Document ID: EPA-HQ-OPP-2007-0398-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-07T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:		01-APRIL-2008

SUBJECT:	Human-Health Risk Assessment for Spirodiclofen for Use on Hops.

		Decision No. 378132.  40 CFR §180.608.  

Ingredient:  Spirodiclofen

 

PC Code:  124871	DP No.:  339672  

MRID No.:  None	Registration No.:  None

Petition No.:  7E7204	Regulatory Action:  Section 3 Registration

Assessment Type:  Single Chemical Aggregate	Reregistration Case No.: 
None

TXR No.:  None	CAS No.:  148477-71-8

From:		Mary Clock-Rust, Biologist, Registration Action Branch 1
(RAB1)/Health Effects Division (HED; 7509P)

Mohsen Sahafeyan, Chemist, RAB1/HED 

Mark Dow, Ph.D., Biologist, Risk Integration Minor Use & Emergency
Response Branch (RIMUERB)/Registration Division (RD; 7505P)

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

		Dana M. Vogel, Branch Chief

RAB1/HED (7509P)

To:		Susan Stanton, Risk Manager Reviewer 

Daniel Rosenblatt, RM 05

Registration Division (RD; 7505P)

The Office of Pesticide Programs (OPP) HED assesses the risks posed to
humans from exposure to pesticide chemicals.  OPP's RD has asked HED to
evaluate hazard and exposure data and conduct dietary, occupational,
residential and aggregate exposure assessments, as needed, to estimate
the risk to human health that will result from the registration of
spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutanoate) on hops.  A summary of the findings and an
assessment of human risk resulting from the registered and proposed
spirodiclofen uses are provided in this document.  The risk assessment
was provided by Mary Clock-Rust (RAB1), the residue chemistry review and
dietary risk assessment were provided by Mohsen Sahafeyan (RAB1), the
occupational/residential exposure (ORE) assessment was provided by Mark
Dow (RIMUERB), and the drinking water assessment was provided by Larry
Lui and Faruque Khan of the Environmental Fate and Effects Division
(EFED).    

Table of Contents

   TOC \o "1-3" \h \z \u  

  HYPERLINK \l "_Toc193079369"  1.0 Executive Summary	  PAGEREF
_Toc193079369 \h  4  

  HYPERLINK \l "_Toc193079370"  2.0  Ingredient Profile	  PAGEREF
_Toc193079370 \h  6  

  HYPERLINK \l "_Toc193079371"  2.1  Summary of Proposed Uses	  PAGEREF
_Toc193079371 \h  6  

  HYPERLINK \l "_Toc193079372"  2.2  Structure and Nomenclature	 
PAGEREF _Toc193079372 \h  7  

  HYPERLINK \l "_Toc193079373"  2.3  Physical and Chemical Properties	 
PAGEREF _Toc193079373 \h  7  

  HYPERLINK \l "_Toc193079374"  3.0  Metabolism Assessment	  PAGEREF
_Toc193079374 \h  8  

  HYPERLINK \l "_Toc193079375"  3.1  Comparative Metabolic Profile	 
PAGEREF _Toc193079375 \h  8  

  HYPERLINK \l "_Toc193079376"  3.2  Nature of the Residue in Foods	 
PAGEREF _Toc193079376 \h  8  

  HYPERLINK \l "_Toc193079377"  3.2.1  Description of Primary Crop
Metabolism	  PAGEREF _Toc193079377 \h  8  

  HYPERLINK \l "_Toc193079378"  3.2.2  Description of Livestock
Metabolism	  PAGEREF _Toc193079378 \h  9  

  HYPERLINK \l "_Toc193079379"  3.2.3  Description of Rotational Crop
Metabolism	  PAGEREF _Toc193079379 \h  9  

  HYPERLINK \l "_Toc193079380"  3.3  Environmental Degradation and
Drinking Water Estimates	  PAGEREF _Toc193079380 \h  9  

