Document ID: EPA-HQ-OPP-2007-0536-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-23T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		July 30, 2009

Subject:	FENARIMOL.  Human Health Risk Assessment for the Proposed Food
Use of Fenarimol on Hops.  

PC Code:  	206600	DP Barcode:	330714

Decision No.:	367682	Registration No.:	10163-273

Petition No.:	6E7074	Regulatory Action:	Section 3

Assessment Type:	Single Chemical, Aggregate	Registration Case No.:	None

TXR No.:	None	CAS No.:	60168-88-9

MRID No.:	None	40 CFR:	§180.421

  SEQ CHAPTER \h \r 1 From:		  SEQ CHAPTER \h \r 1 Breann Hanson,
Biologist

			Alternative Risk Integration and Assessment (ARIA) Team

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

			Registration Division (RD; 7505P)

Through:		  SEQ CHAPTER \h \r 1 William Cutchin, Acting Senior Branch
Scientist

				ARIA

				RIMUERB/RD (7505P)

		

				AND

		

				John Doherty, Toxicologist

				Jack Arthur, Acting Branch Chief

			Risk Assessment Branch 5 (RAB5)

			Health Effects Division (HED; 7509P)

To:	Susan Stanton/Barbara Madden/Dan Rosenblatt, RM Team 05 

			RIMUERB/RD (7505P)

	  SEQ CHAPTER \h \r 1 

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. 
RD of OPP has requested that ARIA 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 proposed and currently registered uses of the active
ingredient fenarimol. 

In this document, ARIA has conducted an assessment of the human exposure
and health risks resulting from these proposed uses and all currently
registered uses.  The dietary and overall risk assessments were provided
by Breann Hanson (ARIA), the residue chemistry assessment by Debra Rate
(ARIA), the water exposure assessment by Greg Orrick (Environmental Fate
and Effects Division (EFED)) and the occupational exposure assessment by
Mark Dow (ARIA).  

This risk assessment incorporates all current, pending and proposed
tolerances for fenarimol as of July 30, 2009.

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc236727262"  1.0 EXECUTIVE
SUMMARY	  PAGEREF _Toc236727262 \h  5  

  HYPERLINK \l "_Toc236727263"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc236727263 \h  12  

  HYPERLINK \l "_Toc236727264"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc236727264 \h  12  

  HYPERLINK \l "_Toc236727265"  2.2	Structure and Nomenclature	  PAGEREF
_Toc236727265 \h  12  

  HYPERLINK \l "_Toc236727266"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc236727266 \h  13  

  HYPERLINK \l "_Toc236727267"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc236727267 \h  13  

  HYPERLINK \l "_Toc236727268"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc236727268 \h  13  

  HYPERLINK \l "_Toc236727269"  3.1.1	Database Summary	  PAGEREF
_Toc236727269 \h  13  

  HYPERLINK \l "_Toc236727270"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc236727270 \h  13  

  HYPERLINK \l "_Toc236727271"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc236727271 \h  14  

  HYPERLINK \l "_Toc236727272"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc236727272 \h  14  

  HYPERLINK \l "_Toc236727273"  3.1.2	Toxicological Effects	  PAGEREF
_Toc236727273 \h  14  

  HYPERLINK \l "_Toc236727274"  3.1.3	Dose-response	  PAGEREF
_Toc236727274 \h  15  

  HYPERLINK \l "_Toc236727275"  3.1.4	FQPA	  PAGEREF _Toc236727275 \h 
16  

  HYPERLINK \l "_Toc236727276"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc236727276 \h  16  

  HYPERLINK \l "_Toc236727277"  3.3	FQPA Considerations	  PAGEREF
_Toc236727277 \h  16  

  HYPERLINK \l "_Toc236727278"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc236727278 \h  16  

  HYPERLINK \l "_Toc236727279"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc236727279 \h  17  

  HYPERLINK \l "_Toc236727280"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc236727280 \h  17  

  HYPERLINK \l "_Toc236727281"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc236727281 \h  17  

  HYPERLINK \l "_Toc236727282"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc236727282 \h  17  

  HYPERLINK \l "_Toc236727283"  3.3.6	Pre-and/or Post-natal Toxicity	 
PAGEREF _Toc236727283 \h  18  

  HYPERLINK \l "_Toc236727284"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc236727284 \h  18  

  HYPERLINK \l "_Toc236727285"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc236727285 \h  18  

  HYPERLINK \l "_Toc236727286"  3.3.7	Recommendation for a Developmental
Neurotoxicity (DNT) Study	  PAGEREF _Toc236727286 \h  18  

  HYPERLINK \l "_Toc236727287"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc236727287 \h  19  

  HYPERLINK \l "_Toc236727288"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc236727288 \h  19  

  HYPERLINK \l "_Toc236727289"  3.5.1    Acute Reference Dose (aRfD)	 
PAGEREF _Toc236727289 \h  19  

  HYPERLINK \l "_Toc236727290"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc236727290 \h  20  

  HYPERLINK \l "_Toc236727291"  3.5.3	Incidental Oral Exposure: Short-
and Intermediate-Term                                                   
    (1 day - 6 months)	  PAGEREF _Toc236727291 \h  22  

  HYPERLINK \l "_Toc236727292"  3.5.4	Dermal Absorption	  PAGEREF
_Toc236727292 \h  24  

  HYPERLINK \l "_Toc236727293"  3.5.4	Dermal Exposure: Short- and
Intermediate-Term (1 day - 6 months)	  PAGEREF _Toc236727293 \h  24  

  HYPERLINK \l "_Toc236727294"  3.5.6	Dermal Exposure: Long-Term (> 6
Months)	  PAGEREF _Toc236727294 \h  25  

  HYPERLINK \l "_Toc236727295"  3.5.7	Inhalation Exposure: Short- and
Intermediate-Term (1 day - 6 months)	  PAGEREF _Toc236727295 \h  26  

  HYPERLINK \l "_Toc236727296"  3.5.8	Inhalation Exposure: Long-Term (>
6 Months)	  PAGEREF _Toc236727296 \h  26  

  HYPERLINK \l "_Toc236727297"  3.5.9	Level of Concern for Margin of
Exposure	  PAGEREF _Toc236727297 \h  27  

  HYPERLINK \l "_Toc236727298"  3.5.10	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc236727298 \h  27  

  HYPERLINK \l "_Toc236727299"  3.5.11	Classification of Carcinogenic
Potential	  PAGEREF _Toc236727299 \h  27  

  HYPERLINK \l "_Toc236727300"  3.5.12	Summary of Toxicological Doses
and Endpoints for Fenarimol for Use in Human Risk Assessments	  PAGEREF
_Toc236727300 \h  28  

  HYPERLINK \l "_Toc236727301"  3.6	Endocrine Disruption	  PAGEREF
_Toc236727301 \h  29  

  HYPERLINK \l "_Toc236727302"  4.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc236727302 \h  30  

  HYPERLINK \l "_Toc236727303"  4.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc236727303 \h  30  

  HYPERLINK \l "_Toc236727304"  4.1.1	Metabolism in Primary Crops and
Livestock Commodities.	  PAGEREF _Toc236727304 \h  30  

  HYPERLINK \l "_Toc236727305"  4.1.2	Analytical Methodology	  PAGEREF
_Toc236727305 \h  30  

  HYPERLINK \l "_Toc236727306"  4.1.3	Multiresidue Methods	  PAGEREF
_Toc236727306 \h  31  

  HYPERLINK \l "_Toc236727307"  4.1.4	Storage Stability	  PAGEREF
_Toc236727307 \h  31  

  HYPERLINK \l "_Toc236727308"  4.1.5	Magnitude of the Reside in Plants	
 PAGEREF _Toc236727308 \h  31  

  HYPERLINK \l "_Toc236727309"  4.1.6	Magnitude in Meat, Milk, Poultry,
and Eggs	  PAGEREF _Toc236727309 \h  32  

  HYPERLINK \l "_Toc236727310"  4.1.7	Confined and Field Accumulation in
Rotational Crops	  PAGEREF _Toc236727310 \h  32  

  HYPERLINK \l "_Toc236727311"  4.1.8	Environmental Degradation	 
PAGEREF _Toc236727311 \h  32  

  HYPERLINK \l "_Toc236727312"  4.1.9	Comparative Metabolic Profile	 
PAGEREF _Toc236727312 \h  33  

  HYPERLINK \l "_Toc236727313"  4.1.10	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc236727313 \h  33  

  HYPERLINK \l "_Toc236727314"  4.1.11	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc236727314 \h  33  

  HYPERLINK \l "_Toc236727315"  4.1.12	Drinking Water Residue Profile	 
PAGEREF _Toc236727315 \h  34  

  HYPERLINK \l "_Toc236727316"  4.1.13	Food Residue Profile	  PAGEREF
_Toc236727316 \h  34  

  HYPERLINK \l "_Toc236727317"  4.1.14	International Residue Limits	 
PAGEREF _Toc236727317 \h  35  

  HYPERLINK \l "_Toc236727318"  4.2	Dietary Exposure and Risk	  PAGEREF
_Toc236727318 \h  35  

  HYPERLINK \l "_Toc236727319"  4.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc236727319 \h  35  

  HYPERLINK \l "_Toc236727320"  4.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc236727320 \h  35  

  HYPERLINK \l "_Toc236727321"  4.2.3	Cancer Dietary Risk	  PAGEREF
_Toc236727321 \h  36  

  HYPERLINK \l "_Toc236727322"  4.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc236727322 \h  37  

  HYPERLINK \l "_Toc236727323"  5.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc236727323 \h  38  

  HYPERLINK \l "_Toc236727324"  5.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc236727324 \h  38  

  HYPERLINK \l "_Toc236727325"  6.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc236727325 \h  39  

  HYPERLINK \l "_Toc236727326"  6.1	Acute Aggregate Risk	  PAGEREF
_Toc236727326 \h  39  

  HYPERLINK \l "_Toc236727327"  6.2	Short-Term Aggregate Risk	  PAGEREF
_Toc236727327 \h  39  

  HYPERLINK \l "_Toc236727328"  6.3	Intermediate/Long-Term Aggregate
Risk	  PAGEREF _Toc236727328 \h  39  

  HYPERLINK \l "_Toc236727329"  6.4	Chronic Aggregate Risk	  PAGEREF
_Toc236727329 \h  39  

  HYPERLINK \l "_Toc236727330"  6.5	Cancer Aggregate Risk	  PAGEREF
_Toc236727330 \h  40  

  HYPERLINK \l "_Toc236727331"  7.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc236727331 \h  40  

  HYPERLINK \l "_Toc236727332"  8.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc236727332 \h  40  

  HYPERLINK \l "_Toc236727333"  8.1	Handler Exposure and Risk	  PAGEREF
_Toc236727333 \h  40  

  HYPERLINK \l "_Toc236727334"  8.2	Post-Application Exposure Risk	 
PAGEREF _Toc236727334 \h  42  

  HYPERLINK \l "_Toc236727335"  8.3	Restricted Entry Interval (REI)	 
PAGEREF _Toc236727335 \h  42  

  HYPERLINK \l "_Toc236727336"  9.0	TOLERANCE SUMMARY	  PAGEREF
_Toc236727336 \h  43  

  HYPERLINK \l "_Toc236727337"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc236727337 \h  43  

  HYPERLINK \l "_Toc236727338"  10.1	Toxicology	  PAGEREF _Toc236727338
\h  43  

  HYPERLINK \l "_Toc236727339"  10.2	Environmental Fate and Effects	 
PAGEREF _Toc236727339 \h  44  

  HYPERLINK \l "_Toc236727340"  10.3	Residue Chemistry	  PAGEREF
_Toc236727340 \h  44  

  HYPERLINK \l "_Toc236727341"  10.4	Occupational and Residential
Exposure	  PAGEREF _Toc236727341 \h  44  

  HYPERLINK \l "_Toc236727342"  11.0	REFERENCES	  PAGEREF _Toc236727342
\h  44  

  HYPERLINK \l "_Toc236727343"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc236727343 \h  46  

  HYPERLINK \l "_Toc236727344"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc236727344 \h  46  

  HYPERLINK \l "_Toc236727345"  A.2   Toxicity Profiles	  PAGEREF
_Toc236727345 \h  49  

  HYPERLINK \l "_Toc236727346"  Appendix B:  Review of Human Research	 
PAGEREF _Toc236727346 \h  49  

  HYPERLINK \l "_Toc236727347"  Appendix C:  Maximum Residue Limits	 
PAGEREF _Toc236727347 \h  50  

  HYPERLINK \l "_Toc236727348"  Appendix D:  International Residue Limit
Status	  PAGEREF _Toc236727348 \h  51  

  HYPERLINK \l "_Toc236727349"  Appendix E:  Immunotoxicity	  PAGEREF
_Toc236727349 \h  52  

 	

1.0 EXECUTIVE SUMMARY

Background

This document is a human health risk assessment to support an
Interregional Research Project No. 4 (IR-4) request for the
establishment of permanent tolerances for residues of fenarimol,
alpha-(2 chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol,
in/on hops (PP# 6E7074).  Fenarimol is a member of the pyrimidine class
of fungicides, which also includes dimethirimol, bupirimate, and
ethirimol, used for control of such pests as scab, powdery mildew,
rusts, and leaf spot.  Fenarimol inhibits fungal growth by adversely
affecting the formation of the fungal sterol ergosterol.  

Tolerances for residues of fenarimol are established under 40CFR
§180.421.  Fenarimol is currently registered for use on fruit and nut
crops such as apples, cherries, filberts (nonbearing), grapes, pears,
and pecans as well as on ornamental plants, trees, and grasses and turf
lawns.  Fenarimol is also used on imported bananas.

The most recent human health risk assessment for fenarimol was conducted
as a status update for the active ingredient which was going through the
Registration Review process (DP #: 336007, D. Drew, 3/21/2007).

This document includes updated dietary (food and drinking water),
occupational (handler and post-application), residue chemistry and
aggregate assessments. 

Rubigan™ EC (EPA Reg. No. 10163-273), a 12% emulsifiable concentrate
liquid which contains 1.0 lb active ingredient (ai) per gallon, for
control of powdery mildew.  Applications should begin when powdery
mildew is observed.  The rate of application is 7.0 fl oz formulation/A
(0.055 lb ai/A).  There is a maximum of 28 fl oz of formulation per acre
per growing season (0.22 lb ai/A/growing season), which equates to 4
applications per growing season.  There is a 14 day application interval
and a 10 day pre-harvest interval (PHI).  

