563"  3.1.1  Adequacy of the Toxicity Database
  PAGEREF _Toc203988563 \h  15  

  HYPERLINK \l "_Toc203988564"  3.1.2  Evidence of Neurotoxicity	 
PAGEREF _Toc203988564 \h  15  

  HYPERLINK \l "_Toc203988565"  3.1.3  Recommendation for a DNT Study	 
PAGEREF _Toc203988565 \h  16  

  HYPERLINK \l "_Toc203988566"  3.1.4  FQPA SF for Infants and Children	
 PAGEREF _Toc203988566 \h  16  

  HYPERLINK \l "_Toc203988567"  3.2  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc203988567 \h  17  

  HYPERLINK \l "_Toc203988568"  3.2.1  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc203988568 \h  19  

  HYPERLINK \l "_Toc203988569"  3.3  Endocrine Disruption	  PAGEREF
_Toc203988569 \h  19  

  HYPERLINK \l "_Toc203988570"  4.0  Dietary Exposure/Risk
Characterization	  PAGEREF _Toc203988570 \h  19  

  HYPERLINK \l "_Toc203988571"  4.1  Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc203988571 \h  19  

  HYPERLINK \l "_Toc203988572"  4.1.1  Metabolism in Primary Crops and
Livestock	  PAGEREF _Toc203988572 \h  19  

  HYPERLINK \l "_Toc203988573"  4.1.2 Metabolism in Rotational Crops	 
PAGEREF _Toc203988573 \h  20  

  HYPERLINK \l "_Toc203988574"  4.1.3  Analytical Methodology	  PAGEREF
_Toc203988574 \h  20  

  HYPERLINK \l "_Toc203988575"  4.1.4  Environmental Degradation	 
PAGEREF _Toc203988575 \h  21  

  HYPERLINK \l "_Toc203988576"  4.1.5  Food Residue Profile	  PAGEREF
_Toc203988576 \h  21  

  HYPERLINK \l "_Toc203988577"  4.1.6  International Residue Limits	 
PAGEREF _Toc203988577 \h  23  

  HYPERLINK \l "_Toc203988578"  4.1.7  Drinking Water Residue Profile	 
PAGEREF _Toc203988578 \h  24  

  HYPERLINK \l "_Toc203988579"  4.2  Dietary Exposure and Risk	  PAGEREF
_Toc203988579 \h  24  

  HYPERLINK \l "_Toc203988580"  4.2.1  Acute Dietary Exposure and Risk	 
PAGEREF _Toc203988580 \h  24  

  HYPERLINK \l "_Toc203988581"  4.2.2  Chronic (Cancer and Non-cancer)
Dietary Exposure and Risk	  PAGEREF _Toc203988581 \h  25  

  HYPERLINK \l "_Toc203988582"  5.0  Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc203988582 \h  26  

  HYPERLINK \l "_Toc203988583"  5.1  Other (Spray Drift)	  PAGEREF
_Toc203988583 \h  26  

  HYPERLINK \l "_Toc203988584"  6.0  Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc203988584 \h  26  

  HYPERLINK \l "_Toc203988585"  6.1  Acute Aggregate Risk	  PAGEREF
_Toc203988585 \h  26  

  HYPERLINK \l "_Toc203988586"  6.2  Short- and Intermediate-term
Aggregate Risk	  PAGEREF _Toc203988586 \h  27  

  HYPERLINK \l "_Toc203988587"  6.3  Long-term (Chronic) Aggregate Risk	
 PAGEREF _Toc203988587 \h  27  

  HYPERLINK \l "_Toc203988588"  6.4  Cancer Risk	  PAGEREF _Toc203988588
\h  27  

  HYPERLINK \l "_Toc203988589"  7.0  Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc203988589 \h  27  

  HYPERLINK \l "_Toc203988590"  8.0  Occupational Exposure/Risk Pathway	
 PAGEREF _Toc203988590 \h  28  

  HYPERLINK \l "_Toc203988591"  8.1  Short-/Intermediate-Term Handler
Risk	  PAGEREF _Toc203988591 \h  28  

  HYPERLINK \l "_Toc203988592"  8.2  Short-/Intermediate-Term
Post-application Risk	  PAGEREF _Toc203988592 \h  30  

  HYPERLINK \l "_Toc203988593"  9.0  Data Needs and Label Requirements	 
PAGEREF _Toc203988593 \h  30  

  HYPERLINK \l "_Toc203988594"  9.1  Toxicology	  PAGEREF _Toc203988594
\h  30  

  HYPERLINK \l "_Toc203988595"  9.2  Residue Chemistry	  PAGEREF
_Toc203988595 \h  30  

  HYPERLINK \l "_Toc203988596"  9.3  Occupational and Residential
Exposure	  PAGEREF _Toc203988596 \h  31  

 

1.0  Executive Summary

References:

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

Memo, 7/17/2008, G. Kramer, DP#s 347247 & 347248.

Memo, 06/03/2008, W.D. Wassell, DP# 352813.

Memo, 6/13/08, K.M. Lowe, DP No. 342695.

Background

  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 to certain plant
pathogenic fungi controlled by other anilinopyridine compounds such as
cyprodinil and mepanipyrim.

Pyrimethanil is formulated as a soluble-concentrate (SC) formulation
containing 16% pyrimethanil as the active ingredient (ai).  Tolerances
are established in 40 CFR §180.518 for residues of pyrimethanil in/on
various plant and livestock commodities.  Specifically, tolerances are
established [40 CFR §180.518(a)(1)] for residues of pyrimethanil in/on
various plant commodities at levels ranging from 0.05 to 150 ppm. 
Additionally, tolerances are established [40 CFR §180.518(a)(2)] for
residues of pyrimethanil and its metabolite
4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol in/on various livestock
tissues ranging from 0.01 to 0.30 ppm and for residues of pyrimethanil
and its metabolite 4,6-dimethyl-2-(phenylamino)-5-pyrimidinol in/on milk
at 0.03 ppm.

Hazard Assessment

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.

When pyrimethanil was orally administered to rats, 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.

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 was 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.  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.

No signs of neurotoxicity were evident at doses up to 392 mg/kg/day in
the subchronic neurotoxicity study in rats.  No evidence of
neuropathology was seen in neurotoxicity studies, subchronic or chronic
studies in mice, rats, and dogs.

In a carcinogenicity study in mice, there was no increase in the
incidence of any tumor types in either sex.  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
Carcinogenicity Peer Review Committee (CPRC; HED Doc. 0050189)
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.

When pyrimethanil was orally administered to rats, 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.

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 database uncertainty factor 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 cRfD would be
protective of any potential immunotoxicity seen at a dose level of 529
mg/kg/day.