  HYPERLINK \l "_Toc193079381"  3.4  Tabular Summary of Metabolites and
Degradates	  PAGEREF _Toc193079381 \h  10  

  HYPERLINK \l "_Toc193079382"  3.5  Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc193079382 \h  10  

  HYPERLINK \l "_Toc193079383"  3.6  Summary of Residues for Tolerance
Expression and Risk Assessment	  PAGEREF _Toc193079383 \h  11  

  HYPERLINK \l "_Toc193079384"  4.0  Hazard Characterization/Assessment	
 PAGEREF _Toc193079384 \h  12  

  HYPERLINK \l "_Toc193079385"  4.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc193079385 \h  12  

  HYPERLINK \l "_Toc193079386"  4.1.1  Database Summary	  PAGEREF
_Toc193079386 \h  12  

  HYPERLINK \l "_Toc193079387"  4.1.2  Toxicological Effects	  PAGEREF
_Toc193079387 \h  13  

  HYPERLINK \l "_Toc193079388"  4.1.3  Dose-Response	  PAGEREF
_Toc193079388 \h  13  

  HYPERLINK \l "_Toc193079389"  4.2  Food Quality Protection Act (FQPA)
Considerations	  PAGEREF _Toc193079389 \h  14  

  HYPERLINK \l "_Toc193079390"  4.2.1  FQPA Hazard Considerations	 
PAGEREF _Toc193079390 \h  14  

  HYPERLINK \l "_Toc193079391"  4.2.2  Adequacy of the Toxicity Database
  PAGEREF _Toc193079391 \h  14  

  HYPERLINK \l "_Toc193079392"  4.2.3  Evidence of Neurotoxicity	 
PAGEREF _Toc193079392 \h  15  

  HYPERLINK \l "_Toc193079393"  4.2.4  Developmental Toxicity Studies	 
PAGEREF _Toc193079393 \h  16  

  HYPERLINK \l "_Toc193079394"  4.2.5  Reproductive Toxicity Study	 
PAGEREF _Toc193079394 \h  17  

  HYPERLINK \l "_Toc193079395"  4.2.6   Developmental Neurotoxicity
Study	  PAGEREF _Toc193079395 \h  20  

  HYPERLINK \l "_Toc193079396"  4.2.7  Additional Information from
Literature Sources	  PAGEREF _Toc193079396 \h  22  

  HYPERLINK \l "_Toc193079397"  4.2.8  Pre- and/or Postnatal Toxicity	 
PAGEREF _Toc193079397 \h  22  

  HYPERLINK \l "_Toc193079398"  4.2.9  Determination of Susceptibility	 
PAGEREF _Toc193079398 \h  22  

  HYPERLINK \l "_Toc193079399"  4.2.10  Degree-of-Concern Analysis for
Pre and/or Post-natal Susceptibility	  PAGEREF _Toc193079399 \h  23  

  HYPERLINK \l "_Toc193079400"  4.3  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc193079400 \h  23  

  HYPERLINK \l "_Toc193079401"  4.3.1  Acute Reference Dose (aRfD) - All
Populations	  PAGEREF _Toc193079401 \h  23  

  HYPERLINK \l "_Toc193079402"  4.3.2  Chronic Reference Dose (cRfD)	 
PAGEREF _Toc193079402 \h  24  

  HYPERLINK \l "_Toc193079403"  4.3.3  Incidental Oral Exposure: 
Short-Term (1-30 days)	  PAGEREF _Toc193079403 \h  24  

  HYPERLINK \l "_Toc193079404"  4.3.4  Incidental Oral Exposure: 
Intermediate-Term (1-6 Months)	  PAGEREF _Toc193079404 \h  26  

  HYPERLINK \l "_Toc193079405"  4.3.5  Dermal Absorption	  PAGEREF
_Toc193079405 \h  26  

  HYPERLINK \l "_Toc193079406"  4.3.6  Short-Term Dermal Exposure (1-30
days)	  PAGEREF _Toc193079406 \h  26  