Additionally, in order to harmonize with a Codex Maximum Residue Limit
(MRL) of 0.3 ppm for apples, EPA has proposed increasing the tolerance
for residues of apples from 0.1 ppm to 0.3 ppm.  The Agency has
determined that with the increased tolerance there is a reasonable
certainty that no harm will result from aggregate exposure (FR Notice:
Volume 72, Number 108, 6/6/2007). 

 

Toxicology and Dose-Response

The toxicity database for fenarimol is substantially complete for the
purpose of assessing human health risks except for the 28-day inhalation
toxicity study and the new requirement for an assessment of
immunotoxicity potential. 

The liver is recognized as a target organ for toxicity.  However the
effects of fenarimol on aromatase, an enzyme involved in the conversion
of androgens to estrogens is the basis for toxicity endpoints.  The
inhibition of aromatase by fenarimol results in adverse effects in both
males and females as indicated in the reproduction and developmental
studies.  Liver toxicity was manifested by liver weight increases and
the presence of "fatty liver" in rats.  In dogs, liver weight was
increased and there were also increases in serum enzymes indicative of
liver toxicity.  The data base for carcinogenicity is considered
complete.  Fenarimol has been classified as not likely to be a human
carcinogen (Group E).  The mutagenicity/genetic toxicity data base is
considered complete and indicates no mutagenicity concern.

	

The data base for prenatal developmental (in rats and rabbits) and
reproductive (in rats) toxicity is considered complete and includes
special studies in addition to the conventional guideline studies.  The
developmental and/or reproductive toxicity studies showed no evidence of
increased sensitivity or susceptibility of young rats or rabbits. 
However, fenarimol affects the male’s reproductive performance and in
females results in dystocia. 

Fenarimol has been evaluated in two special studies in female rats: a
pubertal and an uterotrophic assay.  The pubertal assay screened for
estrogenic and thyroid activity during sexual maturation, and
investigated for abnormalities associated with sex organs and puberty
markers, as well as on thyroid tissue.  The uterotrophic assay screened
for estrogenic effects including uterine weight changes measured in
ovariectomised and immature animals. 

No adverse effects were found in the pubertal assay when rats were
treated at 50 and 250 mg/kg/day for 21 days, except for a decrease in
the thyroid hormone T4 and an increase in circulating TSH levels.  In
the uterotrophic assay, a dose of 200 mg/kg/day resulted in a
significant increase of uterine weights which were accompanied by an
increase in serum FSH levels and a decrease in serum T3 levels.   The
uterotrophic response and the effects found on thyroid hormone levels
are found at much higher doses than the regulatory endpoints (selected
for current fenarimol risk assessment) based on the rat multi-generation
study where fenarimol reduced fertility of males at 1.2 mg/kg/day with a
no observed adverse effect level (NOAEL) of 0.6 mg/kg/day.  

These special studies (the pubertal and uterotrophic assays), along with
the existing standard 2-generation rat reproductive study, provide a
characterization of the reproductive, developmental and endocrine
effects of fenarimol.  With these data from the special studies, there
is greater confidence in the current NOAEL of 0.6 mg/kg/day, and the 3X
FQPA safety factor previously required for residual concerns regarding
endocrine effects should be reduced to 1X.

Residue Chemistry

The nature of the residue in plants and animals is well understood. 
Radioactive metabolism studies with apples and cherries indicated that
fenarimol was the only significant component of the residue.  Although
HED suggested that field trial studies on new crops include data for
parent and metabolites (B &C), the registrant submitted data for
fenarimol only on hops.  

The field trials on hops are   SEQ CHAPTER \h \r 1 adequate.  Three
field trials were conducted in EPA geographical Regions 11 and 12.  The
number and location of these trials are in accordance with OPPTS
Guideline 860.1500. 

  SEQ CHAPTER \h \r 1 An adequate gas chromatography (GC) with an
electrolytic conductivity detector (ECD) method is available for
enforcing the proposed fenarimol tolerances (DowElanco).  Residues were
extracted from the samples using methanol, purified by sodium
bicarbonate and methyl tert-butyl ether liquid/liquid partition and
subjected to alumina column clean-up prior to analysis using GC ECD. 
The lowest level of method validation (LLMV) in this study was 0.100 ppm
fenarimol.  The limit of quantitation (LOQ) for the method was 0.12 ppm,
and the limit of detection (LOD) was 0.041 ppm, approximately one-third
of the LOQ.  

Although it will not affect the recommendation of the tolerance of
fenarimol residues on hops cones, dried, the fenarimol residue chemistry
database does not contain storage stability data for livestock
commodities.  Storage stability data for these commodities are required
to support the storage intervals used in livestock feeding studies.

The storage stability study submitted supports the use of fenarimol
in/on hops.  Although the storage stability recoveries averaged 67%, the
concurrent recoveries and method validation recoveries ranged from 64%
to 94% with an overall average of 78% recovery.  The calculated
tolerance based on reported field trial residues (0.742 ppm maximum) of
fenarimol on hops and residue decay (~30%) support the proposed
tolerance of 1.2 ppm.

ARIA recommends that the requested tolerance of 1.2 ppm be set for the
residues of fenarimol in/on hops cones, dried.  

Dietary Risk (Food and Drinking Water)

Drinking Water

The Environmental Fate and Effects Division (EFED) provided a drinking
water assessment for fenarimol.  The assessment evaluated the maximum
use patterns of the current uses on turf and ornamentals as they appear
on the proposed labels.  With the current use patterns the 1-in-10-year
annual mean estimated drinking water concentration (EDWC) is 226 ppb. 
Additionally, exposure was estimated for fenarimol use on turf that is
restricted to professional stadia and golf course tees, greens, and
fairways at the currently proposed application rates (see Section
4.1.12).  With the revised use patterns proposed by EFED, the exposure
estimate is significantly reduced, resulting in a 1-in-10-year annual
mean EDWC of 66 ppb.

Food

Based on toxicological considerations from HED, acute and cancer
assessments were not required.  HED previously determined that there was
no appropriate endpoint for use in assessing acute dietary exposure and
classified fenarimol as a “not likely carcinogen.” 

The chronic dietary exposure assessment for fenarimol is highly refined
using anticipated residues based on Food and Drug Administration (FDA)
monitoring data for apples, bananas, cherries, grapes and pears.  Field
trial residue data were used for pecans.  Percent crop treated (%CT)
information and processing factors, where available, were used in the
assessment. There were no Pesticide Data Program (PDP) monitoring data
available for fenarimol. The only registered uses of fenarimol in/on
food/feed crops are apples, pears, cherries, pecans, hazelnuts and
grapes.  Bananas were included in the assessment to account for imported
bananas.  

The chronic dietary risk assessment for fenarimol at the EDWC of 226 ppb
showed that chronic dietary risk estimates are above ARIA’s level of
concern (i.e. >100% chronic population adjusted doses (cPAD)) for
infants (<1 year old), the highest exposed population subgroup (260% of
the cPAD), as well as for children 1-2 years old (118% of the cPAD) and
children 3-5 years old (110% of the cPAD).  At the EDWC of 66 ppb, with
turf uses of fenarimol limited to professional stadia and golf course
tees and greens at 11 lbs ai/A and to golf course fairways at 8.1 lbs
ai/A, the chronic dietary risk estimates are below ARIA’s level of
concern (i.e. <100% cPAD) for infants (<1 year old), the highest exposed
population subgroup (76% of the cPAD), as well as for the general US
population (23% of the cPAD).  As such, ARIA is requesting that the use
of fenarimol on turf be restricted to professional stadia and golf
course tees, greens, and fairways according to EFED’s recommendations
(see Section 4.1.12).

Non-Occupational and Residential Risk

The current petition for fenarimol results in no
non-occupational/residential exposures.    However, potential
post-application short-term dermal exposures to adult golfers are
possible.  In a previous HED human health risk assessment short-term
dermal exposure to adult golfers was assessed resulting in a Margin of
Exposure (MOE) of 14,000 (Level of Concern (LOC) is 1000).  The
short-term assessment for golfers need not be revised.

Aggregate Risk

An aggregate exposure risk assessment was conducted by incorporating the
drinking water directly into the dietary exposure assessment for the
following scenarios:  chronic aggregate and short-term aggregate
exposure.  Intermediate- and long-term exposures are not anticipated;
therefore intermediate-/long-term aggregate risk assessments were not
performed.  Acute and cancer aggregate-risk assessments were not
performed because no appropriate endpoint was available to determine the
acute reference dose (aRfD) for the general population or any population
subgroup and fenarimol is not likely carcinogenic.  

Chronic aggregate risk estimates do not exceed ARIA’s level of concern
at an EDWC of 66 ppb.  Since the chronic aggregate risk exposures
include only food and water, and the chronic dietary analyses included
both, no further calculations are necessary.  

The estimated short-term aggregate MOE of 8900 exceeds the target MOE of
1000.  Therefore, the short-term aggregate risk exposure estimate is not
of concern to the Agency and does not exceed ARIA’s or HED’s LOC
(i.e. MOEs less than or equal to 1000) (see Section 6.2). 

Occupational Exposure and Risk

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the Pesticide
Handlers Exposure Database (PHED) (v. 1.1, 1998).

Based upon the proposed use pattern, ARIA believes the most highly
exposed occupational pesticide handlers are mixer/loaders using
open-pour loading of liquids, and applicators using open-cab air-blast
spray machinery.  Since the treatment blocks (i.e., areas treated) are
relatively small in hop yards (as compared to typical field crops such
as cotton, corn, soybeans or wheat), ARIA believes pesticide handlers
will be exposed to short-term duration (1-30 days) exposures but not to
intermediate-term (1-6 months) duration exposures.  Although multiple
applications are possible, they are separated by 14 day retreatment
intervals.  It is unlikely that pesticide handlers would be exposed
continuously for 30 days or more.  A MOE of 1000 is adequate to protect
occupational pesticide handlers from short-term exposures.  The
estimated MOEs range from 7,612 to 472,972; therefore, these exposures
do not exceed ARIA’s or HED’s level of concern.

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  A MOE of 1000 is adequate to protect agricultural workers
from post-application exposures.  The estimated MOE is 24,822;
therefore, the proposed use does not exceed ARIA’s or HED’s level of
concern.

Since fenarimol is classified in acute Toxicity Category II for primary
eye irritation, the interim Worker Protection Standard (WPS) default
re-entry interval (REI) is 24 hours.  The product label should reflect
the interim WPS REI of 24 hours.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations," ( 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 the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, 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 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 the PHED were considered appropriate (ethically
conducted) for use in risk assessments. 

Additional Data Needs and Recommendations

Note to PM:  Turf uses of fenarimol must be limited to professional
stadia and golf course tees and greens at 11 lbs ai/A and to golf course
fairways at 8.1 lbs ai/A, in order for the chronic dietary and chronic
aggregate risks to be acceptable to ARIA and HED.  Additionally, in
order to harmonize with a Codex Maximum Residue Limit (MRL) of 0.3 ppm
for apples, EPA is increasing the tolerance for residues of apples from
0.1 ppm to 0.3 ppm.

Toxicology:

OPPTS 870.3465.  Subchronic (28-day) inhalation study. 

Please See Section 10.1.

OPPTS 870.7800.  Immunotoxicity study. 

Please See Section 10.1.

Environmental Fate and Effects:

Please see Section 10.2.

Residue Chemistry:  

Although it will not affect the recommendation of the tolerance of
fenarimol residues on hops cones, dried, the fenarimol residue chemistry
database does not contain storage stability data for livestock
commodities.  Storage stability data for these commodities are required
to support the storage intervals used in livestock feeding studies.

A 5 gram sample of analytical reference standard must be submitted to
the Agency Pesticide Repository.

Occupational: 

The product label should reflect the interim WPS REI of 24 hours. 

Provided the above recommendations are met, ARIA and HED conclude that
there are no toxicological, residue chemistry or occupational data
requirements that would preclude establishing a conditional registration
and permanent tolerance for residues of fenarimol on hops cones, dried
at 1.2 ppm.

Tolerances are established for residues of the fungicide fenarimol,
including its metabolites and degradates, noted below.  Compliance with
the tolerance levels specified below is to be determined by measuring
only fenarimol
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol]:

Commodity	ppm

Apple	0.3

Apple, dry pomace	2.0

Apple, wet pomace	2.0

Cattle, fat	0.1

Cattle, kidney	0.1

Cattle, meat	0.01

Cattle, meat byproducts, except kidney	0.05

Filbert	0.02

Goat, fat	0.1

Goat, kidney	0.1

Goat, meat	0.01

Goat, meat byproducts, except kidney	0.05

Hops cones, dried	1.2

Horse, fat	0.1

Horse, kidney	0.1

Horse, meat	0.1

Horse, meat byproducts, except kidney	0.05

Pear	0.1

Pecan	0.1

Sheep, fat	0.1

Sheep, kidney	0.1

Sheep, meat	0.01

Sheep, meat byproducts, except kidney	0.05

A tolerance is established for combined residues of the fungicide
fenarimol
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol] and
its metabolites
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-1,4-dihydro-5-pyrimidinem
ethanol and 5-[(2-chlorophenyl)
(4-chlorophenyl)methyl]-3,4-dihydro-4-pyrimidinol measured as the total
of fenarimol and 5-[(2-chlorophenyl)-(4-chlorophenyl)methyl]pyrimidine
(calculated as fenarimol)]:

Commodity	ppm

Banana*	0.5

  (more than 0.25 ppm shall be present in the pulp after peel is
removed)

Cherry	1.0

Grape, juice	0.6

Grape pomace (wet and dry)	2.0

Grape	0.2

Grape, raisin, waste	3.0

Grape, raisin	0.6

* There are no United States registrations for banana as of April 26,
1995.

Milk, eggs, poultry tissue and hog tissue were not included in the
tolerance expression because the Agency has determined that there is no
reasonable expectation of finite residues of fenarimol in these animal
commodities.  There are no poultry or hog feed items associated with the
registered uses of fenarimol.  

2.0	INGREDIENT PROFILE

A summary of the proposed uses associated with these petitions is
presented in Table 2.1.  The nomenclature and physicochemical properties
of fenarimol are presented below in Tables 2.2 and 2.3.

2.1	Summary of Proposed Uses

Table 2.1.  Summary of Directions for Use of Fenarimol.

Application, Timing, Type, and Equipment	

Formulation

[EPA Reg. No.]	