Dietary Exposure Assessment

Acute and chronic dietary exposure and risk assessments were conducted
using the Dietary Exposure Evaluation Model-Food Commodity Intake
Database (DEEM-FCID™, Version 2.03) which uses food consumption data
from the U.S. Department of Agriculture’s (USDA) Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.    SEQ
CHAPTER \h \r 1 

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
lowest-observable-adverse-effect-level (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 Food Quality
Protection Act safety factor (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 population including
infants and children, the aPAD for pyrimethanil is equal to 0.10
mg/kg/day.

The acute dietary analyses assumed DEEM( (ver. 7.81) default processing
factors (as necessary), empirical processing factors for orange and
apple juice, tolerance-level residues, and 100% crop-treated (CT) for
all commodities.  

EFED provided Tier 1 estimated drinking water concentrations (EDWCs) for
ground water (using the Screening Concentration In Ground Water model or
SCI-GROW), and Tier 2 EDWCs for surface water (using the Pesticide Root
Zone Model/Exposure Analysis Modeling System or PRZM/EXAMS) for
pyrimethanil and its major metabolite (2-amino-4,6-dimethylpyrimidine),
for use in the human-health risk assessment.  Maximum EDWCs were
estimated as 4.8 ppb in ground water and 37.8 ppb in surface water.  The
annual-average surface water concentration (5.1 ppb) and the acute peak
surface water concentrations (37.8 ppb) were used for acute and chronic
dietary exposure assessments, respectively.

The acute dietary exposure estimates for food and drinking water are not
of concern to HED (<100% aPAD) at the 95th percentile of exposure. 
Pyrimethanil dietary exposure at the 95th percentile for food and
drinking water is 9.1% of the aPAD for the U.S. population and 33% of
the aPAD for all infants (<1 year old), the most highly-exposed
population subgroup.

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 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) 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, and 100% CT for all
commodities.  The resulting chronic exposure estimates are not of
concern to HED (<100% cPAD) for U.S. general population (12% cPAD) and
all population subgroups; the most highly exposed population subgroup is
children 1-2 years old with 59% 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
(no-observable-adverse-effect-level (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 No. 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).

A separate cancer dietary assessment was not conducted for pyrimethanil
as the chronic assessment is considered protective for carcinogenic
effects.  The MOE for cancer assessment is 830 which is not of concern
to HED (MOE >100).

Residential Exposure and Risk

There are no products containing pyrimethanil proposed or registered
that would result in residential exposure.  Therefore, a residential
exposure assessment was not performed.

Short- and Intermediate-term Endpoints

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.

Occupational Handler Risk

Based on the proposed use, exposure is possible for individuals that
handle the end-use products (EPs), and for individuals that may enter
the treatment area (in this case, a storage room).  The proposed use is
a very specific use pattern (involving a Xeda brand thermal
electrofogger).  Data for this specific exposure scenario are not
available to HED. Therefore, surrogate data from the Pesticide Handlers
Exposure Database (PHED, Version 1.1) were used.  HED conducted a
conservative assessment of short-term risks to handlers. 
Post-application exposure was not assessed as it is expected to be
negligible due to personal-protective equipment (PPE) required on
Xedathane A labels.

A thermal electrofogger is an automatic fogging machine which is located
outside the area where the pears are stored and treatment occurs.  The
fog, which contains pyrimethanil, is piped into the storage room, which
is typically sealed tightly for climate control.  The material is
transferred from the product container into the fogging machine by pipe.
 The machine then slowly draws the solution out of the tank, heats it up
to convert it to fog, and sends the fog into the storage room through a
pipe.  The fog is not released in the presence of the handler. 
Therefore, the only significant source of exposure is during the pouring
of the end-use product into the fogging machine tank.  This exposure was
assessed as a mixer/loader scenario using PHED Version 1.1 (open
mixing/loading of liquids).  

A separate applicator assessment was not conducted.    SEQ CHAPTER \h \r
1 Since the application of pyrimethanil is mechanically automated for
the thermal fogging machine, the applicator in this case is the same as
the mixer/loader.  A mixer/loader assessment was performed and is
considered to result in a conservative estimate of worker risk.  The
combined MOE for dermal and inhalation exposure (4,800) is not of
concern, if workers wear gloves as directed on the label.  	

Occupational Post-Application Risk

Early re-entry into a treated area typically refers to entering a
treated area before the specified re-entry interval (REI).  In such
conditions, scouts or workers may be required to use PPE to limit dermal
and inhalation exposure.  The proposed Xedathane A label requires that
no entry into the treated room be allowed for 8 hours if there is no
ventilation followed by one hour of mechanical ventilation or 24 hours
with no ventilation.  

 

According to a previous review for this type of use (Ethoxyquin. 
Occupational Risk Assessment for Proposed Uses on Stored Pears [D342695;
4-1-2008]), the registrant has indicated that due to the atmospheric
conditions under which the storage rooms are maintained (low levels of
oxygen [1 to 3%] and temperature ranging from 32 to 36oF), anyone who
enters the storage rooms must do so wearing full self-contained
breathing apparatus (SCBA) gear.  Therefore, the more acute danger to
early re-entry workers is lack of oxygen.  Use of SCBA gear will
mitigate these concerns and provide adequate protection from inhalation
exposure.  Since Xedathane A labels require the use of SCBA for early
entry into storage rooms before the required ventilation times, a
quantitative inhalation risk assessment is not needed for early re-entry
workers.  Furthermore, since early re-entry workers are in the storage
room for such a very short period of time to collect residue samples,
dermal exposure is expected to be negligible and a dermal exposure
assessment for early re-entry is not required.

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

Review of Human Research:  This risk assessment relies in part on data
from PHED studies in which adult human subjects were intentionally
exposed to a pesticide or other chemical.  These studies have been
determined to require a review of their ethical conduct, and have
received that review.

HED Recommendations

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

Pending submission of a revised 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.  

Table 1.0.  Tolerance Summary for Pyrimethanil.

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments; Correct Commodity Definition

40 CFR §180.518 (a)(1)

(for residues of pyrimethanil)

Pome Fruits (Crop Group 11) 	14.0	14	Fruit, pome, group 11

Pome Fruit – Wet Pomace	56.0	40	The recommended tolerance will be
identical to the Codex MRL for dry pomace.