  HYPERLINK \l "_Toc193079407"  4.3.7   Intermediate-Term Dermal (1-6
Months)	  PAGEREF _Toc193079407 \h  27  

  HYPERLINK \l "_Toc193079408"  4.3.8  Long-Term Dermal (>6 Months)
Exposure	  PAGEREF _Toc193079408 \h  27  

  HYPERLINK \l "_Toc193079409"  4.3.9  Short-Term Inhalation (1-30 days)
Exposure	  PAGEREF _Toc193079409 \h  27  

  HYPERLINK \l "_Toc193079410"  4.3.10  Intermediate-Term Inhalation
(1-6 months) Exposure	  PAGEREF _Toc193079410 \h  28  

  HYPERLINK \l "_Toc193079411"  4.3.11  Long-Term Inhalation (>6 months)
Exposure	  PAGEREF _Toc193079411 \h  28  

  HYPERLINK \l "_Toc193079412"  4.3.12  Margins of Exposure	  PAGEREF
_Toc193079412 \h  29  

  HYPERLINK \l "_Toc193079413"  4.3.13  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc193079413 \h  29  

  HYPERLINK \l "_Toc193079414"  4.3.14  Carcinogenicity	  PAGEREF
_Toc193079414 \h  30  

  HYPERLINK \l "_Toc193079415"  4.3.15  Mutagenicity	  PAGEREF
_Toc193079415 \h  33  

  HYPERLINK \l "_Toc193079416"  4.4  Endocrine Disruption	  PAGEREF
_Toc193079416 \h  34  

  HYPERLINK \l "_Toc193079417"  5.0  Exposure
Characterization/Assessment	  PAGEREF _Toc193079417 \h  35  

  HYPERLINK \l "_Toc193079418"  5.1  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc193079418 \h  35  

  HYPERLINK \l "_Toc193079419"  5.1.1  Residue Profile	  PAGEREF
_Toc193079419 \h  35  

  HYPERLINK \l "_Toc193079420"  5.1.2  Dietary Exposure and Risk	 
PAGEREF _Toc193079420 \h  36  

  HYPERLINK \l "_Toc193079421"  5.2  Residential (Non-Occupational)
Exposure/Risk Pathway	  PAGEREF _Toc193079421 \h  37  

  HYPERLINK \l "_Toc193079422"  5.3  Spray Drift	  PAGEREF _Toc193079422
\h  37  

  HYPERLINK \l "_Toc193079423"  6.0  Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc193079423 \h  38  

  HYPERLINK \l "_Toc193079424"  6.1  Acute Aggregate Risk	  PAGEREF
_Toc193079424 \h  38  

  HYPERLINK \l "_Toc193079425"  6.2  Short-Term Aggregate Risk	  PAGEREF
_Toc193079425 \h  38  

  HYPERLINK \l "_Toc193079426"  6.3  Intermediate-Term Aggregate Risk	 
PAGEREF _Toc193079426 \h  38  

  HYPERLINK \l "_Toc193079427"  6.4  Chronic Aggregate Risk	  PAGEREF
_Toc193079427 \h  38  

  HYPERLINK \l "_Toc193079428"  6.5  Aggregate Cancer Risk	  PAGEREF
_Toc193079428 \h  39  

  HYPERLINK \l "_Toc193079429"  7.0 Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc193079429 \h  39  

  HYPERLINK \l "_Toc193079430"  8.0 Occupational Exposure/Risk Pathway	 
PAGEREF _Toc193079430 \h  39  

  HYPERLINK \l "_Toc193079431"  8.1  Short- and Intermediate-term
Occupational Handler Risk	  PAGEREF _Toc193079431 \h  40  

  HYPERLINK \l "_Toc193079432"  8.2  Short- and Intermediate-term
Post-Application Risk	  PAGEREF _Toc193079432 \h  41  

  HYPERLINK \l "_Toc193079433"  8.3  Occupational Handler and
Post-Application Cancer Risk	  PAGEREF _Toc193079433 \h  42  