Applic. Rate

(lb ai/A)	

Max. No. Applic. per Season	

Max. Seasonal Applic. Rate

(lb ai/A)	

PHI

(days)	

Use Directions and Limitations

HOPS

Once powdery mildew is observed. Emulsifiable concentrate.	

10163-273	

7 fl oz/A

(0.055)	

4	

28 fl oz/A

(0.22)	

10	

Repeat applications at 14 day intervals, not exceed 28 fl oz /A  (0.22
lb ai/A)

  SEQ CHAPTER \h \r 1 Conclusions.  The proposed use directions are
adequate.

Structure and Nomenclature

Table 2.2.	Test Compound Nomenclature

Compound	Chemical Structure:

 

Common name	Fenarimol

Company experimental name	TSN101587

IUPAC name	RS-2,4-dichloro-α-(pyrimidin-5-yl)benzhydryl alcohol

CAS name	α-(2-chlorophenyl)-α-(4-chlorophenyl)-5-pyrimidinemethanol

CAS #	60168-88-9

End-use product/(EP)	Rubigan™ EC

Physical and Chemical Properties

hexane (1.1 mg/mL); acetonitrile, heavy aromatic naphtha, and xylene
(≤50 mg/mL); benzene and methanol (100-125 mg/mL); acetone (>250
mg/mL); and chloroform and cyclohexanone (>500 mg/mL)	MRID No.   SEQ
CHAPTER \h \r 1 00149382

Vapor pressure at 25°C	  SEQ CHAPTER \h \r 1 2.2 x 10-7 Torr at 25° C
MRID No.   SEQ CHAPTER \h \r 1 00149382

Dissociation constant (pKa)	No hydrolysis up to 52°C at pH 3, 6, or 9.
MRID No.   SEQ CHAPTER \h \r 1 00149382

Octanol/water partition coefficient Log(KOW)	  SEQ CHAPTER \h \r 1 3.69
MRID No.   SEQ CHAPTER \h \r 1 00149382

UV/visible absorption spectrum	Not available.

	

3.0	HAZARD CHARACTERIZATION

Toxicology data are used by ARIA and HED to assess the potential hazards
to humans. The data are derived from a variety of acute, subchronic, and
chronic toxicity tests; developmental/ reproductive tests; and tests to
assess mutagenicity and pesticide metabolism. The database for fenarimol
is considered adequate to support this risk assessment. 

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary

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

Studies available and considered include acute oral, dermal, inhalation,
eye irritation, and skin sensitization; subchronic; chronic,
carcinogenicity, and reproductive/developmental.

There is no evidence of immunotoxicity in the hazard database for
fenarimol. However, the Revised Part 158 requires immunoxicity studies
be submitted.  While the new Part 158 requirement for an immunotoxicity
study has not yet been fulfilled for fenarimol, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.   Note that data
requirements pertaining to immunotoxicity (see Section 10.1) must be
fulfilled as a condition of registration. 

Mode of action, metabolism, toxicokinetic data

Fenarimol is a member of the pyrimidine class of fungicides.  Other
members of this fungicide class include dimethirimol, ethirimol and
bupirimate.  Fenarimol is a localized systemic foliar fungicide used for
control of such pests as acab, powdery mildew, rusts, and leaf spot. 
Fenarimol inhibits fungal growth by adversely affecting the formation of
the fungal sterol ergosterol.  Ergosterol is related to cholesterol and
is needed for cell membrane formation.

Sufficiency of studies/data

The available studies provide sufficient information to determine
whether, and to what extent, fenarimol poses a human health hazard.  A
chronic reference dose for dietary risks as well as doses for
non-dietary risks are based on guideline acceptable studies with
well-characterized endpoints and NOAEL/LOAEL values.  The available
studies have been evaluated for guideline acceptability by individual
reviewers and peer-review committees and the database is considered
sufficient to characterize and quantify risk.

3.1.2	Toxicological Effects

Subchronic oral dosing in rats demonstrates very little toxicity except
for some slight body weight changes and liver pathology of low degree.
In dogs there was also little overt toxicity with there being some
effects in the liver. 

Data are available to assess the chronic toxicity and carcinogenic
potential of fenarimol. The liver appears to be the most evident target
organ for chronic toxicity.  Liver toxicity was manifested by liver
weight increases and the presence of "fatty liver" in rats. In dogs,
liver weight was increased and there were also associated increases in
serum enzymes, -p-Nitroanisole o-demethylase was increased indicating
stimulation of liver enzymes. Fenarimol has been classified as “not
likely to be carcinogenic to humans” (TXR. No. 014662, 7/10/2001).  

There were no indications of a direct effect of fenarimol on the immune
system and no reports were found in the open literature demonstrating
effects on the immune system. 

The data base for prenatal developmental toxicity is considered complete
with acceptable studies in both rats and rabbits. The initial guideline
study with rats was classified as unacceptable, but this study together
with a special study to assess for the reversibility of hydronephrosis
are combined with another special study to assess for developmental
effects.  These three studies combine to make an acceptable study and to
satisfy the guideline requirement for a developmental study in rats. 
The developmental toxicity studies in both rats and rabbits showed no
evidence of increased sensitivity or susceptibility to fetuses following
gestational exposure to fenarimol. 

The multi-generation reproduction studies indicate that fenarimol causes
reduced fertility in males and dystocia. Separate cross dosing studies
(dosing males and mating with untreated females and dosing females and
mating with untreated males) indicated that the reduced fertility is due
to an effect in males. These effects of fenarimol were attributed to
inhibition of aromatase or the enzyme that converts androgens to
estrogens. In addition to the guideline multi-generation reproduction
study in rats, there are nonguideline studies that assess for the
reproductive performance in mice (MRID No.: 45502307), guinea pigs (MRID
No.: 00126525, 00133474 and 00137159) and rabbits (MRID No.: 00084967).
Mice are similar to rats in that there is a decrease in the reproductive
performance in the males. However, neither the guinea pig nor rabbit
studies demonstrated a decrease in reproductive performance indicating
that the effect of fenarimol on male reproductive performance is not
seen in all species tested. 

The absorption, excretion and identification of metabolites of fenarimol
have been demonstrated in a general metabolism study. 

A 5% dermal absorption factor is appropriate to use for risk assessment
purposes. The 5% dermal absorption factor was derived primarily from the
monkey dermal absorption study (MRID No.: 00162538, 1985) using the
Feldman-Maibach model. Dermal absorption rates of 1.36%, 2.32%, 3.12%
and 4.12% (mean 2.73%±1.17%) were observed for the four individual
monkeys in the study. However, from 8 to 29% of the dermally applied
radioactivity was not accounted for. Since there was variation in the
dermal absorption in the four monkeys and there was unaccounted for
radioactivity, a dermal absorption value of 5% from this study was
considered appropriate for risk assessment.  Refer to a previous HED
report (TXR No., 0051030, J. Doherty, 7/29/2002) for a more detailed
discussion of dermal absorption.

3.1.3	Dose-response

An acute toxicity endpoint and dose for risk assessment could not be
identified. That is, no appropriate endpoint was available to quantitate
risk to the general population or females 13-50 years old from a
single-dose administration of fenarimol.  Although hydronephrosis seen
in the rat developmental and multigeneration reproductive toxicity
studies had been identified as an acute adverse toxic effect (endpoint)
in earlier fenarimol risk assessments, HED concluded that it is not
appropriate because the hydronephrosis is not severe (its is considered
an effect of low degree or magnitude); the hydronephrosis was shown to
be reversible; the hydronephrosis developed after multiple exposures and
there is no indication that it would develop following a single
exposure; and, the hydronephrosis may be related to a developmental
delay and not a target specific effect of fenarimol.

For risks associated with chronic dietary exposures, HED identified a
reference dose for chronic exposure (cRfD) of 0.006 mg/kg/day from the
multi-generation reproduction study based on a NOAEL of 0.6 mg/kg/day,
and a 10X uncertainty factor for interspecies extrapolation and a 10X
uncertainty factor for intraspecies variation.  The NOAEL of 0.6
mg/kg/day is based on decreased live born litter size at a lowest
observed adverse effect level (LOAEL) of 1.2 mg/kg/day.  HED calculated
a cPAD of 0.006 mg/kg/day. The cPAD is the RfD divided by the FQPA
safety factor (1X).  Chronic dietary exposure estimates greater than
100% of the cPAD would exceed HED’s level of concern.  

For risks associated with intermediate-term residential exposures (1-6
months), the same endpoint (NOAEL of 0.6 mg/kg/day) was used for
incidental oral, dermal, and inhalation risk assessments. A MOE greater
than or equal to 100 does not exceed ARIA’s or HED’s level of
concern for intermediate-term risk assessments.  Because the same
endpoint was used for all intermediate-term exposure assessments, the
risk estimates for the various routes of exposure may be aggregated.

For the short-term (1-30 day) incidental oral, dermal, and inhalation
risk assessments, a LOAEL of 35 mg/kg/day was selected.  This endpoint
is based on decreased fertility and dystocia, an indicator of hormonal
effects, observed in a special non-guideline cross breeding
reproduction/developmental toxicity study in rats.  Because a NOAEL
could not be identified in the study, and effects were seen at the
lowest dose tested, a LOAEL was used, and an additional 10x uncertainty
factor was applied.  Therefore, a MOE greater than 1000 does not exceed
ARIA’s or HED’s level of concern for short-term risk assessments.
Because the same endpoint was used for all short-term exposure
assessments, the risk estimates for the various routes of exposure may
be aggregated.

3.1.4	FQPA

HED re-evaluated the conclusion related to the need for the special
developmental study, in light of new information available from the
literature, in which fenarimol was subjected to additional testing. 
Based on these studies, HED concluded the special developmental study
was not needed, and the 3X uncertainty factor retained for the lack of
the study could be removed.  A memorandum supporting this conclusion was
dated 4/6/2006; given that the 4/6/2006 memo did not have a barcode, HED
provided a memorandum that captures the decision for the purpose of
citing it in future Agency actions involving fenarimol (DP#: 331611, C.
Swartz, 3/22/2007).

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

The database for metabolism is considered to be complete. The biliary
route is the predominant

route of elimination in the rat but the urinary route is the most
prominent route of elimination in the rabbit.  In rats, fenarimol is
rapidly absorbed from the gastro-intestinal tract and the half life of
the plasma level was determined to be 11.8 to 16.8 hours.  Most of the
radiolabeled material was recovered in the urine (5 to 15%) or feces
(~80% of the recovered isotope) by day 7.  Biliary

excretion was the major route of elimination.  Fenarimol is extensively
metabolized in the rat; less than one percent of the parent is
recovered, while more than 30 metabolites are recovered.

Metabolism of fenarimol occurs by the oxidation of the carbinol
phenyl-ring and pyrimidine ring

and some qualitative and quantitative differences in sexes and dose
level were noted.

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

As of July 2009, the toxicity data base is complete except for a
870.3465 subchronic (28-day) inhalation toxicity study and the new
requirement for an 870.7800 immunotoxicity assessment. 

Evidence of Neurotoxicity

HED concluded that there is not a concern for neurotoxicity resulting
from exposure to fenarimol.  There is, however, a concern for potential
adverse effects on hormones.          

Developmental Toxicity Studies

Rat

There are three rat developmental toxicity studies (MRID Nos.: 00132988
and 00084968) with fenarimol including an original study following the
83-3 guidelines (MRID No.: 00042543) which indicated hydronephrosis in
fetuses at dose levels equal to or possibly below doses causing maternal
toxicity.  The original study was followed by a special non-guideline
study that assessed the reversibility of hydronephrosis (MRID No.:
00132988) and this study demonstrated sporadic dystocia.  A third
special non-guideline study was a cross-dosing study designed to
investigate the effects of fenarimol on both the male and female
reproductive performance: male (reduced mating) and female (dystocia). 
Overall, HED concluded that the hydronephrosis was reversible and may
reflect a common physiological phenomenon.  The parental effects on male
fertility and the birthing process are considered more important and
related to the effects of fenarimol inhibition or aromatase.  

Rabbit

The rabbit developmental toxicity study (MRID No.: 44716001)
demonstrated maternal toxicity, but did not indicate developmental
toxicity at the highest dose tested.  	

Reproductive Toxicity Study

There are two rat reproductive toxicity studies.  The first study (MRID
No.: 45502301) did not demonstrate a NOAEL because decreased fertility
was observed at the lowest dose tested. This decrease in fertility
precluded evaluation of developmental effects.   The second study (MRID
No.: 45502302) demonstrated decreased liveborn litter size in a dose
dependent manner in at least one generation that was potentially
attributed to the hormonal effects of fenarimol on the adults.   

3.3.5	Additional Information from Literature Sources

	

Several literature searches were previously made and several additional
references were identified that describe the role of aromatase in human
physiology.  One paper (Vinggaard et al, Toxicol. Vita. June(14):227-34
(2000)), establishes that fenarimol inhibits aromatase in human tissues.
 Consequently, the Agency has valid scientific concerns regarding
potential aromatase inhibition in humans.  

The publications on fenarimol also investigate the mechanisms underlying
the possible interaction of fenarimol as a liver toxin as well as
investigate possible mutagenicity potential.

3.3.6	Pre-and/or Post-natal Toxicity

HED concluded that based on the submitted studies there is not a concern
for developmental toxicity following pre- and/or postnatal exposure to
fenarimol.  HED recognized that fenarimol is associated with transient
hydronephrosis but considered this to be reversible and reflecting a
physiological phenomenon.  However, there is a concern for parental
effects related to the reproductive outcome, i.e. decreased live born
litter size, and fertility and mating.  

3.3.6.1	Determination of Susceptibility

The available rat developmental and reproduction studies and the rabbit
developmental study do not show increased susceptibility of the progeny
relative to the parents.  The decrease in live born litter size is
considered to be a sequela of parental effects (e.g. dystocia and
fertility). 

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties

There is a low degree of concern for residual uncertainties.  There are,
however, data base concerns that may be addressed by a special
developmental toxicity study (see Section 3.3.7, below).  

3.3.7	Recommendation for a Developmental Neurotoxicity (DNT) Study

HED previously determined that a developmental neurotoxicity study in
rat that incorporated a special provision to assess for hormonal effects
is required (TXR.No. 014662, 7/10/2001). The Registrant in their
response requested “that the Agency rescind the requirement for a
developmental neurotoxicity study of unproven design” since the DNT is
not designed to investigate the endpoints mentioned (mating behavior in
male and difficult labor in females) (Letter from Gowan, dated
4/10/2002).