Apple, wet pomace

40 CFR §180.518 (a)(2)

(for residues of pyrimethanil and its metabolite
4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol)

Kidney of cattle, goat, horse, and sheep	0.6	2.5	Cattle, kidney

Goat, kidney,

Horse, kidney,

Sheep, kidney

40 CFR §180.518 (a)(3)

(for residues of pyrimethanil and its metabolite
4,6-dimethyl-2-(phenylamino)-5-pyrimidinol)

Milk	0.06	0.05

	

For an unconditional registration, the petitioner is instructed to
resolve all deficiencies associated with the analytical method (see
requirements under Residue Analytical Methods) and toxicological
requirements (see Toxicology)

Note to RD:  The tolerance expression listed in 40 CFR 180.518 (a)(2)
should be revised to correct the metabolite name.  The expression in
180.518 (a)(2) should be revised to:  “the combined residues of the
fungicide pyrimethanil [4,6-dimethyl-N-phenyl-2-pyrimidinamine] and its
metabolite 4-[4,6-dimethyl-2-(pyrimidinyl) amino]phenol.”

Residue Chemistry Requirements:

Directions for Use

Label revision is required to clearly specify that Xedathane™ A may
only be applied once for postharvest use by electrofog machine on pome
fruits and to prohibit application to fruit that has been previously
treated with pyrimethanil via drench or dip/wash application.

Residue Analytical Methods

The Analytical Chemistry Branch of the Biological and Economic Analysis
Division (ACB/BEAD does not currently have the gas chromatography/mass
spectroscopy (GC/MS)/MS ion-trap instrument necessary to validate the
proposed enforcement method for livestock.  Since GC ion-trap MS/MS has
not been demonstrated to be a robust quantitative instrument, ACB/BEAD
is now recommending that the petitioner revise the method to use liquid
chromatography- (LC) MS/MS for pyrimethanil and its metabolites (E-mail
from C. Stafford of ACB/BEAD, 4/23/08).  If Bayer can provide adequate
recovery data using an LC-MS/MS method in livestock commodities, then an
independent laboratory validation (ILV) will not be required.

  SEQ CHAPTER \h \r 1 Submittal of Analytical Reference Standards

Analytical reference standards of the regulated metabolites
4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol (AEC614276) and
4,6-dimethyl-2-(phenylamino)-5-pyrimidinol (AEC614277) should be
supplied and supplies replenished as requested by the Repository.  The
reference standards should be sent to the Analytical Chemistry Lab,
which is located at Fort Meade, to the attention of either Theresa Cole
or Thuy Nguyen at the following address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

Proposed Tolerances

A summary of the recommended tolerances along with recommendations for
commodity definitions are presented in Table 1.0.  The petitioner is
required to submit a revised Section F to reflect the recommendations in
Table 1.0.

Toxicology Data Requirements: 

Mouse carcinogenicity study was requested by the DART (HED Doc. 0050408)
because the high dose in the existing study was judged to be inadequate
for assessing the carcinogenic potential of pyrimethanil.

90-day inhalation study to address concerns for exposure associated with
greenhouse use.

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

2.0  Ingredient Profile

2.1  Summary of Proposed Uses

™ A (EPA File Symbol No. 64864-xx) for postharvest use on pome fruits.
 The product is applied undiluted through a thermal electrofogger.

HED notes that the proposed label for Xedathane™ A states on the front
page of the label that the product is a special liquid form of
pyrimethanil intended for use with a Xeda Brand Thermal Electrofogger to
form a fine fog.  Under Section A of the petition, the end-use product
(EP) composition is identified as an aqueous SC fungicide formulation
containing 16% pyrimethanil.  

™ A (EPA File Symbol No. 64864-xx) on pome fruits are presented in
Table 2.1.

The paragraphs below list the registered pyrimethanil EPs and briefly
describe the use patterns which are currently registered for use on pome
fruits.

™ contains 37.4% pyrimethanil (3.34 pounds (lb) ai per gallon (gal));
however, an updated specimen label Scala™ specifies that it now
contains 54.6% pyrimethanil (5.0 lb ai/gal).  Scala™ is registered for
multiple foliar spray treatments of pome fruits for the control of scab
(Venturia spp.) using ground or aerial equipment at a maximum rate of
0.39 lb ai per acre (A) per application with a 7-day retreatment
interval (RTI).  The maximum seasonal rate is 1.6 lb ai/A, and the
established preharvest interval (PHI) is 72 days.

™ 400 SC Fungicide (PH066 SC) (EPA Reg. No. 43813-32) is a SC
formulation registered to Jannsen Pharmaceutica for postharvest uses on
pome fruits to control gray mold and blue mold.  Penbotec™ contains
37.14% pyrimethanil (3.27 lb ai/gal).  The registered postharvest
application methods (and maximum rates in parentheses) include dip/wash
tanks (1,000 ppm), drenchers (1,000 ppm), and line spray (aqueous and
wax, 2,000 ppm).

Table 2.1.  Summary of 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

Pome Fruits

Postharvest

Electrofog

Machine	SC1

[64864-xx]	9.6 g ai/metric ton of fruit (or 0.3 oz ai/US ton)	Not
applicable (NA)	NA	NA	Do not apply this product in a way that will
contact workers or other persons, either directly or through drift. 
Only protected handlers may be in the area during application.  Do not
apply this product on fruit that has been previously treated with
pyrimethanil via drench application.

	Recommendations

™ A by adding a tonnage value of 20% of the empty volume to the real
tonnage of the fruit.

Electrofogger Operation

Place the Electrofog machine horizontally outside the treatment room at
a height of about 3 feet from the floor.  Cover the door or window to
the treatment room with a plastic sheet and insert the fogging pipe
through a hole in the plastic.  Place a bucket under the nozzle to catch
any drops.  Seal the opening around the nozzle so no fog can escape
during treatment.  Set the Electrofog machine resistance temperature
between 500° to 600°C.  Insert input pipe into product container and
start pump.  Stop pump when product reaches the pump body.  Start fan
and resistance, and start pump again when fog exit temperature reaches
180° C.  Adjust pump as necessary during operation to maintain 180°C.

Application Procedures

Avoid breathing the fog.  Turn off cooling systems and humidifiers 12
hours prior to and during treatment.  Turn off circulation fans
immediately prior to and during treatment.  Allow fog to stay overnight
or until the fog has totally disappeared (about 5 hours posttreatment)
before restarting fans and cooling systems.  Do not rinse apples after
treatment.

Re-Entry

Entry into the treatment area by any person other than properly trained
and equipped handlers is prohibited from the start of the application
until the treated area is ventilated as follows:  8 hours with no
ventilation followed by 1 hour of mechanical ventilation; or 24 hours
with no ventilation.  In case it is necessary to enter during treatment
or before ventilation requirements have been met, handlers must wear
chemical-resistant headgear and a self contained breathing apparatus.

1  SC = suspension-concentrate formulation; product is applied
undiluted.

Conclusions.  The proposed use directions are adequate to allow
evaluation of the residue data relative to the proposed postharvest use
by electrofog machine of pyrimethanil.  However, HED recommends label
revisions to clearly specify that Xedathane™ A may only be applied
once for postharvest use by electrofog machine on pome fruits and to
prohibit application to fruit that has been previously treated with
pyrimethanil via drench or dip/wash application (the tolerance is based
on preharvest + postharvest by line spray aqueous and wax + postharvest
by thermal fogging).