  HYPERLINK \l "_Toc193079434"  9.0  Data Needs and Label Requirements	 
PAGEREF _Toc193079434 \h  43  

  HYPERLINK \l "_Toc193079435"  Attachment 1: Chemical Names and
Structures of Spirodiclofen and its Metabolites	  PAGEREF _Toc193079435
\h  45  

  HYPERLINK \l "_Toc193079436"  Attachment 2: Toxicity Profile for
Spirodiclofen	  PAGEREF _Toc193079436 \h  46  

 

1.0 Executive Summary tc \l1 "1.0  Executive Summary 

Introduction

Spirodiclofen is part of a new class of chemicals called tetronic acid
insecticides.  Tectronic acids are primarily acaricides with
insecticidal uses at higher doses.  The mode of action occurs through
the inhibition of lipid biosynthesis, which inhibits the ability to
develop through the various mite growth stages and the ability to
reproduce in adults.  Spirodiclofen is structurally similar to
spiromesifen, which is also a tetronic acid insecticide.  Spirodiclofen
is currently registered for use on grapes, citrus fruits, pome fruits,
stone fruits and tree nuts.  There are no registered or proposed
residential uses.

The residue chemistry, toxicology and exposure data bases are sufficient
to assess risk from the proposed use on hops.  The available data are
adequate to assess exposure and risk from all relevant sources. 

Proposed Uses

IR-4 proposed Section 3 registration and permanent tolerances for
spirodiclofen on hops.  No residential uses are proposed.  The use
pattern summary is taken from proposed draft labeling for Envidor® 2 SC
Miticide (EPA Reg. No. 264-831).  Envidor® is formulated as a liquid
soluble concentrate (SC) and contains 2.0 lb active ingredient (ai)
(22.3 %) spirodiclofen per gallon.  The target pest on hops is the
twospotted spider mite.

The rate of application is 18.0-24.7 fl oz formulation/A (0.28-0.39 lb
ai/A).  It is to be applied in a minimum of 50 gallons of spray per acre
using a ground airblast sprayer.  Spirodiclofen is to be applied to hops
once per season.  The maximum application rate is 0.39 lb ai/A/crop
season.  The preharvest interval (PHI) is 14 days.  The restricted entry
interval (REI) is 12 hours for all use sites.  

Hazard Characterization

The critical effect for the overall risk assessment is based on the
toxic effects on the most sensitive target organ, the adrenal gland. 
The dog was the most sensitive species and the selected endpoints
provide the more protective limits for potential effects on humans.

For dietary exposure, no appropriate single-dose endpoint was available
for assessment of acute dietary risk for the general population,
including infants and children.  A one-year oral toxicity study in dogs
was selected for the chronic reference dose (cRfD).  The endpoint is
based on increased relative adrenal weights in both sexes, increased
relative testis weight in males and histopathology findings in the
adrenal gland of both sexes.

The endpoint for short-term incidental oral exposure is based on a
subchronic oral toxicity study in dogs and is based on increased adrenal
gland weight (two out of four animals) which corroborated with
histopathology findings (cytoplasmic vacuoles in the Zona fasciculata of
the adrenal glands) in females; a no-observed-adverse-effect-level
(NOAEL) for females was not established.

The endpoint for short-term dermal and inhalation risk assessments is
based on a subchronic oral toxicity study in dogs.  For intermediate-
and long-term dermal and inhalation risk assessments, a chronic oral
toxicity study in dogs was selected.  An oral study was selected because
the endpoint of concern (i.e., adrenal, testes, etc.) was not measured
in the 28-day dermal toxicity study.  

A dermal-absorption factor of 2% based on a monkey dermal-absorption
study is used for all dermal exposure assessments since dermal endpoints
are from an oral study.  Inhalation absorption is assumed to be 100%
(default assumption) in the absence of a 21/28 day inhalation study.