HED concurred with the Registrant’s rationale and rescinded their
previous request for the DNT.  HED instead is requesting a special
developmental toxicity study that assesses the hormonal effects in rats
especially related to inhibition of aromatase.  The protocol for this
study should be submitted to HED for review prior to initiating the
study.  

Evidence that suggests requiring a DNT study:  The NOAEL and LOAEL for
risk assessments are based on the physiological expression (reduced
fertility in males and dystocia in females) for fenarimol's potential to
affect hormones in adult rats.  The potential for fenarimol to affect
the hormonal system in developing rats needs to be assessed to determine
if the developing fetus and neonate may also be affected as can be
judged by the special developmental toxicity study that will have
special emphasis on potential disruption of the hormonal system by
biochemical methods and include special provisions to assess for
physiological manifestations of hormonal disruption.   

Evidence that does not support a need for a DNT study:  The issue of the
need for a DNT (or other special DNT like study including the assessment
for hormonal effects) was addressed (V. Dellarco, 4/6/2006) where
special studies considered in EPA’s Endocrine Disruptor Screening
Program including the Pubertal Female and Uterotrophic Assays.  Dr.
Dellarco’s analysis states: 

The Pubertal Female Assay involves the use of rats to screen for
estrogenic and thyroid activity in females during sexual maturation, and
examines abnormalities associated with sex organs and puberty markers,
as well as thyroid tissue.  This assay examines abnormalities associated
with sex organs and puberty markers, as well as thyroid tissue.  The
Uterotrophic assay involves the use of female rats to screen for
estrogenic effects. In this in vivo assay, uterine weight changes are
measured in ovariectomised or immature female rats.

No adverse effects were found in the female pubertal assay when SD rats
were treated at 50 and 250 mg/kg day for 21 days, except for a decrease
in T4 and an increase in circulating TSH levels (George et al., 2002). 
In the Uterotrophic assay, a dose of 200 mg/kg day results in a
significant increase of uterine weights which were accompanied by an
increase in serum FSH levels and a decrease in serum T3 levels (Anderson
et al, 2006).   The uterotrophic response and the effects found on
thyroid hormone levels are found at much higher doses than the
regulatory endpoints based on the rat multi-generation study where
fenarimol reduced fertility of males at 1.2 mg/kg per day with a NOAEL
of 0.6 mg/kg per day.  The 0.6 mg/kg NOAEL is over 300-fold lower than
the uterotrophic response found in rats at 200 mg/kg.

In conclusion, there is greater confidence in the current NOAEL of 0.6
mg/kg per day given these recent studies on the reproductive/endocrine
effects of fenarimol.  It is therefore recommended that the 3X FQPA
safety factor, based on the need for additional testing, be removed.   

FQPA Safety Factor for Infants and Children

In 2006, HED re-evaluated the conclusion related to the need for the
special developmental study, in light of new information available from
the literature, in which fenarimol was subjected to additional testing. 
Based on these studies, HED concluded the special developmental study
was not needed, and the 3X uncertainty factor, retained for the lack of
the study, could be removed.  

Hazard Identification and Toxicity Endpoint Selection

3.5.1    Acute Reference Dose (aRfD)  

Study Selected:   None 

MRID No.:   None

Executive Summary:   None

Dose and Endpoint for Establishing aRfD:   Not applicable

Uncertainty Factor (UF):  Not applicable 

Comments about Study/Endpoint/Uncertainty Factor:  An appropriate
endpoint attributable to a single exposure was not available from the
oral toxicity studies including the developmental toxicity studies in
rats and rabbits. 

3.5.2	Chronic Reference Dose (cRfD) 

Study Selected: Set of two rat multi generation reproduction studies.  
Guideline #: 83-4.

Study 1

MRID No.: 45502302

Executive Summary:  In a 2-generation reproduction toxicity study (MRID
No.: 45502302), fenarimol (97.9% ai, Lot/Batch# B30-C69-220) was
administered to Wistar rats (20-30/sex/dose) at nominal dietary dose
levels of 0, 12.5, 25, or 50 ppm. These doses correspond to 0, 0.6 to
0.7, 1.2 to 1.3 and 2.5 to 2.7 mg/kg/day for males and 0, 0.8 to 1.0,
1.7 to 1.8 and 3.2 to 3.8 mg/kg/day for females.  The parental (P) rats
were mated at 3 months of age to produce the F1 litters.  After weaning,
F1 animals were selected to become the parents of the F2a generation.
Due to decreased fertility, the F1 animals were mated a second time with
different males of the same test group to produce the F2b litters. 
After weaning, F2a animals were selected to become the parents of the F3
generation. 

Parental systemic toxicity.  There were no effects indicative of
systemic toxicity (i.e. not related to reproductive parameters).  The
LOAEL for parental systemic toxicity was not established.  A NOAEL of
2.5 mg/kg/day can be assumed.  

Parental reproductive toxicity.   In the F2b generation, liveborn litter
size was decreased (p(0.05) at 25 ((17%) and 50 ((28%) ppm.  The F2a
generation also had higher percentages of dead fetuses with there being
16% in the 25 ppm and 25.4% in the 50 ppm but only 5.4% in the control
group.  The percent dead fetuses was always highest in the 50 ppm dose
group for the other generations (although only slightly for the F1
group).  At 50 ppm, decreased (p(0.05) fertility was observed in the
females of the F1 (1st mating: 35% treated vs. 83% controls; 2nd mating:
 40% treated vs. 83% controls) and F2 (70% treated vs. 93% controls)
generations.  One 50 ppm F2 adult died of dystocia that appeared to be
treatment related.  Gestation length was otherwise comparable between
treated and control animals in all generations.  The LOAEL for parental
reproductive toxicity is 25 ppm (1.2 mg/kg/day) based on decreased
liveborn litter size in the F2b generations.  The NOAEL is 12.5 ppm
(approximately 0.6 mg/kg/day).

Developmental toxicity.  Pathological examination revealed that the
incidence of 

hydronephrosis was higher in the 50 ppm F3 pups (fetal incidence: 7%
treated vs. 2% controls; litter incidence: 54% treated vs. 21% controls)
although statistical significance was not achieved.  There were no
treatment-related findings at necropsy in the F1 or F2 pups.  Decreases
in survival indices were noted in the F2a and F2b generations but not in
the F1 or F3 generations and no consistent effect was noted.  The LOAEL
for developmental toxicity  toxicity is 50 ppm (2.5 mg/kg/day) based on
possible presence of hydronephrosis.  The NOAEL is 25 ppm (approximately
1.2 mg/kg/day). 

The reproductive study in the rat is acceptable/guideline (83-4) and
satisfies the requirements for a multi generational reproductive
toxicity study in rats.

Study 2

A previous multi generation reproduction study at higher doses shows the
same effects.  This study supports Study 1, discussed above.  

MRID No.:  45502301

Executive Summary:  In a 2-generation reproduction toxicity study (MRID
No.: 45502301) that was classified as unacceptable and not upgradeable,
fenarimol (97.9% purity) was administered in the diet to Wistar rats
(20/sex for groups dosed and 30/sex for the controls) at nominal dose
levels of 0, 50, 130, or 350 ppm. These doses correspond to
approximately 0, 2.9, 7.9, and 20 mg/kg/day in males and 0, 3.4, 9 and
23.5 mg/kg/day for females. The parental (P) animals were given test
diets for 8 weeks prior to mating to produce the F1a litters.  Due to
decreased fertility and live-born litter size at 350 ppm, a second
mating of the P females to different P males from the same dose group
was conducted to produce the F1b generation.  Additionally, the P
females were mated for a third time with different P males from the same
dose group to produce the F1c litters, due to decreased fertility (130
and 350 ppm groups) and live-born litter size (350 ppm group) observed
after the second mating.  On post-natal day (PND) 21, F1b animals were
selected to become the F1 parents of the F2 generation.  The F1 parents
were given the same concentration test formulation as their dam for at
least 8 weeks prior to mating to produce the F2 litters.  Decreased
fertility was observed at 130 and 350 ppm; therefore, all the F1 animals
were fed control diet for 9 weeks and re-mated using the same pairs to
assess the reversibility of the anti-fertility effect. 

Parental systemic toxicity.   In the P and F1 adults, no
treatment-related changes related to systemic were observed.   The LOAEL
for parental systemic is > 350 ppm. 

 

Parental reproductive toxicity.  Decreased fertility was apparent in the
50 ppm dose group for only the F1 second mating since only 65% pregnancy
was attained.  Decreased (p(0.05) fertility was observed in the 130 ppm
dose group of the P (1st mating: 84% treated vs. 93% controls [not
statistically significant]; 2nd mating: 79% treated vs. 97% controls
[not statistically significant]; 3rd mating: 63% treated vs. 93%
controls) and F1 (1st mating:  20% treated vs. 93% controls; 2nd mating:
 45% treated vs. 80% controls) generations.   Decreased (p(0.05)
fertility was observed in the 350 ppm females of the P (1st mating: 75%
treated vs. 93% controls [not statistically significant]; 2nd mating: 
61% treated vs. 97% controls; 3rd mating:  58% treated vs. 93% controls)
and F1 (1st mating: 0% treated vs.  93% controls; 2nd mating: 10%
treated vs. 80% controls) generations.  It should be noted that F1
animals that underwent the second mating, which occurred after the
animals received the control diet for 9 weeks, continued to show
decreased fertility; therefore, no evidence of recovery from the
anti-fertility effects was observed.  Gestation length was comparable
between treated and control animals in all generations.   The LOAEL for
parental reproductive toxicity is 50 ppm (2.5 mg/kg/day) based on
decreased fertility in the F1 generation second mating.  The NOAEL is <
50 ppm (2.5 mg/kg/day).  A subsequent study was conducted to verify the
NOAEL. 

Developmental toxicity.   Pup viability data were not evaluated by the
Reviewers for the following reasons: the data and/or text provided by
the sponsor were illegible; extreme anti-fertility effects in the
parental animals prevented valid assessment of pup data; and a second
reproduction study was conducted at lower doses.  It was noted, however,
that the incidence of hydronephrosis was higher in the 350 ppm F1c pups
than concurrent controls (fetal incidence: 14.2% treated vs. 5.2%
controls; litter incidence: 37% treated vs. 8% controls).  These
findings were not statistically significant but are a known effect of
treatment in the rat developmental toxicity study.   The LOAEL and NOAEL
for offspring toxicity were not established due to anti-fertility
effects in the parental generations, which prevented valid assessment of
the pup data.  

This reproductive study in the rat is unacceptable/not upgradeable and
does not satisfy the requirements for a multi generational reproductive
toxicity study in rats.  Extreme anti-fertility effects indicate that
dosing was too high in this study. 

Dose and Endpoint for Establishing RfD:  NOAEL of 0.6 mg/kg/day based on
decreased

litter size at 1.2 mg/kg/day (LOAEL).  

Comments about Study/Endpoint/Uncertainty Factor(s):   HED determined
that the reduced male fertility and dystocia effects of fenarimol were
appropriate endpoints for human health risk assessment.  It is noted
that the endpoint from the multi-generation reproduction study is based
on decreased litter size.  This decrease in litter size may be a
reflection of the parental toxicity or the potential for fenarimol to
inhibit aromatase.   In this regard, it would be a relevant endpoint for
all populations.  

Uncertainty Factor(s):  100 (10 X for intraspecies variation, 10 X for
interspecies extrapolation,  1X FQPA SF)

Chronic RfD  =      0.6 mg/kg/day (NOAEL)    =	0.006 mg/kg/day

				100 (UF)

Incidental Oral Exposure: Short- and Intermediate-Term (1 day - 6
months) 

Short-Term

Study Selected:  Special non-guideline cross breeding
reproduction/developmental toxicity study in rats.

MRID No.: 00084968

Executive Summary:  In this special non-guideline developmental toxicity
study (MRID No.: 00084968) six groups of 20 Wistar strain rats were
dosed with 35 mg/kg/day fenarimol (97.9% purity) by gavage in a 5%
acacia suspension for a total of 10 weeks (4 weeks prior to mating, a
two week mating period and through gestation and day 7 of lactation) in
three different assessment groups.   The first (A) group consisted of 20
males and females dosed with the vehicle only, in the second (B) group
females were dosed with fenarimol and males were not and in the third
(C) group males were dosed with fenarimol and females were not.   The
purpose of this study was to determine if fenarimol affects the males or
the females with regard to causing decreased fertility and/or dystocia. 

Treatment of males only (C) only resulted in decreasing the mating as
indicated by a fertility index of 0.65 (p < 0.05) as compared to 1.00
for the control (A) and female (B) treated groups.  This observation
established that the decrease in fertility is due to an effect in the
males. Another finding in group C was that there was decreased
epididymidal weight (absolute/relative of 12%/8%, p < 0.05).  Treatment
of the females only (B) resulted in two deaths that were attributed to
dystocia. There were also a decrease in the liveborn litter size (to
6.6±0.9 from 10.2±0.6, p < 0.05), decreased mean gestation survival
(down to 69%±6.1% from 84.2%±2.1%), gestation length (about half as
many deliveries in the normal 21st and 22nd day of gestation) and a
decrease in progeny survival to day 7 (may be related to weaker pups at
birth).   Thus, the dystocia and related parameters result from
treatment of the females.  

Several parameters that were common to both males and females were also
affected as indicated by there being affects in both groups B and C. 
These included increased body weight and gain and increased food
consumption, increased hepatic p-nitroanisole O-demethylase (about 70%
in both males and females), increased liver weight (absolute/relative
about 40%/45% in males and 24%/30% in females, p < 0.05 or 0.01),
increased thyroid weight (absolute/relative about 17%/21% in males and
19%/25% in females, p either not significant or 0.05 or 0.01).  The
LOAEL for both males (decreased mating and epididymal weight) and
females (dystocia and related parameters) was 35 mg/kg/day both sexes
had increased body weight and food consumption and increased liver and
thyroid weight and p-nitroanisole 0-demethylase.  The NOAEL was not
established.  Note: The pups were not examined for hydronephrosis. 

This study is classified as ACCEPTABLE/Non-Guideline and contains data
useful for risk assessment purposes and to establish that fenarimol
affects the males and the females with regard to reproductive function. 

    

Dose and Endpoint for Risk Assessment: LOAEL = 35 mg/kg/day based on
decreased mating and epididymal weight in males and dystocia and related
parameters in females.

Comments about the Study/Endpoint:   This study is based on an endpoint
that indicates hormonal disruption as indicated by reduced fertility in
males and dystocia in females thought to be the result of the inhibition
of aromatase conversion of androgens to estrogens.  