2.2  Structure and Nomenclature

Table 2.2.  Test Compound Nomenclature.

Compound	

Common name	Pyrimethanil

Company experimental names	Janssen:  R215559; PH0666

Aventis:  SN 100309; ZK 100309; AE B100309

IUPAC name	2-Anilino-4,6-dimethylpyrimidine

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

CAS registry number	53112-28-0

End-use product (EP)	Xedathane A (EPA File Symbol No. 64864-xx), an
aqueous SC formulation containing 16% pyrimethanil

2.3  Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of Pyrimethanil.

Parameter	Value	Reference

Melting point	~95 oC	43301601

pH	Data unavailable.

	Density	Bulk density = 650-700 Kg/m3	43301601

Water solubility (25 (C)	0.121 g/L (pH 6.1)	44908503

Solvent solubility (g/L at 20 (C)	Dichloromethane:	1000.2

Ethyl acetate:	616.9

Acetone:	388.8

n-Hexane:	23.7	44908503

Vapor pressure at 25 (C	2.2 x 10-3 Pa	44908503

Dissociation constant (pKa)	pKa = 3.52 ± 0.02	43301601

Octanol/water partition coefficient Log(KOW)	2.48
http://www.hb-p.com/pyrimethanil.htm

UV/visible absorption spectrum	Data unavailable.

	

3.0  Hazard Characterization/Assessment

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, 4/24/03.

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 was 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 (HED Doc. TXR No. 0052257) 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 (HED Doc. 0050408)
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 (HED Doc. 0050189) 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.

When pyrimethanil was orally administered to rats, 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.

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 database uncertainty factor 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 cRfD would be
protective of any potential immunotoxicity seen at a dose level of 529
mg/kg/day.

Table 3.1.  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

	

3.1  	FQPA Considerations

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:  

A mouse carcinogenicity study is requested by the DART (HED Doc.
0050408) because the high dose in the existing study was judged to be
inadequate for assessing the carcinogenic potential of pyrimethanil.

A 90-day inhalation study is requested to address concerns for exposure
associated with greenhouse use.

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

3.1.2  Evidence of Neurotoxicity

The HIARC (HED Doc. TXR No. 0052257) 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).
 

3.1.2.1  Determination of Susceptibility

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.

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 were no effects on fertility or reproduction in the
two-generation reproduction study in rats.

3.1.2.2  Degree of Concern Analysis

There are no concerns or residual uncertainties for pre- and/or
post-natal 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 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.

3.1.4  FQPA SF for Infants and Children

On April 23, 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-/post-natal
toxicity.  No additional SFs are needed for database uncertainties. 
Based on the HIARC conclusions and the pyrimethanil risk assessment
team’s evaluation of the hazard and exposure data, the FQPA SF can be
reduced to 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
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.

3.2  Hazard Identification and Toxicity Endpoint Selection

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
3.2.a and 3.2.b.

Table 3.2.a  Summary of Toxicological Doses and Endpoints for
Pyrimethanil for Use in Dietary and Non-Occupational Human-Health Risk
Assessments.

Exposure

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

Acute Dietary

(Females 13-50 yrs)	NOAEL = 45 mg/kg/day

UF = 100

Acute RfD = 0.45 mg/kg/day	FQPA SF = 1

aPAD = acute RfD

= 0.45 mg/kg	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

UF = 100

Acute RfD =    1 mg/kg/day

	FQPA SF = 1

aPAD = acute RfD

= 1 mg/kg	Acute Neurotoxicity- Rat

LOAEL = 1000 mg/kg 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

UF = 100

Chronic RfD =

0.17 mg/kg/day

	FQPA SF = 1

cPAD =

chronic RfD

= 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, and
thyroid follicular cell tumors in both sexes.

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; 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);
acceptable MOE was not defined by the HIARC or CPRC.  However, for
threshold cancer effects where the mode of action is well understood,
like thyroid carcinogens such as pyrimethanil, the margin of exposure
that indicates a reasonable certainty of no harm would be 100
(representing 2 factors of 10 for inter-species and intra-species
extrapolation).  

Table 3.2.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 decreased mean body weights and
body-weight gains in the reproduction study.

Intermediate-Term

Dermal (1 to 6 months)	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 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 = 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. 

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.  The CPRC recommended that the
NOAEL of 17 mg/kg/day be used to calculate the MOE for cancer risk (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. 
FQPA SF = FQPA safety factor.  MOE = margin of exposure.  LOC = level of
concern.

3.2.1	  Recommendation for Aggregate Exposure Risk Assessments

The toxicity endpoints selected for the following routes of exposure may
be aggregated as follows:  for short-, and intermediate-term aggregate
exposure risk assessments, the dermal and inhalation routes can be
combined because of the endpoints came from the same study (Reproductive
Toxicity – Rat).

3.3  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
recommendations of its Endocrine Disruptor 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
the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and, to
the extent that effects in wildlife may help determine whether a
substance may have an effect in humans, FFDCA authority to require the
wildlife evaluations.  As the science develops and resources allow,
screening of additional hormone systems may be added to the Endocrine
Disruptor Screening Program (EDSP).  Pyrimethanil database did not
indicate any endocrine mediated effects.  When additional appropriate
screening and/or testing protocols being considered under the Agency’s
EDSP have been developed, pyrimethanil may be subjected to further
screening and/or testing to better characterize effects related to
endocrine disruption.  

4.0  Dietary Exposure/Risk Characterization

4.1  Pesticide Metabolism and Environmental Degradation

References:

Memo, 01/12/2004, J. Morales and G. Kramer, DP#s 284001 & 284870.

Memo, 07/17/2008, G. Kramer, DP#s 347247 & 347248.

4.1.1  Metabolism in Primary Crops and Livestock

4.1.1.1  Metabolism in Primary Crops

  SEQ CHAPTER \h \r 1 

  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 Metabolism
Assessment Review Committee (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.

  SEQ CHAPTER \h \r 1 

4.1.1.2  Metabolism in Livestock

  SEQ CHAPTER \h \r 1 A ruminant metabolism study indicated that the
major residue is AEC614276, which accounted for 46% of total radioactive
residues (TRR) in kidney and 64% TRR in milk.  Metabolite AEC614277 is a
minor metabolite and accounted for 5% of TRR in kidney.  However, in the
feeding study, AEC614277 was found only in milk and AEC614276 was
quantifiable only in some tissues.  Based on the results of the
metabolism study and feeding study, and the fact that both AEC614276 and
AEC614277 are likely to share the same toxicity as the parent (from
structure similarity), MARC concluded that for risk assessment and the
tolerance expression, parent, AEC614276 (tissues only), and AEC614277
(milk only) are the residues of concern.  Analytical methods are
available to detect these metabolites.