The Cancer Assessment Review Committee (CARC) classified spirodiclofen
as “likely to be carcinogenic to humans,” and assigned a Q1* value
of 1.49 x 10-2 mg ai/kg bw/day.  Quantification of cancer risk used a
Q1*(mg/kg/day)-1 of 1.49 x 10-2 in human equivalents based on male rat
testes Leydig cell adenoma.

Since there is a low concern for increased susceptibility, toxicological
database is complete including two DNT studies,  dietary analysis is
based on  DEEM default processing factors, projected average 100% crop
treated (%CT), and drinking water estimates based on model estimates,
HED concluded that the 10X FQPA SF is reduced to 1X for all exposure
scenarios, except short-term, dietary/residential, for which a 3X FQPA
SF has been retained due to the use of a LOAEL for a NOAEL.  

Dietary Exposure

Chronic and cancer dietary risk assessments (for food and drinking
water) were conducted using the Dietary Exposure Evaluation Model - Food
Consumption Intake Database (DEEM-FCID(, ver. 2.03).

An endpoint of concern for the assessment of acute dietary risk was not
identified in the hazard database.  Therefore, acute dietary risk was
not assessed.  The chronic and cancer analyses incorporated average
field trial residues, experimental and DEEM default processing factors,
and projected average %CT estimates and drinking water estimates
generated using the Pesticide Root Zone/Exposure Analysis Modeling
System (PRZM/EXAMS) model.  

The resulting chronic (food + water) exposure estimates were not of
concern to HED [<100% of the chronic population-adjusted dose (cPAD)]
for general U.S. population (1.8 % of the cPAD) and all population
subgroups; the most highly exposed population subgroup was all infants
(<1 year old) with 3.2% of the cPAD.  

The cancer risk estimate (food + water) was 3 x 10-6 for the general
U.S. population, which is not of concern.  Hops, water, and orange juice
were major contributors to the cancer risk. 

Aggregate Risk Assessment

No residential uses are proposed for spirodiclofen at this time. 
Therefore, aggregate risk consists of exposure from food and drinking
water sources only.  Only chronic and cancer aggregate risks were
assessed.  

 

Occupational Risk

For occupational exposure and risk assessment, pesticide handlers and
workers exposed to post-application residues were assessed.  Cancer
risks were calculated for both pesticide handlers and post-application
workers. 

Based upon the proposed use pattern, HED believes the most highly
exposed occupational pesticide handlers (i.e., mixers, loaders,
applicators) will be mixer/loaders using an open-pour technique and
applicators using open-cab, air-blast equipment.  No chemical-specific
data are available to assess potential exposure to pesticide handlers,
so estimates of exposure to handlers are based upon surrogate study data
available in the Pesticide Handler’s Exposure Database (PHED) (v. 1.1,
1998).  All handler MOEs are above 300 for handlers wearing baseline
personal protective equipment (PPE) and are not of concern to HED. 
Cancer risk for handlers is also not of concern to HED, with risks no
greater than 10-5.

Post-application activities for hops include training vines, scouting,
stripping vines and harvesting.  Hops are typically mechanically
harvested.  The highest transfer coefficient (TC) for hops is for
training vines (TC=2,000 cm2/hr).  HED conducted a post-application risk
assessment for the training vines exposure scenario.  Post-application
inhalation exposure is expected to be negligible.  Post-application
dermal risk resulted in an MOE of 2,200, and is not of concern. 
Post-application cancer risk also was not of concern to HED.

HED Recommendations 

HED recommends for a permanent registration for spirodiclofen on hops
and the following permanent tolerance:

Hop, dried cones1	30 ppm

1 Tolerance expression for plants includes residues of spirodiclofen
(3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl
2,2-dimethylbutanoate) per se, and for livestock includes combined
residues of  spirodiclofen and BAJ 2510
(3-(2,4-dichlorophenyl)-4-hydroxy-1-oxaspiro[4,5]dec-3-en-2-one).