Intermediate-Term

Study selected:   Set of two rat multi generation reproduction studies. 
 Guideline #: 83-4.

MRID Nos:  45502301 and 45502302. 

Executive Summary:   See 3.5.2, Chronic Reference Dose (cRfd). 

Dose and Endpoint for Risk Assessment:   NOAEL of 0.6 mg/kg/day based on
decreased litter size at 1.2 mg/kg/day (LOAEL).  

Comments about study:  It is noted that the endpoint from the
multi-generation reproduction study is based on decreased litter size. 
This decrease in litter size may be a reflection of the maternal
toxicity or the potential for fenarimol to inhibit aromatase.  

3.5.4	Dermal Absorption

Dermal Absorption Factor:  5%

Comments about Study/Endpoint:  The 5% dermal absorption factor was
derived primarily from a monkey dermal absorption study (MRID No.:
00162538, 1985) which demonstrated that for 4 monkeys using the
Feldman-Maibach model, dermal absorption was 1.36%, 2.32%, 3.12% and
4.12% (mean 2.73%±1.17%) but that from 8 to 29% of the dermally applied
radioactivity was not accounted for.   Since there was variation in the
dermal absorption in the four monkeys and there was unaccounted for
radioactivity, a value of 5% was considered appropriate for this study. 
 In addition, the result of a dermal absorption study with rabbits (MRID
No.: 00046639, 1980) with three formulations indicated up to
approximately 15% dermal absorption. Comparison of the rabbit
developmental toxicity study (MRID No.: 47716001) and the rabbit 21-day
dermal toxicity study (MRID No.: 00153312) also indicated approximately
15% dermal absorption.  However, the rabbit is recognized as being a
poor model for estimating dermal absorption in humans, since rabbit skin
in more permeable.   The 5% value, based primarily on the monkey study,
is considered appropriate. 

Dermal Exposure: Short- and Intermediate-Term (1 day - 6 months)

Short-Term

Study Selected:  Special non-guideline cross breeding developmental
toxicity study in rats. 

MRID No.: 00084968

Executive Summary:  See 3.5.3, Incidental Oral Exposure: Short- Term 

Dose and Endpoint for Risk Assessment:  LOAEL = 35 mg/kg/day based on
decreased mating and epididymal weight in males and dystocia and related
parameters in females.

Comments about Study/Endpoint:  HED did not select the 21-day dermal
toxicity study in rabbits with a NOAEL of 1000 mg/kg/day because of
concerns about developmental and reproductive effects seen in other
guideline and special studies such as: 1) hydronephrosis seen in the
fetuses of rats treated with oral doses of fenarimol; 2) decreased
fertility and dystocia at 35 mg/kg/day and at 1.2 mg/kg/day in either
the developmental studies or the reproduction (as indicated by decrease
in mean live born pups) studies in the parental animals.   Since these
endpoints of concern are not evaluated in a 21-day dermal study, HED
recommended use of the oral toxicity studies that yielded NOAEL/LOAELs
protective for these effects. 

Since an oral dose was selected a 5% dermal absorption factor should be
used for route to route extrapolation.  

Intermediate-Term

Study selected:   Set of two rat multi generation reproduction studies. 

MRID No.: 45502301 and 45502302. 

Executive Summary:  See 3.5.2, Chronic Reference Dose (cRfd)

Dose and Endpoint for Risk Assessment:   NOAEL of 0.6 mg/kg/day based on
decreased

litter size at 1.2 mg/kg/day (LOAEL).    

Comments about Study/Endpoint:  It is noted that the endpoint from the
multi-generation reproduction study is based on decreased litter size. 
This decrease in litter size may be a reflection of the maternal
toxicity or the potential for fenarimol to inhibit aromatase.  

Since an oral dose was selected a 5% dermal absorption factor should be
used for route to route extrapolation.  

3.5.6	Dermal Exposure: Long-Term (> 6 Months)

Study Selected:  Set of two multi-generation reproduction studies 

MRID No.: 45502301 and 45502302 

Executive Summary: See 3.5.2, Chronic Reference Dose (cRfD) 

Dose and Endpoint for Risk Assessment: NOAEL of 0.6 mg/kg/day based on
decreased

litter size at 1.2 mg/kg/day (LOAEL).   

Comments about Study/Endpoint:  It is noted that the endpoint from the
multi-generation reproduction study is based on decreased litter size. 
This decrease in litter size may be a reflection of the maternal
toxicity or the potential for fenarimol to inhibit aromatase.  

Since an oral dose was selected a 5% dermal absorption factor should be
used for route to route extrapolation.  

Inhalation Exposure: Short- and Intermediate-Term (1 day - 6 months)

Short-Term

Study Selected:  Special non-guideline cross breeding developmental
toxicity study in rats. 

MRID No.: 00084968

Executive Summary:  See 3.5.3, Incidental Oral Exposure: Short- Term

Dose and Endpoint for Risk Assessment:  LOAEL = 35 mg/kg/day based on
decreased mating and epididymal weight in males and dystocia and related
parameters in females.

Comments about Study/Endpoint:  Except for an acute inhalation study
[Toxicity Category III (LC50 > 5.2 mg/L for males and between 2.8 and
5.2 mg/L for females)], no repeated exposure studies are available. 
Therefore, HED selected the oral doses for inhalation exposure risk
assessments.   Absorption via the inhalation route is assumed to be
equivalent to oral absorption.

Intermediate-Term

Study Selected:  Set of two multi-generation reproduction studies 

MRID No.: 45502301 and 45502302 

Executive Summary: See 3.5.2, Chronic Reference Dose (cRfD) 

Dose and Endpoint for Risk Assessment:  NOAEL of 0.6 mg/kg/day based on
decreased litter size at 1.2 mg/kg/day (LOAEL).   

Comments about Study/Endpoint:  It is noted that the endpoint from the
multi-generation reproduction study is based on decreased litter size. 
This decrease in litter size may be a reflection of the maternal
toxicity or the potential for fenarimol to inhibit aromatase. 
Absorption via the inhalation route is assumed to be equivalent to oral
absorption.

3.5.8	Inhalation Exposure: Long-Term (> 6 Months)

Study Selected:  Set of two multi-generation reproduction studies 

MRID No.: 45502301 and 45502302

Executive Summary: See 3.5.2 Chronic Reference Dose (cRfD)

Dose and Endpoint for Risk Assessment: NOAEL of 0.6 mg/kg/day based on
decreased litter size at 1.2 mg/kg/day (LOAEL).    

Comments about Study/Endpoint:  It is noted that the endpoint from the
multi-generation reproduction study is based on decreased litter size. 
This decrease in litter size may be a reflection of the maternal
toxicity or the potential for fenarimol to inhibit aromatase. 
Absorption via the inhalation route is assumed to be equivalent to oral
absorption.

3.5.9	Level of Concern for Margin of Exposure

The target MOEs for risk assessments are noted below, in Table 3.5.9. 

Table 3.5.9. Summary of Levels of Concern for Risk Assessment.

Route                         	Short-Term

(1-30 Days)	Intermediate-Term

(1 - 6 Months)	 Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	1000	100	100

Inhalation	1000	100	100

Residential (Non-Dietary) Exposure

Oral	1000	100	100

Dermal	1000	100	100

Inhalation	1000	100	100

For short-term dermal and inhalation exposure risk assessments a MOE of
1000 is required since a LOAEL was used for risk assessment (i.e., a
NOAEL was not established in the critical study).  Note: A MOE of 300
was previously used but has since been raised to 1000 (DP#: 331611, C.
Swartz, 3/22/2007). 

3.5.10	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:  this assessment includes short-term dermal route of exposure
due to turf use on golf courses.  

3.5.11	Classification of Carcinogenic Potential

HED considered the weight-of-evidence including the rat and mouse
carcinogenicity studies and the mutagenicity studies and in accordance
with the 1999 Draft Guidance for Carcinogen Risk Assessment classified
fenarimol as “not likely to be carcinogenic to humans.”   In
particular, HED recognized the presence of the adenomas in the two
highest dose groups only but did not consider this finding to be
evidence for carcinogenicity because of the low magnitude of the
response and because these adenomas did not progress to carcinomas.  HED
also considered that the demonstration of the reduced fertility noted in
the reproduction studies in rats and mice at the same doses used for
carcinogenicity assessment also provided a basis for concluding that the
dose levels were adequate.  	

  

Summary of Toxicological Doses and Endpoints for Fenarimol for Use in
Human Risk Assessments

The following toxicological endpoints were provided by HED (DP#: 331611,
C. Swartz, 3/22/2007).   A more comprehensive discussion of the endpoint
selection is in the HIARC report (TXR # 0051030, 7/29/2002).  Note that
for scenarios using the special reproduction study, the UF was increased
from the original 3 X to 10 X to be consistent for the situation when a
LOAEL is used for the endpoint and the study does not demonstrate a
NOAEL. 

Table 3.5.12.a  Summary of Toxicological Doses and Endpoints for
Fenarimol for Use in Dietary and Non-Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (All Populations)	N/A	N/A	N/A	No appropriate hazard was
identified for single dose risk assessment.

Chronic Dietary (All Populations)	NOAEL= 0.6

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=1X

	Chronic RfD =0.006

mg/kg/day

cPAD =0.006

mg/kg/day	Rat reproduction

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size.

Incidental Oral Short-Term (1-30 days)	LOAEL= 

35

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=10X

(UFL)	Residential LOC for MOE 1000	Special Reproduction Study (Rat)

LOAEL = 35 mg/kg/day based on decreased fertility and dystocia, an
indication of hormonal effects.

Incidental Oral Intermediate-Term (1-6 months)	NOAEL= 0.6

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=1X

	Residential LOC for MOE=100

	Rat reproduction

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size.

Dermal Short-Term (1-30 days)	LOAEL= 

35

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=10X

(UFL)	Residential LOC for MOE 1000	Special Reproduction Study (Rat)

LOAEL = 35 mg/kg/day based on decreased fertility and dystocia, an
indication of hormonal effects.

Dermal Intermediate-Term (1-6 months)	NOAEL= 0.6

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=1X

	Residential LOC for MOE=100

	Rat reproduction

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size.

Inhalation Short- Term (1-30 days)	LOAEL= 

35

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=10X

(UFL)	Residential LOC for MOE 1000	Special Reproduction Study (Rat)

LOAEL = 35 mg/kg/day based on decreased fertility and dystocia, an
indication of hormonal effects.

Inhalation Intermediate-Term (1-6 months)	NOAEL= 0.6

mg/kg/day	UFA=10X

UFH=10X

FQPA SF=1X

	Residential LOC for MOE=100

	Rat reproduction

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.  For extrapolation from an oral study
for dermal risk assessment, a 5% dermal absorption factor should be
used.  For extrapolation from an oral study for inhalation risk
assessment, a 100% inhalation factor should be used.

Table 3.5.12.b  Summary of Toxicological Doses and Endpoints for
Fenarimol for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short-Term (1-30 days)	LOAEL= 

35

mg/kg/day

5% DA	UFA=10X

UFH=10X

UFL=10X	Occupational LOC for MOE = 1000	Special Reproduction Study (Rat)

LOAEL = 35 mg/kg/day based on decreased fertility and dystocia, an
indication of hormonal effects.

Dermal Intermediate-Term (1-6 months)	NOAEL= 0.6

mg/kg/day

5% DA	UFA=10X

UFH=10X

	Occupational LOC for MOE = 100	Rat reproduction

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size.

Inhalation Short-Term (1-30 days)	LOAEL= 

35

mg/kg/day

100% IA	UFA=10X

UFH=10X

UFL=10X	Occupational LOC for MOE = 1000	Special Reproduction Study (Rat)

LOAEL = 35 mg/kg/day based on decreased fertility and dystocia, an
indication of hormonal effects.

Inhalation Intermediate-term (1-6 months)	NOAEL= 0.6

mg/kg/day

100% IA	UFA=10X

UFH=10X

	Occupational LOC for MOE = 100	Rat reproduction

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.  For
extrapolation from an oral study for dermal risk assessment, a 5% dermal
absorption factor should be used.  For extrapolation from an oral study
for inhalation risk assessment, a 100% inhalation factor should be used.

3.6	Endocrine Disruption

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

Fenarimol has been evaluated in studies considered in EPA’s Endocrine
Disruptor Screening Program including the Pubertal Female and
Uterotrophic Assays. The Pubertal Female Assay involves the use of rats
to screen for estrogenic and thyroid activity in females during sexual
maturation, and examines abnormalities associated with sex organs and
puberty markers, as well as thyroid tissue.  This assay examines
abnormalities associated with sex organs and puberty markers, as well as
thyroid tissue.  The Uterotrophic assay involves the use of female rats
to screen for estrogenic effects. In this in vivo assay, uterine weight
changes are measured in ovariectomised or immature female rats.

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, fenarimol 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

4.1.1	Metabolism in Primary Crops and Livestock Commodities.

Plants

The registration requirements for plant metabolism are fulfilled. 
Acceptable studies depicting the metabolism of fenarimol in plant
matrices (apple, cherry, grape and banana) are available.  HED has
determined that for enforcement purposes, fenarimol would be an adequate
indicator of misuse, and that the tolerance should be expressed in terms
of parent only.  However, the dietary assessment for grapes and bananas
should also include the metabolites B and C. 

Livestock

The qualitative nature of the residue in milk and ruminant tissues is
adequately understood.  For the purpose of this registration, since hops
are not items of animal feed, considerations of secondary tolerances in
meat, meat byproducts, milk, poultry, and eggs do not apply.

Rotational Crops

There are no rotational crops germane to this action.

4.1.2	Analytical Methodology

Analytical methodology exists for the enforcement of currently
established tolerances for fenarimol.  The method, GC/ECD, is published
in PAM Vol II (Method R039).  For the purposes of this Section 3
registration action, Method R039 may be used to enforce the required
tolerance for fenarimol in/on hops.  Adequate recovery data was
submitted with MRID No. 46842801 for the residues of fenarimol.  This
data included method validation recoveries, concurrent recoveries and
storage stability concurrent recoveries.  The range of recoveries was
64%-94% with an average of 78%.

4.1.3	Multiresidue Methods

The Pesticide Analytical Manual (PAM) Vol. II lists three GC/ECD
methods, designated as Methods I, II, and III, for the enforcement of
tolerances for fenarimol residues in/on plant and animal commodities. 
Method I determines residues of fenarimol in/on fruits, vegetables, and
miscellaneous other crops (including, but not limited to, apples,
grapes, bananas, grains, beans).  Method II determines residues of
fenarimol in animal commodities (cattle, eggs, milk, and poultry). 
Method III determines residues of fenarimol and its regulated
metabolites (B and C), which are measured as dehydroxyfenarimol, in/on
grapes and its processed commodities.