A poultry metabolism study is not required as there are no poultry
feedstuffs associated with the proposed use on pome fruits.    SEQ
CHAPTER \h \r 1 Table 4 is a summary of the HED MARC decisions
concerning the residues of concern in plants, ruminants, and milk for
tolerance expression and risk assessment purposes.

Table 4.1.1.  Residues of Concern in Plants and Ruminants.

Matrix	For Risk Assessment	For Tolerance Expression

Plants	Parent Only	Parent Only

Ruminant	Parent + AEC614276	Parent + AEC614276

Milk	Parent + AEC614277	Parent + AEC614277

4.1.2  Metabolism in Rotational Crops

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

4.1.3  Analytical Methodology

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, 7/7/2004, E. Kolbe).  This method is
adequate for enforcement of the proposed tolerances.

The livestock analytical method determines pyrimethanil and AEC614276 in
tissues and AEC614277 in milk.  Following methylation, samples are
analyzed by GC/MS/MS.  The LOQ for each analyte has been set at 0.01 ppm
in milk and 0.05 ppm in livestock tissues. The ILV of this method was
deemed adequate, and the method was subsequently forwarded to ACB/BEAD
for a PMV (DP# 288255, 3/10/2003, G. Kramer).    SEQ CHAPTER \h \r 1
ACB/BEAD concluded that the analytical method only marginally meets the
applicable guideline requirements to enforce livestock tolerances and
recommended that further laboratory validation of this method was
necessary before permanent tolerances were granted (DP# 288256,
7/7/2004, E. Kolbe).  Since GC ion-trap MS/MS has not panned out as a
robust quantitative instrument, ACB/BEAD is now recommending that the
petitioner revise the method to use LC-MS/MS for pyrimethanil and its
metabolites (E-mail from C. Stafford of ACB/BEAD, 4/23/08).  If Bayer
can provide adequate recovery data using an LC-MS/MS method in livestock
commodities, then an ILV will not be required.

4.1.4  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.

4.1.5  Food Residue Profile

Apple:  Adequate postharvest data, reflecting the proposed thermal
fogging of fruits according to label directions, were submitted for
apples and pears, the representative crops of fruit, pome, group 11. 
These data indicate that following one postharvest treatment via thermal
fogging of pome fruits using an SC formulation at 0.32-0.38 oz ai/ton
(1.0-1.3x the proposed rate), maximum residues of pyrimethanil were 4.1
ppm in/on pears and 9.47 ppm in/on apples.  The available data suggest
that the proposed crop group tolerance of 14 ppm for pome fruits will
not be exceeded when maximum residues from all routes of pyrimethanil
exposure to pome fruits are considered (preharvest + postharvest by line
spray aqueous and wax + postharvest by thermal fogging).  Maximum
residues following preharvest treatment at 1.59-1.62 lb ai/A (1.0x) and
PHIs of 71-73 days were 0.16 ppm for apples and <0.05 ppm for pears
(DP#s 284001 & 284870, 01/12/2004, J. Morales and G. Kramer).  Maximum
residues following postharvest treatment by line spray aqueous and wax
at 1x were 2.84 ppm.

In a study reported in MRID 47203201, unwashed and freshly harvested
pear fruits were transported to a treatment facility and treated with
pyrimethanil.  For dip treatment, the 10% EC formulation was applied by
dipping fruits into pyrimethanil solutions of 139-322 ppm for 30
seconds.  For electrofog treatment, the 10% SC formulation was applied
at a rate of 0.32 oz ai/ton (~1.0x the maximum proposed rate for thermal
fogging).  The treated fruits were allowed to surface dry prior to
sample collection.  Table 4.1.5a summarizes the results of a postharvest
field test using electrofog treatment.  

Table 4.1.5a.  Summary of Residue Data from Postharvest Trials with
Pyrimethanil (MRID 47271201).

Commodity	Method of Applic.	Total Applic. Rate

(oz ai/ton)	Pyrimethanil Residue Levels (ppm)

	N	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Pome Fruits (proposed use = 0.3 oz ai/ton total application rate)

Pears	Postharvest electrofog	0.32	2	2.92	4.1	NA1	3.51	3.51	--

Apples

(sampled on the same day of treatment)	Postharvest electrofog	0.17	4
1.69	6.2	NA	4.02	3.98	1.94

0.28	4	4.28	8.62	NA	5.21	5.83	1.96

0.38	4	4.92	7.94	NA	5.22	5.83	1.43

Apples

(sampled after 7 months of treatment and storage)	Postharvest electrofog
0.17	4	1.65	6.81	NA	4.50	4.36	2.13

0.28	4	5.46	8.68	NA	5.60	6.33	1.57

0.38	4	5.43	9.47	NA	6.61	7.03	1.72

1  HAFT = Highest-Average Field Trial; NA = Not applicable to this
submission.

A small-scale study (MRID 47226701) was conducted in WA State in 2007 at
a simulated commercial pome fruit cold-storage facility.  Pyrimethanil
was applied to Red Delicious apples inside storage bins using an
electric thermal fogger at a rate of 0.30 oz ai/ton (1.0x).  Fruits
samples were randomly collected from the treated crates on the day of
application.  Maximum residues of pyrimethanil in/on treated apples were
0.882 ppm.

Another postharvest study (MRID 47201502) on apples was conducted in
France in 2007. Pyrimethanil was applied as a thermal fog to crated
Jonagold apples inside storage bins at a rate of 0.28 oz ai/ton (~0.9x).
 Fruit samples were collected on the day of application, and samples
were collected according to an established pattern to investigate the
relation of pyrimethanil residues to sample position within the
treatment cell.  Maximum residues of pyrimethanil in/on treated apples
were 2.33 ppm; see Table 4.1.5b.  Higher residues were observed in/on
samples collected from the tops of the palloxes than those collected
from the bottoms.  Residues were also higher in/on samples collected
from the back of the treatment cell (farther from the thermofogger) than
those samples collected from the front of the cell.

Table 4.1.5b.  Summary of Residue Data from Postharvest Trials with
Pyrimethanil (MRID 47201502).