2.0  Ingredient Profile tc \l1 "2.0  Ingredient Profile 

Spirodiclofen is a tetronic acid with acaricidal action.  It acts by
interfering with mite development, thereby controlling such pests as
Panonychus spp., Phyllocoptruta spp., Brevipalpus spp., and Aculus and
Tetranychus species.  Spirodiclofen is active by contact to mite eggs,
all nymphal stages, and adult females (adult males are not affected).

Permanent tolerances are established for spirodiclofen on grapes, citrus
fruits, pome fruits, stone fruits and the tree nut crop groups at
0.10-2.0 ppm, and on processed commodities from these crops at 0.60-20
ppm [40 CFR §180.608(a)].  Tolerances are also established for the
combined residues of spirodiclofen and its free enol metabolite, BAJ
2510 (3-(2,4-dichlorophenyl)-4-hydroxy-1-oxaspiro[4,5]dec-3-en-2-one),
in/on livestock commodities at 0.01-0.10 ppm.

Spirodiclofen is currently registered to Bayer CropScience as a 2.0
lb/gal SC formulation (Envidor® 2 SC Miticide, EPA Reg. No. 264-831)
for use as a single broadcast foliar application to grapes and fruit and
nut trees at rates of 0.19-0.53 lb ai/A with PHIs of 14 days for grapes
and 7 days for all other crops.  

2.1  Summary of Proposed Uses tc \l2 "2.1	Summary of Registered/Proposed
Uses 

Interregional Research Project No. 4 (IR-4) is proposing the use of
spirodiclofen (SC) on hops as a single foliar-directed application at
0.28-0.39 lb ai/A with a PHI of 14 days.  Applications are restricted to
the use of ground equipment in a minimum of 50 gal/A.  HED concludes
that the use directions provided in the submitted Section B are
adequate.  

Table 2.1. Summary of Proposed Uses for Spirodiclofen (Envidor( 2 SC
Miticide).

Applic. Timing, Type, and Equip.	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 2

Hops

Single foliar application at the early stages of mite infestation; 
Ground equipment	2 lb/gal SC

[264-831]	0.28-0.39	1	0.39	14	Apply in a minimum of 50 gal/A using
conventional ground airblast spray

1Do not apply through any type of irrigation equipment or with aerial
equipment.

2PHI = pre-harvest interval.

All proposed uses for spirodiclofen are agricultural; there are no
registered or proposed residential uses.  

2.2  Structure and Nomenclature tc \l2 "2.2  Structure and Nomenclature 

There are no isomeric forms of spirodiclofen.  

Table 2.2.	Spirodiclofen Nomenclature.

Compound	

Common name	Spirodiclofen

Company experimental name	BAJ2740

IUPAC name	3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutyrate

CAS name	3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutanoate

CAS registry number	148477-71-8

End-use product (EP)	2 lb/gal SC (ENVIDOR® 2 SC Miticide; EPA Reg. No.
264-831)

2.3  Physical and Chemical Properties tc \l2 "2.3  Physical and Chemical
Properties 

50μg/L

Solvent solubility (g/L at 20°C)	n-heptane  

xylene  

dichloromethane 

2-propanol

1-octanol

polyethylene glycol

acetone

ethyl acetate

acetonitrile

dimethylsulfoxide	20

>250

>250

47

44

24

>250

>250

>250

75

Vapor pressure (20ºC)	3 x 10-7 Pa

Dissociation constant, pKa	Not determinable due to the instability in
aqueous solutions at >pH 4

Octanol/water partition coefficient, Log(KOW) at pH 4 and 20ºC	5.83

UV/visible absorption spectrum	λmax = 201 nm:  Not expected to absorb
UV at λ >350 nm

Reference: DP# 315459, S. Mathur, 4/20/05.

3.0  Metabolism Assessment tc \l1 "3.0  Metabolism Assessment 

See Attachment 1 for metabolite structures.