4.1.4	Storage Stability

Adequate storage stability data for plants are available.  The maximum
storage interval of the hops samples from harvest to extraction was 294
days.  The storage stability study submitted supports the use of
fenarimol in/on hops.  There was only a 65-68% recovery from samples
frozen for 286 days.  However, the concurrent recoveries and method
validation recoveries ranged from 64% to 94% with an overall average of
78% recovery.  These recoveries show stability for fenarimol, and the
33% drop over time is accounted for in the recommended tolerance by the
maximum residue level (MRL) calculator.  

4.1.5	Magnitude of the Reside in Plants

Hops

Three field trials were conducted encompassing Regions 11 (Prosser, WA
and Parma, ID) and Region 12 (Hubbard, OR) during the 1998 growing
season.  Because 94% of hops are currently grown in Region 11, the
Agency recommends that most of the trials be performed in Region 11. 
The number and locations of field trials are in accordance with those
recommended in OPPTS Guideline 860.1500.

ons of Rubigan™ EC at 0.0547 lb ai/A (1X the proposed label rate). 
Each treatment was applied to hop bines for a total of approximately
0.22 lb ai/A.  In the Idaho trial, a fifth application was added to
allow the cones to mature.  A total of approximately 0.27 lb ai/A was
applied in the Idaho trial (0.0547 lb ai/A above the label maximum).  No
adjuvant was added to the spray mixture.  Hops were harvested at 9 to 12
days PHI. 

IR-4 conducted the sample analysis for residues of fenarimol.  The
procedure used was derived from DowElanco: Letcombe Laboratory method,
“Determination of Fenarimol Residues in Fresh, Dried and Spent
Hops.”  Residues were extracted from the samples using methanol,
purified by sodium bicarbonate and methyl tert-butyl ether liquid/liquid
partition and subjected to alumina column clean-up prior to analysis
using GC ECD.  The LLMV in this study was 0.100 ppm fenarimol.  The LOQ
for the method was 0.12 ppm, and the LOD was 0.041 ppm, approximately
one-third of the LOQ.  

Samples were extracted and analyzed on the same day.  Analytical sets
typically consisted of calibration standards, unfortified controls,
fortified controls, and treated samples.  The analytical standard
solutions were stored frozen (-20 ± 6°C).  

The results from the three trials show that the maximum residues in hops
(cones) following a total application of approximately 0.22 lb ai/A and
a PHI of 9 to 12 days was 0.742 ppm (98-OR11 (Hubbard, OR)).  In Idaho,
where approximately 0.2743 lb ai/A was applied, the residues were 0.661
ppm and 0.627 ppm.  Residues of fenarimol have been shown to be stable
for the duration of storage (286 days) that occurred during the conduct
of this study, with a reported recovery of 65-68%.  Residue decline data
were not provided with this study of fenarimol residues on hops.

Conclusions.  The study reflects a 1X use pattern on hops as directed by
the proposed label.  The residue data are supported by the storage
stability study.  The analytical methods are adequate to determine the %
fenarimol in hops.  The requested tolerance level is supported by the
submitted residue data, based on the MRL calculator.  The study included
adequate recovery/method validation data ranging from 64%-94%
recoveries.  Adjustments for the 33% loss in storage stability residue
recovery are incorporated in the calculated tolerance made by the MRL
spreadsheet.  That is, the calculated tolerance is high enough that when
even the highest field trial value (0.742 ppm) is adjusted for residue
decay, the resulting value (1.1 ppm) is still less than the proposed
tolerance value.  The requested tolerance level of 1.2 ppm for fenarimol
on hops is supported by the submitted field trial data.  

4.1.6	Magnitude in Meat, Milk, Poultry, and Eggs

The qualitative nature of the residue in milk and ruminant tissues is
adequately understood.  For the purpose of this registration, since hops
are not items of animal feed, considerations of secondary tolerances in
meat, milk, poultry, and eggs do not apply to this action.  However, it
should be noted that the fenarimol residue chemistry database does not
contain storage stability data for livestock.  Storage stability data
for livestock commodities are required to support the storage intervals
used in the livestock feeding studies.  The registrant is required to
submit the appropriate data upon request of a tolerance for commodities
of animal feed items.

4.1.7	Confined and Field Accumulation in Rotational Crops

There are no rotational crops germane to this action.

4.1.8	Environmental Degradation

Fenarimol is moderately mobile and stable to hydrolysis and
biodegradation.  The only known degradation pathway for fenarimol is
photolysis, which is slow on soil (half-life of 134 days), rapid in
water (half-life of 0.80 days), and may be accelerated by
photosensitizers in the natural environment (half-life of 0.19-0.38
days).  Fenarimol does not hydrolyze at environmental pH values and does
not significantly biodegrade in aerobic or anaerobic soil or water. 
Therefore, fenarimol is likely to degrade quickly in shallow, clear, and
well lit water bodies and persist in deep, turbid, and/or poorly
illuminated water.

Comparative Metabolic Profile

In pome fruit (apple), stone fruit (cherry), and grapes, fenarimol was
either the only, or the most predominant, residue identified in the
metabolism studies.  In a banana metabolism study, nuarimol per se, a
compound analogous to fenarimol, was the predominant residue.

Fenarimol is extensively metabolized in the rat; less than one percent
of the parent is recovered, while more than 30 metabolites are
recovered.  Metabolism of fenarimol occurs by the oxidation of the
carbinol phenyl-ring and pyrimidine ring and some qualitative and
quantitative differences in sexes and dose level were noted.

4.1.10	Toxicity Profile of Major Metabolites and Degradates

The primary degradation process in the environment appears to be
photolysis.  The degradation pathways appear to be by oxidation of the
quaternary carbon and possible hydroxalation of the chlorobenzene rings.
Ring closure, ring migration and reduction of the quaternary carbon may
also occur.  Major degradates of fenarimol include the photolysis
products 4-chloro-2-(5-pyrimidyl)-2'-chlorobenzophenone (U-1),
6-chloro-1-hydroxy-9H-fluoren-9-one (U-2), 3-chloro-9H-fluoren-9-ol
(U-7), and an unidentified compound, U-6.  Because no submitted aqueous
photolysis studies have reported a complete mass balance, there is
uncertainty in the identity and rates of formation and decline of major
degradates of fenarimol.  Over 80 minor photolysis products have been
observed, most of which are chlorinated.  No information is available on
the toxicity, fate, and/or transport properties of these or other
possible degradates, therefore they were assumed to have similar
toxicity to the parent compound.  

 

4.1.11	Pesticide Metabolites and Degradates of Concern

Table 4.1.11.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop*	Fenarimol	Fenarimol

	Rotational Crop	Not Determined	Not Determined

Livestock

	Ruminant	Fenarimol	Fenarimol

	Swine

	Poultry

Drinking Water	Fenarimol and U-1, U-2, U-7, and U-6	Fenarimol and U-1,
U-2, U-7, and U-6

* Registered and proposed crops

HED concluded that residues of parent plus metabolites B and C
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-1,4-dihydro-5-pyrimidinem
ethanol and
5-[2-chlorophenyl)-(4-chlorophenyl)methyl]-3,4-dihydro-4-pyrimidinol
measured as the total of 5-[(2-
chlorophenyl)-(4-chlorophenyl)methyl]pyrimidine ] should be included in
the dietary risk assessment for banana and grape commodities (DP#:
277692, D. Drew, 9/17/2001) only.

4.1.12	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED (DP#: 363249; G. Orrick; 6/30/2009) and incorporated
directly into this dietary assessment.  Water residues were incorporated
in the DEEM-FCID into the food categories “water, direct, all
sources” and “water, indirect, all sources.”   Because a previous
dietary assessment resulted in dietary risk exceedances, revisions to
the current labels were submitted to the Agency.   The revised
assessment evaluated the maximum use patterns of the current uses on
turf and ornamentals as they appear on the proposed labels. 
Additionally, exposure was estimated for fenarimol use on turf that is
restricted to professional stadia and golf course tees, greens, and
fairways at the currently proposed application rates.  Exposure
estimates reflect total residues of concern that include fenarimol and
its degradates, U-1, U-2, U-6, and U-7, of risk concern.

The Pesticide Root Zone Model (PRZM v3.12.2) and Exposure Analysis
Modeling System (EXAMS v2.98.4.6) simulation models coupled with the
input shell PE (v5.0) was used to generate EDWCs of fenarimol residues
that may occur in surface water used as drinking water.  Screening
Concentration in Ground Water (SCI-GROW v2.3) is a regression model used
as a screening tool to estimate pesticide concentrations found in ground
water used as drinking water.

The surface water EDWCs for the currently proposed use patterns are
similar to those in the previous drinking water assessment (DP#: 330715;
G. Orrick; 9/13/2007), as the maximum use pattern for turf has not
changed with the exception that application is currently limited to
ground equipment.   If turf uses of fenarimol are limited to
professional stadia and golf course tees and greens at 11 lbs ai/A and
to golf course fairways at 8.1 lbs ai/A, exposure estimates are reduced,
resulting in a 1-in-10-year annual mean EDWC of 66 µg/L.  

Table 4.1.12.  Tier II Total Residue EDWCs in Surface Water and Ground
Water from Currently and Potentially Proposed Labels for Current and
Proposed Fenarimol Uses.

Source	Use (modeled rate)	1-in-10-year Peak Exposure (ppb)	1-in-10-year
Annual Mean Exposure (ppb)	30-year Mean Exposure (ppb)

Current Use Pattern

Surface water	Turf (11 lbs ai/A/year)	283	226	154

Ground water

19	19	<19

EFED Proposed Use Pattern

Surface water

	Professional stadia, golf course tees and greens (at 11 lbs ai/A/year)
and golf course fairways (at 8.1 lbs ai/A/year)	80	66	44

Ground water

19	19	<19

4.1.13	Food Residue Profile

The registration requirements for magnitude of the residue in plants
have been evaluated and deemed fulfilled.  The field trials on hops are 
 SEQ CHAPTER \h \r 1 adequate.  An adequate number of trials were
conducted reflecting the proposed use patterns in the appropriate
geographic regions, and the appropriate commodities were collected at
the proposed PHIs.  Samples were analyzed using adequate analytical
methods.  The available data will support a tolerance for residues of
1.2 ppm on hops.  

4.1.14	International Residue Limits

Residues definitions are harmonized across US/Mexico/Codex (Appendix C).
 Specific tolerances in the US are either the same as Codex values or
lower.  Therefore, there are no issues for US exports.  An International
Residue Limits Status (IRLS) sheet is attached (Appendix D).

Additionally, in order to harmonize with a Codex MRL of 0.3 ppm for
apples, EPA has proposed increasing the tolerance for residues of apples
from 0.1 ppm to 0.3 ppm.  The Agency has determined that with the
increased tolerance there is a reasonable certainty that no harm will
result from aggregate exposure. 

4.2	Dietary Exposure and Risk

A chronic dietary (food + drinking water) exposure analysis for
fenarimol was conducted by ARIA (PP#: 6E7074, DP#: 331895, B. Hanson,
7/23/2009).  

4.2.1	Acute Dietary Exposure/Risk

There was no appropriate endpoint for assessing acute dietary exposure;
therefore, no acute dietary risk assessment was performed.

4.2.2	Chronic Dietary Exposure/Risk

The chronic dietary exposure assessment for fenarimol is highly refined
using anticipated residues based on FDA monitoring data for apples,
bananas, cherries, grapes and pears.  Field trial residue data were used
for pecans.  %CT information and processing factors, where available,
were used in the assessment. There were no PDP monitoring data available
for fenarimol. Bananas were included in the assessment to account for
imported bananas.  As part of the current petition (PP#: 6E7074), ARIA
recommended (DP#: 331894, D. Rate, 11/15/2006) for a tolerance of 1.2
ppm in/on hops cones, dried.  

The chronic dietary risk assessment for fenarimol at the EDWC of 226 ppb
showed that chronic dietary risk estimates are above ARIA’s level of
concern (i.e. >100% cPAD) for infants (<1 year old), the highest exposed
population subgroup (260% of the cPAD), as well as for children 1-2
years old (120% of the cPAD) and children 3-5 years old (110% of the
cPAD).

At the EDWC of 66 ppb as a result of EFED’s proposed changes in the
use pattern (i.e., limited to professional stadia and golf course tees
and greens at 11 lbs ai/A and to golf course fairways at 8.1 lbs ai/A),
the chronic dietary risk estimates are below ARIA’s level of concern
(i.e. <100% cPAD) for infants (<1 year old), the highest exposed
population subgroup (76% of the cPAD), as well as for the general US
population (23% of the cPAD).

Table 4.2.2.a.  Summary of Dietary Exposure and Risk for Fenarimol with
an EDWC of 226 ppb.  

Population Subgroup1	DEEM Acute Dietary Analysis,

95th Percentile	DEEM Chronic Dietary Analysis

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

General U.S. Population	

NA1

	0.004775	80

All Infants (< 1 year old)

0.015626	260

Children 1-2 years old

0.007088	120

Children 3-5 years old

0.006630	110

Children 6-12 years old

0.004571	76

Youth 13-19 years old

0.003448	58

Adults 20-49 years old

0.004464	74

Adults 50+ years old

0.004687	78

Females 13-49 years old

0.004436	74

1 NA = Not Applicable; no acute dietary endpoint was identified for
these population subgroups.

Table 4.2.2.b.  Summary of Dietary Exposure and Risk for Fenarimol with
an EDWC of 66 ppb.  

Population Subgroup1	DEEM Acute Dietary Analysis,

95th Percentile	DEEM Chronic Dietary Analysis

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

General U.S. Population	

NA 1

	0.001402	23

All Infants (< 1 year old)

0.004570	76

Children 1-2 years old

0.002080	35

Children 3-5 years old

0.001942	32

Children 6-12 years old

0.001337	22

Youth 13-19 years old

0.001010	17

Adults 20-49 years old

0.001315	22

Adults 50+ years old

0.001374	23

Females 13-49 years old

0.001300	22

1 NA = Not Applicable; no acute dietary endpoint was identified for
these population subgroups.

4.2.3	Cancer Dietary Risk

HED classified fenarimol as a “not likely to be carcinogenic to
humans” based on the absence of significant tumor increases in two
adequate rodent carcinogenicity studies; therefore, quantification of
human cancer risk is not required.