Commodity	Method of Applic.	Total Applic. Rate (oz ai/ton)	Pyrimethanil
Residue Levels (ppm)

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Pome Fruits (proposed use = 0.3 oz ai/ton total application rate)

Apple, fruit	Postharvest electrofog	0.28-0.30	20	0.25	2.33	NA1	1.06	1.12
0.26

1  HAFT = Highest-Average Field Trial.  NA = Not applicable to this
submission.

Livestock:  The only livestock feedstuff associated with the proposed
use in this petition is wet apple pomace.  For the estimation of dietary
burdens of pyrimethanil to beef and dairy cattle, only wet apple pomace
was used in the calculation since it is very unlikely that more than one
minor feed item (i.e., apple pomace, dried citrus pulp, and almond
hulls) will be used at this time. The dietary burden to beef and dairy
cattle was estimated to be 1.1 mg/kg and 10 mg/kg, respectively.  There
are no poultry and swine feedstuffs associated with the proposed uses.

Based upon the evaluation of the submitted ruminant feeding study, only
the tolerances for residues in milk and kidney will be affected as all
other ruminant commodity tolerances are set at the LOQ of the
enforcement method (no residues of concern were identified in these
tissues in the ruminant metabolism and feeding studies). Based on the
dietary exposure levels and the residue data from an available ruminant
feeding study, the existing pyrimethanil tolerances have been
reassessed.  The appropriate tolerances are:

for the combined residues of pyrimethanil and AEC614276
(4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol) in:

Sheep, kidney; Goat, kidney; Horse, kidney; Cattle, kidney	2.5 ppm

and for the combined residues of pyrimethanil and AEC614277
(4,6-dimethyl-2-(phenylamino)-5-pyrimidinol) in: 

Milk	0.05 ppm

The petitioner is required to submit a revised Section F.

  SEQ CHAPTER \h \r 1 4.1.5.1  Tolerance Summary

The pyrimethanil tolerances proposed by the registrant in the subject
petition are listed below in Table 4.1.5.1, along with HED’s
recommended tolerance levels.   SEQ CHAPTER \h \r 1  

Table 4.1.5.1.  Tolerance Summary for Pyrimethanil in/on Pome Fruit and
Livestock Commodities.

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments; Correct Commodity Definition

40 CFR §180.518 (a)(1)

Pome Fruits (Crop Group 11) 	14.0	14	Fruit, pome, group 11

Pome Fruit – Wet Pomace	56.0	40	The recommended tolerance will be
identical to the Codex MRL for dry pomace.

Apple, wet pomace

40 CFR §180.518 (a)(2)

Kidney of cattle, goat, horse, and sheep	0.6	2.5	Cattle, kidney

Goat, kidney,

Horse, kidney,

Sheep, kidney

40 CFR §180.518 (a)(3)

Milk	0.06	0.05

	

4.1.6  International Residue Limits

Codex maximum residue limits (MRLs; step 8/CXL) have been established
for pyrimethanil per se in/on plant commodities.  Codex MRLs have also
been established for milk in terms of the sum of pyrimethanil and
2-anilino-4,6-dimethylpyrimidin-5-ol, expressed as pyrimethanil, and for
livestock tissues (excluding poultry) as the sum of pyrimethanil and
2-(4-hydroxyanilino)-4,6-dimethylpyrimidine, expressed as pyrimethanil. 
Codex MRLs are listed for pome fruit at 7 ppm (postharvest), milk at
0.05 ppm, dry apple pomace at 40 ppm, and edible offal at 0.1 ppm. 
Except for apple pomace and milk, harmonization is not feasible at this
time, presumably due to differences in good agricultural practices.

A Canadian MRL for pome fruit is established at 3 ppm.  There are no
Mexican MRLs established for residues of pyrimethanil in commodities
associated with this review.  

4.1.7  Drinking Water Residue Profile

Drinking Water Estimates

EFED provided Tier 1 EDWCs for ground water (using SCI-GROW), and Tier 2
EDWCs for surface water (using PRZM/EXAMS) for pyrimethanil and its
major metabolite (2-amino-4,6-dimethylpyrimidine), for use in the
human-health risk assessment.

Table 4.1.7.  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.

4.2  Dietary Exposure and Risk

References:

Memo, 06/03/2008, W.D. Wassell, DP# 352813.

Aggregate (food + water) acute and chronic dietary exposure and risk
assessments were conducted using the DEEM-FCID(, ver. 2.03 model.  This
model uses food consumption data from the USDA’s CSFII; 1994-1996 and
1998.  

4.2.1  Acute Dietary Exposure and Risk

The acute analyses assumed DEEM( (ver. 7.81) default processing factors
(as necessary), empirical processing factors for orange and apple juice,
tolerance-level residues, and 100% CT for all commodities.  The EDWC of
37.8 ppb was used to account for exposure from residues in water.

The acute dietary exposure estimates for food and drinking water are not
of concern to HED (<100% aPAD) at the 95th percentile of exposure. 
Pyrimethanil dietary exposure at the 95th percentile for food and
drinking water is 9.1% of the aPAD for the U.S. population and 33% of
the aPAD for all infants (<1 year old), the most highly-exposed
population subgroup.  The results of the analysis are summarized in
Table 4.2.1.

Table 4.2.1.  Results of Pyrimethanil Acute Dietary (Food + Drinking
Water) Exposure Analysis Using DEEM( FCID.

Population Subgroup	aPAD (mg/kg/day)	95th Percentile

Exposure (mg/kg/day)	% aPAD

General U.S. Population	1.0	0.090506	9.1

All Infants (< 1 year old)	1.0	0.328721	33

Children 1-2 years old	1.0	0.321734	32

Children 3-5 years old	1.0	0.235579	24

Children 6-12 years old	1.0	0.120736	12

Youth 13-19 years old	1.0	0.056963	5.7

Adults 20-49 years old	1.0	0.048778	4.9

Adults 50+ years old	1.0	0.058329	5.8

Females 13-49 years old	0.45	0.053689	12



4.2.2  Chronic (Cancer and Non-cancer) Dietary Exposure and Risk

The chronic analyses assumed DEEM( (ver. 7.81) default processing
factors (as necessary), empirical processing factors for orange and
apple juice, tolerance-level residues, and 100% CT for all commodities. 
The EDWC of 5.1 ppb was used to account for exposure from residues in
water.  The results of the analysis are summarized in Table 4.2.2. 

The resulting chronic food exposure estimates are not of concern to HED
(<100% cPAD) for U.S. general population (12% cPAD) and all population
subgroups; the most highly exposed population subgroup is children 1-2
years old with 59% cPAD.  A separate cancer dietary assessment was not
conducted for pyrimethanil as the chronic assessment is considered
protective for carcinogenic effects.  The MOE for cancer assessment is
830 which is not of concern to HED (MOE >100).

Table 4.2.2.  Results of Pyrimethanil Chronic Dietary (Food + Drinking
Water) Exposure Analysis Using DEEM( FCID.