3.1  Comparative Metabolic Profile tc \l2 "3.1  Comparative Metabolic
Profile 

The metabolic pathway in the proposed primary crops, ruminant, and rat
were similar and involved cleavage of the parent ester linkage with the
formation of the free enol metabolite (BAJ 2510) followed by
hydroxylation of the cyclohexane ring of BAJ 2510.  In the rat and in
the proposed crops, metabolism continued with cleavage of the enol ring
structure leading to the formation of 2,4-dichloro-mandelic acid-
cyclohexylester compounds which are further metabolized to
2,4-dichloro-mandelic acid derivatives (see Attachment 1 for
structures).

3.2  Nature of the Residue in Foods tc \l2 "3.2  Nature of the Residue
in Foods 

3.2.1  Description of Primary Crop Metabolism tc \l3 "3.2.1  Description
of Primary Crop Metabolism 

The apple, orange, lemon, grapefruit, and grape metabolism studies
indicated that metabolism of spirodiclofen in these crops was similar
and involved the following steps:  cleavage of the parent ester linkage
with the formation of the free enol metabolite (BAJ 2510); hydroxylation
of BAJ 2510 in the 3- or 4- position of the cyclohexyl ring (3-OH-enol,
4-OH-enol); cleavage of the enol ring structure leading to the formation
of 2,4-dichloro-mandelic acid-cyclohexylester compounds; and
hydroxylation and/or conjugation of 2,4-dichloro-mandelic
acid-cyclohexylester with carbohydrates followed by further degradation
to 2,4-dichloro-mandelic acid (free or conjugated).  

rall spirodiclofen accounted for 34-99% of the total radioactive
residues (TRR).  Minor amounts of the following compounds were also
identified:  BAJ 2510 (≤2% TRR), 3-OH-enol (≤3% TRR), 4-OH-enol (<1%
TRR), 2,4-dichloro-mandelic acid-cyclohexylester compounds (free and
conjugated; ≤9% TRR), and 2,4-dichloro-mandelic acid (free and
conjugate; ≤12% TRR).  However, grape processing study indicates that
residues of spirodiclofen degrade to BAJ 2510 during processing of
grapes to juice, juice concentrate, jelly and raisin (T. Bloem, D341847,
10-OCT-07).  

Based on available plant metabolism studies and recently submitted and
reviewed apple and grape processing studies, HED concludes the
following:  (1) citrus fruit, pome fruit, stone fruit,  tree nut, and
hop - the residue of concern for risk assessment and tolerance
enforcement is spirodiclofen per se and (2) grape - the residue of
concern for tolerance enforcement is spirodiclofen per se and residues
of concern for risk assessment are spirodiclofen and BAJ 2510 (T. Bloem,
D341847, 10-OCT-07).  

As hops are a minor crop, the available metabolism data will be used to
support the use on hops. However, additional plant metabolism data may
be required for future crop uses.  For purposes of this tolerance
petition, HED concludes that the residue of concern in/on dried hops
consists of spirodiclofen per se.

3.2.2  Description of Livestock Metabolism tc \l3 "3.2.2  Description of
Livestock Metabolism 

Based on the results of the goat metabolism study and feeding study, HED
concludes that the residues of concern in ruminants, for purposes of
tolerance enforcement and risk assessment, are spirodiclofen and BAJ
2510.  There are no livestock feedstuffs associated with hops.

3.2.3  Description of Rotational Crop Metabolism tc \l3 "3.2.3 
Description of Rotational Crop Metabolism 

Because neither hops nor any of the registered crops are rotated, data
pertaining to rotational crops are not required to support the proposed
use.