4.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The DEEM-FCID( chronic analysis was performed using ARs from field trial
data, processing factors and updated %CT information.  

Table 4.3.a.  Processing Factors Used in the Chronic Dietary Analysis
for Fenarimol

Commodity	Data Used	Anticipated Residue (PPM)	Processing Factor

Apples

   juice

   dried	1996-1999 FDA Data for Apples	0.0015	1x

0.05x

8x

Bananas

   dried	1996-1999 FDA Data for Bananas	0.0045	1x

3.9x

Cherries

   juice

   dried	1996-1999 FDA Data for Cherries	0.0034	1x

1.5x

4x

Filberts	Field Trial Data

(MRID 43758901)	0.01	1x

Grapes

   juice

   raisin

   wine	1996-1999 FDA Data for Grapes	0.0060	1x

1.2x

1.6

1x

Pears

   juice

   dried	1996-1999 FDA Data for Pears	0.0015	1x

0.05x

6.25x

Pecans	Field Trial Data

(MRID 00145943)	0.0037	1x

Meat-lean (fat/free) w/o bones	

Ruminant Feeding Study

(MRID 40098605)	0.00009	1x

Meat-fat w/o bones

0.0001	1x

Dried meat*

0.00009	1.92x

Meat byproducts*

0.0003	1x

Other organ meats*

0.0003	1x

Kidney*

0.0001	1x

The DEEM default processing factors were used for all food forms except
apple juice, pear juice, grape juice, and raisins, for which the
aforementioned factors derived from the processing studies were used. 
Since the previous DEEM, tolerances on liver have been revoked since it
is considered to be included in the meat byproducts tolerance.

A Screening Level Usage Analysis (SLUA) for fenarinol was provided by
BEAD based on data years 2001-2007 (DP#: 366920, A. Grube, 7/15/2009).
The maximum %CT was used for estimating chronic dietary exposure.  Of
the currently registered uses of fenarimol, wet apple pomace is the only
commodity that is considered a livestock feed item; therefore, the
maximum %CT for apples was used for livestock commodities.

Table 4.3.b.  SLUA %CT Information

Crop	Max. %CT

Apples	20

Cabbage	< 2.5

Cherries	15

Grapes	25

Peaches	< 2.5

Pears	10

5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

The current petition for fenarimol results in no
non-occupational/residential exposures.    However, potential
post-application short-term dermal exposures to adult golfers are
possible.  In a previous HED human health risk assessment (DP#: 285162,
B. O’Keefe, 9/3/2002) short-term dermal exposure to adult golfers was
assessed.  Resulting risk estimates were not of concern for adult
golfers (MOE of 14,000 vs. a LOC of 1000; at a dermal daily dose of
0.0026 mg/kg).  Because no changes have occurred for use rates on golf
courses, the short-term assessment for golfers need not be revised.

5.1	Other (Spray Drift, etc.)

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

AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

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

6.1	Acute Aggregate Risk

An acute aggregate-risk assessment was not performed because no
appropriate endpoint was available to determine the aRfD for the general
population or any population subgroup.   

6.2	Short-Term Aggregate Risk 

The short-term aggregate risk assessment takes into account average
exposure estimates from dietary consumption of fenarimol (food and
drinking water) and residential/non-occupational exposures.  Because
ARIA/HED is requesting that changes be made to the labels of all
fenarimol products restricting use to turf use on professional stadia
and golf course tees, greens, and fairways at the currently proposed
application rates, the only residential/non-occupational exposure
scenario to be evaluated is short-term dermal exposure to adult golfers.
 Short-term dermal exposure was previously assessed by HED (DP#: 285162,
B. O’Keefe, 9/3/2002).  The target maximum daily exposure to fenarimol
residues is 35 mg/kg/day.  The estimated MOE of 8900 exceeds the target
MOE of 1000.  Therefore, the short-term aggregate risk exposure estimate
is not of concern to the Agency and does not exceed ARIA’s or HED’s
LOC (i.e. MOEs less than or equal to 1000). 

Table 6.2.  Short-Term Aggregate Risk for Fenarimol

Population	NOAEL	Food + Drinking Water	Dermal	LOC	MOE Aggregate

EXP	EXP

Adults 20-49 years old	35	0.001315	0.0026	1000	8900

	LOC=Level of Concern

	MOE= NOAEL (or LOAEL)/exp

MOE Aggregate= NOAEL/(EXPfood +EXPdermal)

6.3	Intermediate/Long-Term Aggregate Risk

Intermediate/long-term exposures are not anticipated.  Therefore an
intermediate-term aggregate risk assessment was not performed.  

6.4	Chronic Aggregate Risk

Since the chronic aggregate risk assessment includes exposure from food
and drinking water only, and the chronic dietary analysis that was
performed included both, no further calculations are necessary.  As
noted in the DEEM memo from ARIA (PP#: 6E7074, DP#: 331895, B. Hanson,
7/23/2009), at the maximum rates of the current uses, as they appear on
the proposed labels, the chronic dietary risks exceed ARIA’s and
HED’s level of concern.  With EFED’s suggestions for restricting
fenarimol use on turf to professional stadia and golf course tees,
greens, and fairways at the currently proposed application rates
(resulting in an EDWC of 66 ppb) the chronic dietary and, therefore,
chronic aggregate risks are below ARIA’s and HED’s level of concern.

6.5	Cancer Aggregate Risk

Fenarimol is “not likely to be carcinogenic to humans”; therefore,
an aggregate cancer risk assessment was not performed.      

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

8.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

8.1	Handler Exposure and Risk

Based upon the proposed use pattern, RD believes the most highly exposed
occupational pesticide handlers are mixer/loaders using open-pour
loading of liquids, and applicators using open-cab air-blast spray
machinery.    Since the treatment blocks (i.e., areas treated) are
relatively small in hop yards (as compared to typical field crops such
as cotton, corn, soybeans or wheat), ARIA believes pesticide handlers
will be exposed to short-term duration (1-30 days) exposures but not to
intermediate-term (1-6 months) duration exposures.   Although multiple
applications are possible, they are separated by 14 day retreatment
intervals.   It is unlikely that pesticide handlers would be exposed
continuously for 30 days or more.  

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  The HED Science Advisory Council for
Exposure (ExpoSAC) SOP Number 12 (29 March 2000) directs that although
the same individual may perform all those tasks, they shall be assessed
separately.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998).   

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).   The product label directs applicators and other handlers
to wear coveralls over short-sleeved shirt and short pants,
chemical-resistant footwear over socks, chemical-resistant eyewear,
chemical-resistant headgear for overhead spraying and chemical-resistant
apron when cleaning equipment, mixing or loading.

Relative to this assessment of the proposed use on hops, HED previously
identified short-term dermal and inhalation toxicological endpoints. 
The NOAEL is 35 mg ai/kg bw/day for dermal and inhalation exposure.  The
NOAEL is identified from a "special reproduction study" (MRID 00235175)
where the toxic effects seen were decreased fertility and dystocia.  HED
also identified a 5% dermal absorption factor for use in dermal risk
assessment.  HED assumes 100% absorption via the inhalation route.  See
Table 8.1 for a summary of exposures and risks to occupational pesticide
handlers. 



Table 8.1    Estimated Handler Exposure and Risk from the Use of
Fenarimol on Hops

Unit Exposure1

mg ai/lb handled	

Applic. Rate2	

Units Treated3

Per Day	

Average Daily

Dose4

mg ai/kg bw/day	

NOAEL5

mg ai/kg bw/day	

MOE6

Mixer/Loader - Liquid - Open-pour

Dermal:

SL No glove   2.9 HC

SL W gloves     0.023 HC

Inhal.                0.0012 HC	

0.055 lb ai/A	

40 A	

Dermal:

SL No gloves 0.00456

SL W gloves   0.000036

Inhal         0.000038	

35	SL No gloves

7,612

SL W gloves

472,972

Applicator - Airblast - Open Cab

Dermal:

SL No gloves  0.36 HC

SL W gloves   0.24 HC

Inhal               0.0045  HC	

0.055 lb ai/A	

40 A	

Dermal:

SL No gloves 0.000566

SL W gloves  0.000377

Inhal        0.00014	

35	

SL No gloves

49,575

SL W gloves

67,698

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Dermal = dermal exposure.  SL No
gloves = single layer work clothing no gloves.  SL W gloves = single
layer work clothing WITH the use of protective gloves   Inhal. =
Inhalation.  Units = mg a.i./pound of active ingredient handled.  Data
Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2.  Applic. Rate. = Taken from the Rubigan label.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.   Science Advisory Council for
Exposure; Revised 7/5/2000; 

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated *
5.0 % (dermal absorption) ( Body Weight (70 kg).  

5.  NOAEL = No Observable Adverse Effect Level (35 mg ai/kg bw/day for
short-term dermal and inhalation exposures)

6.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL)  ( ADD.    Dermal and inhalation exposures are summed then
divided into NOAEL to determine MOE

A MOE of 1000 is adequate to protect occupational pesticide handlers
from short-term exposures.  Since the estimated MOEs range from 7,612 to
472,972, these exposures do not exceed ARIA’s or HED’s level of
concern.

8.2	Post-Application Exposure Risk

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  HED in conjunction with the Agricultural Re-entry Task
Force (ARTF) has identified a number of post-application agricultural
activities that may occur and which may result in post-application
exposures to pesticide residues.  HED has also identified Transfer
Coefficients (TC) (cm²/hr) relative to the various activities which
express the amount of foliar contact over time, during each of the
activities identified.  For hops, the highest TC is 2,000 cm²/hr which
results from harvest activities or stripping or training the vines.   
As a “screening” level assessment, RD herein uses 2,000 cm²/hr. 
The transfer coefficients used in this assessment are from an interim
transfer coefficient Standard Operating Procedure (SOP) developed by
HED’s ExpoSAC using proprietary data from the ARTF database (SOP #
3.1).  

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20 % of the application rate is available as dislodgeable foliar
residue on the day of application (day 0).  This is adapted from the
ExpoSAC SOP No. 003 (5/7/1998 - Revised 8/7/2000).  

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

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

 and where:

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

0.055 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 0.123 µg/cm2 , therefore,

0.123 µg/cm2 * 2,000 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.05 (5% dermal
absorption) ( 70 kg bw = 0.00141mg/kg bw/day.

MOE = NOAEL ( ADD then 35.0 mg/kg bw/day ( 0.00141 mg/kg bw/day =
24,822.

A MOE of 1000 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOE is 24,822 on the
day of application, the proposed use does not exceed ARIA’s or HED’s
level of concern.

8.3	Restricted Entry Interval (REI)

Fenarimol is classified in Toxicity Category III for acute dermal
toxicity and acute inhalation toxicity.  It is classified in Toxicity
Category II for primary eye irritation.  There was no study available
with which to classify primary dermal irritation.  It is not a dermal
sensitizer by the Magnusson and Kligman method.  The Rubigan® label
lists a 12 hour REI.    Since fenarimol is classified in acute Toxicity
Category II for primary eye irritation, the interim WPS default REI is
24 hours (see Title 40 Code of Federal Regulations § 156.208 (c) (1)
and (2).  The product label should reflect the interim WPS REI of 24
hours.

9.0	TOLERANCE SUMMARY

The available data support a tolerance for residues of fenarimol on hops
cones, dried at 1.2 ppm.

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

The scientific quality and completeness of the available toxicology data
base are considered adequate to support the registration and proposed
tolerances for fenarimol.  Pending receipt of a reference sample and
provided the following requirements are met, ARIA and HED conclude that
there are no toxicological, environmental, residue chemistry or
occupational data requirements that would preclude establishing a
conditional registration and permanent tolerance for residues of
fenarimol on hops.

Turf uses of fenarimol must be limited to professional stadia and golf
course tees and greens at 11 lbs ai/A and to golf course fairways at 8.1
lbs ai/A, in order for the chronic dietary and chronic aggregate risks
to be acceptable to ARIA and HED.  Additionally, in order to harmonize
with a Codex Maximum Residue Limit (MRL) of 0.3 ppm for apples, EPA is
increasing the tolerance for residues of apples from 0.1 ppm to 0.3 ppm.

10.1	Toxicology

	

OPPTS 870.3465.  Subchronic (28-day) inhalation study. 

A 28-day subchronic inhalation study is required. The Gowan Company
(letter April 10, 2002) requested that the Agency rescind this data
requirement.  They disagree on its need and cite that this issue was
addressed by CropLife America, an industrial organization and in a
presentation to OPP.   In a response to comments (DP#: 282386, B.
O’Keefe, 5/8/2002), HED stated there have been some changes in HED
policy regarding the need for subchronic inhalation toxicity studies. As
a result of these changes, the Gowan Company may submit a waiver for the
28-day inhalation study. This waiver must contain sufficient data on the
particle size of the sprays and other preparations that may result in
inhalation exposure. It also must contain sufficient other information
regarding the potential inhalation exposure such as duration of exposure
in terms of hours per day, per week, etc. The completed waiver request
will be presented to a peer review committee that will determine the
need for the subchronic inhalation toxicity study. This peer review
group will consist of toxicologists with expertise in inhalation
toxicology as well as occupational and residential exposure
representatives. The decision on the need for the subchronic inhalation
toxicity study will be based on all relevant factors. The limited
information provided in the April 10, 2002 letter is not sufficient to
bring to a peer review committee.  HED is already using an oral toxicity
endpoint for the inhalation exposure scenarios. However, the subchronic
inhalation toxicity study is considered a more appropriate route
specific endpoint for risk assessment for inhalation exposures.

OPPTS 870.7800.  Immunotoxicity study. 

An immunotoxicity study is required.  Please see Appendix E.

10.2	Environmental Fate and Effects

1)   Reduce the maximum single application rate for hops from 14 to 7 fl
oz, which is the originally proposed rate.

	2)  Change “recommended” to “listed” in directions for roses.

10.3	Residue Chemistry

	1)  Although it will not affect the recommendation of the tolerance of
fenarimol residues on hops, the fenarimol residue chemistry database
does not contain storage stability data for livestock commodities. 
Storage stability data for these commodities are required to support the
storage intervals used in the livestock feeding studies. 

	2)  A previously submitted 0.5 gram sample has expired.  A 5 gram
sample of analytical reference standard must be submitted to the Agency
Pesticide Repository.

10.4	Occupational and Residential Exposure

The Rubigan® label lists a 12 hour REI.  Since fenarimol is classified
in acute Toxicity Category II for primary eye irritation, the interim
WPS default REI is 24 hours.  The product label should reflect the
interim WPS REI of 24 hours.