Population Subgroup	Chronic Dietary

	Dietary Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.020568	12

All Infants (< 1 year old)	0.080562	47

Children 1-2 years old	0.100505	59

Children 3-5 years old	0.069538	41

Children 6-12 years old	0.030853	18

Youth 13-19 years old	0.012122	7.1

Adults 20-49 years old	0.010880	6.4

Adults 50+ years old	0.014426	8.5

Females 13-49 years old	0.011894	7.0

5.0  Residential (Non-Occupational) Exposure/Risk Characterization

There are no products containing pyrimethanil proposed or registered
that would result in residential exposure.  Therefore, a residential
exposure assessment was not performed.

5.1	  Other (Spray Drift)

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

6.0  Aggregate Risk Assessments and Risk Characterization

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

6.1  Acute Aggregate Risk

No acute residential/recreational exposures are expected.  Since the
dietary assessment included food and water, the exposures in Table 4.2.1
represent acute aggregate exposures.  The acute aggregate risk estimates
are not of concern to HED. 

6.2  Short- and Intermediate-term Aggregate Risk

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

6.3  Long-term (Chronic) 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.

6.4  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); acceptable MOE was not defined by
the 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 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.  Based upon chronic food plus water exposure of the General
U.S. Population, the MOE for cancer assessment is 830 which is not of
concern to HED.

7.0  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
tolerance action, therefore, EPA 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 OPP 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/. 

8.0	  Occupational Exposure/Risk Pathway

Reference:

Memo, 6/13/08, K.M. Lowe, DP No. 342695.

8.  Short-/Intermediate-Term Handler Risk

Based on the proposed use, occupational exposure is possible for
individuals that handle the EPs, and for individuals that may enter the
treatment area (in this case, a storage room).  The proposed use is a
very specific use pattern (involving a Xeda brand thermal
electrofogger).  Data for this specific exposure scenario are not
available to HED.  Therefore, surrogate data from the PHED, Version 1.1,
were used.  HED conducted a conservative assessment of short-term risks
to handlers.  Post-application exposure was not assessed as it is
expected to be negligible due to PPE required on Xedathane A labels.

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, which comprise the PHED have been determined
to require a review of their ethical conduct, and have received that
review. The studies in PHED were considered appropriate (or ethically
conducted) for use in risk assessments.

A thermal electrofogger is an automatic fogging machine which is located
outside the area where the fruit are stored and treatment occurs.  The
fog, which contains pyrimethanil, is piped into the storage room, which
is typically sealed tightly for climate control.  The material is
transferred from the product container into the fogging machine by pipe.
 The machine then slowly draws the solution out of the tank, heats it up
to convert it to fog, and sends the fog into the storage room through a
pipe.  The fog is not released in the presence of the handler. 
Therefore, the only significant source of exposure is during the pouring
of the end-use product into the fogging machine tank.  This exposure was
assessed as a mixer/loader scenario using PHED Version 1.1 (open mixing
loading of liquids).  

A separate applicator assessment was not conducted.    SEQ CHAPTER \h \r
1 Since the application of pyrimethanil is mechanically automated for
the thermal fogging machine, the applicator in this case is the same as
the mixer/loader.  A mixer/loader assessment was performed and is
considered to result in a conservative estimate of worker risk.  There
are no risk estimates that are of concern to HED.  

Chemical-specific data for assessing exposure during pesticide handling
activities were not submitted to the Agency in support of this Section 3
application for pyrimethanil.  It is HED policy to use data from PHED,
Version 1.1, to assess handler exposures for regulatory actions when
chemical-specific data are not available (HED Science Advisory Council
for Exposure (ExpoSAC), SOP Number .007, January 1999).

The assumptions, parameters and factors used in the risk and exposure
calculations include:

Application Rate:  The application rate is the maximum rate identified
on the proposed Xedathane A label.  The maximum application rate for
treatment of pears using a thermal fogger is 0.021 lb ai/metric ton
(2200 lb) fruit, or 0.00000959 lb ai/lb fruit. 

Unit Exposures (UE):  The PHED UE for mixer/loaders, open pour, liquids
is 0.023 mg/lb ai for dermal exposure (wearing gloves, as required on
the label) and 0.0012 mg/lb ai for inhalation exposure (without a
respirator, although respirator is required on the label).

Amount Treated:  Information on amount of fruit treated per day was
taken from previously assessed active ingredients (i.e., imazalil,
thiabendazole, diphenylamine) used in similar postharvest applications. 
For this assessment, it was assumed that 1,440,000 lbs of pome fruit
could be treated per day. 

Body Weight (BW):  The average body weight of an adult (70 kg) was used
for all risk assessments. 

Equations/Calculations:  The following equations were used to calculate
handler exposure and risk:

Exposure (mg/kg/day) = Rate (lb ai/lb fruit) x UE (mg /lb ai) x Amount
Treated (lbs/day) / BW (kg)

Where:

Rate			=	Maximum application rate on product label (lb ai/lb fruit);

UE (Unit Exposure)	=	Exposure value derived from August 1998 PHED
Surrogate Exposure Table;

Amount Treated		=	Maximum amount treated per day (lb fruit/day); and 

BW			=	Body weight (70 kg).

				

Total MOE (for Dermal and Inhalation Risk) = NOAEL (2 mg/kg/day) /
Exposure (mg/kg/day)

Dermal and inhalation exposures were combined since the NOAEL and
endpoint for both dermal and inhalation risk assessment are the same
(23.1 mg/kg/day; decreased mean body weights and body-weight gains).

The mixer/loader dermal and inhalation exposure scenarios resulting from
thermal fogging of pome fruit are presented below in Table 8.1.  The
combined MOE for dermal and inhalation exposure (4,800) is not of
concern, if workers wear gloves as directed on the label.  

Table 8.1.  Occupational Handler Dermal and Inhalation Exposures and
Risks.

Dermal and

Inhalation Unit Exposures

(mg/lb ai)	Application rate

(lb ai/lb fruit)a	Amount Treated Daily (lb fruit/day)b	Short- and
Intermediate-term Doses (mg/kg/day)c	Short- and Intermediate-term MOEsd
Combined Short- and Intermediate-term MOEsi

Mixer/Loader – Aerial Application

Dermal

Baselinee: 2.9 (HC)h

Single layer w/glovesg: 0.023 (HC)

Inhalation

Baselinef: 0.0012 (HC)	0.00000969	1,400,000	Dermal

Baseline: 0.58

Single layer w/gloves: 0.0046	Dermal

Baseline: 40

Single layer w/gloves: 5,000	Baseline:  40

Single layer w/gloves:  4,800

	Inhalation

Baseline: 0.00024	Inhalation

Baseline: 97,000

	a	Application rate is the maximum recommended rates provided on the
pyrimethanil product label.

b	Amount treated per day value is an HED estimate based on previous
assessments.

c	Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/lb
fruit) x Amount Treated (lb fruit/day) x  %Absorption (100% dermal and
inhalation assumed) / Body weight (70 kg). 

d	MOE = NOAEL/Dose; where the short- and intermediate-term dermal and
inhalation NOAEL = 23.1 mg/kg/day .

e	Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves.

f	Baseline Inhalation: no respirator.

g	Single layer w/gloves: Single layer baseline attire plus
chemical-resistant gloves (This is the PPE required on the label).

h	Data Confidence for PHED unit exposures: LC = Low Confidence, MC =
Medium Confidence, HC = High Confidence.

i.	Combined MOE = NOAEL / (dermal + inhalation daily dose).