11.0	REFERENCES

Endpoint Selection Document

Fenarimol – Third Report of the Hazard Identification Assessment
Review Committee; J. Doherty, TXR No. 0051030, 7/29/2002.

Risk Assessments

Fenarimol. Updated HED Human Health Assessment for the Tolerance
Reassessment

Eligibility Decision (TRED) Document; DP#: 285162; B. O’Keefe,
9/3/2002.

Fenarimol (PC 206600) Scoping Document in Support of Registration
Review, DP#: 336007, D. Drew, 3/21/2007.

Dietary Exposure Memorandum

Fenarimol.  Chronic Dietary (Food and Drinking Water) Exposure
Assessment for the Petition Proposing Tolerances for Residues of
Fenarimol on Hops; DP#: 331895, B. Hanson, 7/23/2009.

Drinking Water Memorandum

Fenarimol: Follow-up Tier II Drinking Water Exposure Assessment for the
Section 3 New Use on Hops; DP#: 363249; G. Orrick; 6/30/2009.

Residue Chemistry Data Reviews

Fenarimol.  Section 3 Registration on Hops.  Summary of Analytical
Chemistry and Residue Data.  Petition Number 6E7074, DP#: 331894, D.
Rate, 11/15/2006.

Occupational and Residential Exposure Memorandum

FENARIMOL:  Amendment to Document DP Code 330744 Regarding the Use of
Fenarimol on Hops; DP#: 367402; M. Dow; 7/27/2009.

Appendix A:  Toxicology Assessment

A.1	Toxicology Data Requirements 

Table A.1.  Toxicology Data Requirements

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

870.3100

90-Day oral toxicity rodents (rat)	00235175, 45502302,

45502304 (1978)/

Acceptable/Non-Guideline

0, 2.5, 6.5 or 17.5 both sexes.	NOAEL = 6.5 mg/kg/day

LOAEL = 17.5 mg/kg/day based on increased relative liver weight and
increased severity of fatty liver.

870.3150

90-Day oral toxicity in Non-rodents (dog)	00056090 (1975)/

Acceptable/Guideline

0, 1.25, 5 or 20 mg/kg/day.	NOAEL and LOAEL > 20 mg/kg/day (HDT). A
one-year study (MRID 00146959 satisfies this guideline).

870.3200

21/28-Day dermal

toxicity (rat)	00153312 (1985)

Acceptable/Guideline

0, 500 or 1000 mg/kg/day for RUBIGAN

(emulsifiable) formulation and 1000 mg/kg/day for technical fenarimol.
NOAEL < 1000 mg/kg/day

LOAEL = 1000 mg/kg/day based on slight liver weight effects.

Although this study is acceptable, it is of limited usefulness for risk
assessment because it did no assess for reproductive effects or possible
effects on aromatase.

870.3250

90-Day dermal toxicity	

No study.	

No study.

870.3465

90-Day inhalation toxicity	

No study.  Required.	

No study.  Required/

870.3700a

Prenatal

developmental in

rodents	0042543/(1979)

Unacceptable/

Guideline but acceptable with other

studies (see below).

0, 5, 13, 35 mg/kg/day	Maternal NOAEL > 35 mg/kg/day (HDT)

LOAEL not established

Developmental NOEL = 13 mg/kg/day

LOAEL = 35 mg/kg/day based on hydronephrosis (this effect was shown to
be reversible and is not considered adverse).

Special study to

assess for

reversibility of

hydronephrosis.	00132988/(1983)

Acceptable/Non-

Guideline. 

0 and 35 mg/kg/day.	Maternal NOAEL = not established

LOAEL = 35 mg/kg/day based on sporadic dystocia.

Developmental NOEL < 35 mg/kg/day.

LOAEL = 35 mg/kg/day based on kidney effects

(hydronephrosis, this effect was shown to be reversible and is not
considered adverse)

Above two studies combine to satisfy the guideline requirement for a
developmental toxicity study in rats.

870.3700b

Prenatal developmental in non-rodent (rabbit)	44716001/ 1990/

Acceptable/Guideline

0, 15, 50 or 150 mg/kg/day.	Maternal NOAEL = 50 mg/kg/day

LOAEL = 150 mg/kg/day based on increased abortions and decreased body
weights and gain and food consumption.

Developmental NOAEL = > 150 mg/kg/day

870.3800

Reproduction and fertility effects (rat)	00235175, 45502301

(1977)

Unacceptable/Not

Upgradeable

0, 2.9, 7.9 or 20 mg/kg/day in males; 0, 3.4, 9 or 23.5 mg/kg/day in
females	Parental/Systemic NOAEL > 23.5 mg/kg/day (HDT)

LOAEL not established

Reproductive LOAEL < 2.9 mg/kg/day based on decreased fertility in the
F1 generation second mating.  Offspring NOAEL and LOAEL could not be
established due to anti-fertility effects in the parental generations,
which prevented valid assessment of the pup generations.

Second study	00235175, 45502302

(1978)

Acceptable/Guideline

0, 0.6, 1.2, 2.5 mg/kg/day in males and 0, 0.8, 1.7 or

3.2 mg/kg/day in females.	Parental/Systemic NOAEL > 2.5 mg/kg/day in
males and 3.2 mg/kg/day in females (HDT) 

LOAEL not established

Parental Reproductive NOAEL = 0.6 mg/kg/day

LOAEL = 1.2 mg/kg/day based on decreased liveborn litter size in the F1
and F2 generations.

Offspring. NOAEL = 1.2 mg/kg/day.

LOAEL = 2.5 mg/kg/day based on decreased survival indices and possible
presence of hydronephrosis

Above two studies combine to satisfy the guideline requirement for a
multi generation reproduction study in rats.

870.3800

Reproduction and fertility effects

(Special Study)	00084968

Acceptable/Non-Guideline

0, 35 mg/kg/day	LOAEL for males and females > 35 mg/kg/d

(males decreased mating and epididymal weight,

females dystocia and related parameters)

NOAEL not established

870.4100a

Chronic toxicity rodents	See combined chronic feeding and

carcinogenicity study.	

NA

870.4100b

Chronic toxicity (dog)	00146959/1985/

Acceptable/Guideline

0, 1.25, 12.5 or 125 mg/kg/day.	NOAEL = 12.5 mg/kg/day

LOAEL = 125 mg/kg/day based on reversible increase in liver weight and
increase in alkaline phosphatase.

870.4200 Combined

Chronic Feeding and

Carcinogenicity (rats)	00235175/1978/

Acceptable/Guideline

0,2, 5.3, or 14.6 mg/kg/day for male and 0, 2.8, 7.6 or 21.55 mg/kg/day
for females.	NOAEL = 5.3 mg/kg/day.

LOAEL = 14.6 mg/kg/day based on hormonal changes (prolactin and
luteinizing hormone) and possibly fatty liver change and decreased WBC
count in females.

870.4200 Combined

Chronic Feeding and

Carcinogenicity rats	00153313/1985/

Acceptable/Guideline

0.5, 1, 2 mg/kg/day for males and 0, 0.6, 1.2 or 2.3 mg/kg/day for
females.	NOAEL = 1 mg/kg/day in males and > 2.3 mg/kg/day in females.

LOAEL = 2 mg/kg/day in males based on minimal gross and microscopic
changes in liver and possibly testis.

There was no evidence of carcinogenicity or increase in liver tumors.

The above two studies combine to satisfy the guideline requirement for
carcinogenicity testing in rats. It should be noted that the potential
for fenarimol to cause decreased fertility and dystocia at the dose
levels tested in the rat studies contributed to the weight of evidence
that the rat was assessed at adequate dose levels.

870.4300

Carcinogenicity mice	0071920/1978/

Acceptable/Guideline

0, 7, 24 and 86 mg/kg/day for both sexes.	NOAEL = > 86 mg/kg/day (HDT).

The HIARC and CARC concluded that there was no evidence of
carcinogenicity although liver tumors were highest in the high dose
group but incidence was considered too low to be meaningful.

870.6200a

Acute neurotoxicity screening battery

(rat)	No study.	No study.  Not required.

870.6200b

Subchronic neurotoxicity screening battery (rat)	No study.	No study. Not
required.

870.6300

Developmental neurotoxicity (rat)	Study is being required and special
inclusions to assess for possible effects due to hormonal disruption
required.

870.7485

Metabolism and pharmacokinetics

(rat)	00261349 and 00261350 (1985)	A series of studies with radioactive
label in different positions established that fenarimol is readily
absorbed and excreted with the biliary route being most important in
rats but the urinary route being important in rabbits. Metabolism was
extensive with 30 or more metabolites noted. Little radioactivity
remained in the tissue.

870.7600

Dermal penetration	00162538, 1985	Dermal absorption rates of 1.36%,
2.32%, 3.12% and 4.12% (mean 2.73%±1.17%) were observed for the four
individual monkeys in the study. However, from 8 to 29% of the dermally
applied radioactivity was not accounted for. Since there was variation
in the dermal absorption in the four monkeys and there was unaccounted
for radioactivity, a dermal absorption value of 5% from this study was
considered appropriate for risk assessment. In addition, the result of a
dermal absorption study with rabbits (MRID No.: 00046639, 1980), using
three formulations, indicated up to approximately 15% dermal absorption.
By comparison the rabbit developmental toxicity study (MRID No.:
47716001) and the rabbit 21-day dermal toxicity study (MRID No.:
00153312) also indicated approximately 15% dermal absorption. However,
the rabbit is recognized as being a poor model for estimating dermal
absorption in humans, since rabbit skin is more permeable; therefore,
the 5% value based primarily on the monkey study is considered
appropriate. Refer to the Third Report of the HIARC (J. Doherty,
7/29/2002) for a more detailed discussion of dermal absorption.

Special studies	Several special studies were presented to investigate
the mechanism of the decreased fertility and dystocia. These are listed
above in this table under the heading for the study type which they most
closely resemble (i.e. reproduction or developmental)

A.2   Toxicity Profiles

Table A.2.  Acute Toxicity Profile for Fenarimol

Guideline

No.	

Study Type	

MRID No.:	

Result

870-1100	

Acute Oral Toxicity - rat.

Elanco, Study No.: R-O-289-82, December 30, 1982	

00125392	

LD50 > 599 mg/kg.  

Toxicity Category III

Classification: Guideline

870-1200	

Acute Dermal Toxicity - rabbit.  Elanco Study No.: B-D-27-82, February
17, 1983	

00125392	

LD50 >1998 mg/kg.

Toxicity Category III

Classification: Minimum

870-1300	

Acute Inhalation

Toxicity - rat.  Elanco, Study No.: R-H-102-82, November 16, 1982.	

00125292	

LC50   > 5.20 mg/L for males.

LC50 between 2.87 and 5.2 mg/L for females.

Toxicity Category III

Classification: Guideline

870-2400	

Primary Ocular Irritation - Rabbit.  Elanco, Study No.: B-E-32-82,
February 1, 1982	

00125392	

Day 1: 6/6 corneal opacity (score of 5); 5/6 iris irritation (score 5);
6/6 conjunctival irritation (score of 1-2).   Day 7: 3/6 corneal opacity
and conjunctival irritation.  Day 14 all irritation cleared.  

Toxicity Category II

Classification: Minimum

870-2500	

Primary Dermal Irritation - rabbit.	

--	

No study available. 

870-2600	

Dermal Sensitization - guinea pig.  Elanco, Study No.; GP-9538, January
1, 1980.	

00084966	

No evidence of dermal sensitization in the Guinea Pig Maximization test
of Magnusson and Kligman. 

Classification: Minimum.  

Appendix B:  Review of Human Research

No MRID - PHED Surrogate Exposure Guide

Appendix C:	Maximum Residue Limits

Table C.  Summary of US and International Tolerances and Maximum Residue
Limits1 

US	Canada	Mexico	Codex

Residue Definition:

40CFR180.421.

fenarimol,
alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol  
None	fenarimol	fenarimol

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity	US	Canada	Mexico	Codex

Apple	0.1	None	0.1	0.3 (pome fruit)

Apple, wet pomace	0.3

	5 (dry)

Banana	0.25

0.5	0.2

Cattle, fat	0.01

	Cattle, kidney	0.01

	0.02 (*)

Cattle, meat	0.01

	0.02 (*)

Cattle, meat byproducts, except kidney	0.05

	0.05 (liver)

Cherry, sweet	1.0

	1

Cherry, tart	1.0

	1

Goat, fat	0.01

	Goat, kidney	0.01

	Goat, meat	0.01

	Goat, meat byproducts, except kidney	0.05

	Grape	0.1.

0.2	0.3

Hazelnut	0.02

	Horse, fat	0.01

	Horse, kidney	0.01

	Horse, meat	0.01

	Horse, meat byproducts, except kidney	0.05

	Pear	0.1

0.1	0.3 (pome furit)

Pecan	0.02

	0.02 (*)

Sheep, fat	0.01

	Sheep, kidney	0.01

	Sheep, meat	0.01

	Sheep, meat byproducts, except kidney	0.05

	1 includes comparison only where there is a US tolerance.

Appendix D:  International Residue Limit Status

Table D.  International Residue Limit Status

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  

α-(2-chlorophenyl)-α-(4-chlorophenyl)-5-pyrimidinemethanol	Common
Name: Fenarimol

	X Proposed tolerance

( Reevaluated tolerance

( Other	Date:  18/SEP/2006

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

( No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	Petition
Number:  6E7074

DP Num:  331894

Other Identifier:

Residue definition (step 8/CXL): 

fenarimol	Reviewer/Branch:  Debra Rate/RIMUER Branch

	Residue definition: fenarimol
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol] and
its metabolites
[alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-1,4-dihydro-5-pyrimidinem
ethanol and 5-[(2-chlorophenyl)
(4-chlorophenyl)methyl]-3,4-dihydro-4-pyrimidinol measured as the total
of fenarimol and 5-[(2-chlorophenyl)-(4-chlorophenyl)methyl]pyrimidine

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

Hops, dry	5.	Hops

	Limits for Canada	Limits for Mexico

X   No Limits

(No Limits for the crops requested	(No Limits

X No Limits for the crops requested

Residue definition: N/A

	Residue definition:  fenarimol

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

	

S.Funk, 09/18/2006

Appendix E:  Immunotoxicity 

Guideline Number: 870.7800

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Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use
in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. For
example, animal studies have demonstrated that immunotoxicity in rodents
is one of the more sensitive manifestations of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive,
and endocrinologic toxicities.  Additionally, the EPA has established an
oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed
immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

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