8.2  Short-/Intermediate-Term Post-application Risk

Early re-entry into a treated area typically refers to entering a
treated area before the specified REI.  In such conditions, scouts or
workers may be required to use PPE to limit dermal and inhalation
exposure.  The proposed Xedathane A label requires that no entry into
the treated room be allowed for 8 hours if there is no ventilation
followed by one hour of mechanical ventilation or 24 hours with no
ventilation.  

 

According to a previous review for this type of use (Ethoxyquin. 
Occupational Risk Assessment for Proposed Uses on Stored Pears [D342695;
4-1-2008]), the registrant has indicated that due to the atmospheric
conditions under which the storage rooms are maintained (low levels of
oxygen [1 to 3%] and temperature ranging from 32 to 36oF), anyone who
enters the storage rooms must do so wearing full SCBA gear.  Therefore,
the more acute danger to early re-entry workers is lack of oxygen.  Use
of SCBA gear will mitigate these concerns and provide adequate
protection from inhalation exposure.  Since Xedathane A labels require
the use of SCBA for early entry into storage rooms before the required
ventilation times, a quantitative inhalation risk assessment is not
needed for early re-entry workers.  Furthermore, since early re-entry
workers are in the storage room for such a very short period of time to
collect residue samples, dermal exposure is expected to be negligible
and a dermal exposure assessment for early re-entry is not required.

9.0  Data Needs and Label Requirements

9.1  Toxicology

Mouse carcinogenicity study was requested by the DART (HED Doc. 0050408)
because the high dose in the existing study was judged to be inadequate
for assessing the carcinogenic potential of pyrimethanil.

90-day inhalation study to address concerns for exposure associated with
greenhouse use.

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

9.2  Residue Chemistry

Label revision is required to clearly specify that Xedathane™ A may
only be applied once for postharvest use by electrofog machine on pome
fruits and to prohibit application to fruit that has been previously
treated with pyrimethanil via dip/wash application. 

ACB/BEAD does not currently have the GC/MS/MS ion-trap instrument
necessary to validate the proposed enforcement method for livestock. 
Since GC ion-trap MS/MS has not been demonstrated to be a robust
quantitative instrument, ACB/BEAD is now recommending that the
petitioner revise the method to use LC/MS/MS for pyrimethanil and its
metabolites (E-mail from C. Stafford of ACB/BEAD, 4/23/08).  If Bayer
can provide adequate recovery data using an LC-MS/MS method in livestock
commodities, then an ILV will not be required.

  SEQ CHAPTER \h \r 1 

Analytical reference standards of the regulated metabolites
4-[4,6-dimethyl-2-pyrimidinyl)amino]phenol (AEC614276) and
4,6-dimethyl-2-(phenylamino)-5-pyrimidinol (AEC614277) should be
supplied and supplies replenished as requested by the Repository.  The
reference standards should be sent to the Analytical Chemistry Lab,
which is located at Fort Meade, to the attention of either Theresa Cole
or William Chism at the following address:

		USEPA

		National Pesticide Standards Repository/Analytical Chemistry
Branch/OPP

		701 Mapes Road

		Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

A summary of the recommended tolerances along with recommendations for
commodity definitions are presented in Table 1.0.  The petitioner is
required to submit a revised Section F to reflect the recommendations in
Table 1.0.

9.3  Occupational and Residential Exposure

None.

RDI: RAB1: 07/09/2008

Petition Number:  PP#7F7250

DP Number:  352814

PC Code:  288201

WDWassell:S10316:Potomac Yard:703-305-6135:7509P:RAB1



Appendix 1.  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,
vomi楴杮‬楤牡桲慥‬慳楬慶楴湯‬票潰捡楴楶祴ܮ㠇〷
㌮〷⠰⥡䐍癥汥灯敭瑮污吠硯捩瑩⁹爨瑡ഩ㐇㌳㄰ㄶഷ
㌴㐳〵㠱㐍㌳㄰ㄶ‹ㄨ㤹⤱愍捣灥慴汢⽥畧摩汥湩൥ⰰ
㜠‬㔸ㄬ〰‰杭欯⽧慤ݹ丠䅏䱅㴠䴠瑡牥慮㩬㠠‵杭欯
⽧慤⁹䐍癥汥灯敭瑮污›㔸洠⽧杫搯祡

,

L

N

R

f

h

‚

’

¶

Þ

à

f

h

„

’

¸

Þ

@

瑹⩠ÅԀÞ

à

@

@

@

	

 

 

-

v

w

y

„

Š

º

ß

à

á

à

á

␃ഃࣆȀᥐ᪸

ༀꂄᄅ悄ㇺĤ葞֠葠褐摧㘺#ༀá

â

é

ê

ï

ò

÷

ø

ù

똁ਡ

㄀Ĥ摧『5

␃ഃࣆȀᥐ᪸

␃ഃࣆȀᥐ᪸

j

@

摧㘺#ऀ

ho

/

hn

	ԀĤ␆㄁Ĥ摧㘺#

 hDZ

㄀Ĥ摧㘺#

H* h

ഀ׆Ā褐㄀Ĥ摧㘺#

혈Fᴃ똀괗$餆

 h

¶

¶

¶

¶

¶

¶

¶

h

hæH

…

†

  h

 h

 h

  h

H*

 h

 h

  h

  h

H* h

 h

yt

H*

 h

 h

  h

yt

yt

yt

yt

hº

h

h

h

h

h

 h¼

 h¼

  h¼

혈\☄꛼鈈

혈\☄꛼鈈

  h¼

혈\☄꛼鈈

혈\☄꛼鈈

혈\☄꛼鈈

  h¼

  h¼

 h¼

 h¼

h¹3

  h¼

 h

q

þ

 h

 h

 h

  h

þ

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

	

	 gastric intubation.



Appendix 2.  Pyrimethanil Metabolites of Concern.

Common name/

Pyrimethanil	Human-Health Risk Assessment	PC Code: 288201

Page   PAGE  1  of   NUMPAGES  35 

Pyrimethanil	 Human-Health Risk Assessment	PC Code: 288201