3.3  Environmental Degradation and Drinking Water Estimates

 tc \l2 "3.3  Environmental Degradation 

The major routes of degradation for spirodiclofen in the laboratory
studies were hydrolysis, photolysis in water, and metabolism. 
Spirodiclofen is expected to be moderately persistent in the soil
(half-life of 10-64 days), but dissipate rapidly from aquatic
environments (half-life of <1 hour-4 days).  The major residue
identified in the aerobic soil and anaerobic/aerobic aquatic degradation
studies was BAJ 2510 (52-95% the applied dose at intervals of (56 days;
EFED refers to this compound as BAJ 2740-enol).  The aerobic soil
degradation study also resulted in significant residues of BAJ
2740-dihydroxy (17% of the applied dose at an interval of 120 days), BAJ
2740-ketohydroxy (44% of the applied dose at an interval of 30 days),
and DCB-acid (40% of the applied dose at an interval of 120 days).  The
aquatic photolysis study resulted in significant residues of BAJ
2740-dioxoketone (26% of the applied dose after an interval of 1 day). 
Under terrestrial field conditions, the major transformation products of
spirodiclofen were BAJ 2510, BAJ 2740-ketohydroxy, BAJ 2740-dihydroxy,
and DCB-acid.  Spirodiclofen is expected to be immobile in soil (Koc
range 31,037 to 238,000) while the identified degradation products are
expected to be mobile.  

HED determined that aquatic photolysis is not expected to be an
important degradation route and, therefore, concluded that BAJ
2740-dioxoketone is not of concern in drinking water.  In addition, HED
concluded that DCB-acid is likely to be significantly less toxic than
spirodiclofen and, therefore, this compound was excluded from the risk
assessment (see Section 3.5).  Based on the currently available data,
HED concludes that the residues of concern in drinking water for
purposes of risk assessment are spirodiclofen, BAJ 2510, BAJ
2740-dihydroxy, and BAJ 2740-ketohydroxy.

nd 1.67 μg/L, respectively. 

3.4  Tabular Summary of Metabolites and Degradates tc \l2 "3.4  Tabular
Summary of Metabolites and Degradates 

See Attachment 1, Chemical Names and Structures of Spirodiclofen and its
Metabolites. 

3.5  Toxicity Profile of Major Metabolites and Degradates tc \l2 "3.5 
Toxicity Profile of Major Metabolites and Degradates 

The endpoints chosen for spirodiclofen risk assessment were based on
steroidogenesis effects. Based on the structure of BAJ 2510, BAJ
2740-dihydroxy, and BAJ 2740-ketohydroxy (significant residues in
ruminant metabolism and/or environmental fate studies), HED concluded
that these compounds are likely to be toxicologically similar to parent.
 The petitioner submitted a study which indicated that
2,4-dichlormandelic acid did not cause steroidogenesis effects.  On the
basis of this study, along with the general conclusion that the
structure of 2,4-dichlormandelic acid lends itself to being less toxic
than spirodiclofen and the low overall potential dietary exposure to
2,4-dichlormandelic acid as compared to spirodiclofen, HED concluded
that 2,4-dichlormandelic acid should not be included in the dietary risk
assessment.  Furthermore, HED concluded that 2,4-dichloro-mandelic acid
cyclohexylester-glucosyl pentoside; 2,4-dichloro-mandelic
acid-hydroxyl-cyclohexylester; and DCB-acid (significant residues
identified in washed fruit or the aerobic soil metabolism study) are
substituted versions or structurally similar to 2,4-dichloro-mandelic
acid and may be excluded from the risk assessment using the same reasons
as those established for 2,4-dichloro-mandelic acid.

Enol Metabolite of Spirodiclofen (BAJ-2510) 

The acute LD50 toxicity study for spirodiclofen showed no deaths and no
clinical signs of toxicity up to 2,000 mg/kg.  In the acute LD50 study
for the enol metabolite of spirodiclofen, no deaths were observed in
either sex at 200 mg/kg; however clinical observations revealed
decreased motility in females only.  Deaths (1/3 males and 2/3 females)
occurred at 500 mg/kg with clinical signs of toxicity in both sexes
exposed to the enol metabolite, indicating that the LD50 had been
achieved.  These differences in acute toxicity between spirodiclofen and
the enol metabolite could be partially explained based on the rat
metabolism study with spirodiclofen.  In the spirodiclofen rat
metabolism study at 2 mg/kg, approximately 62 and 33% of the
radioactivity from a single bolus gavage dose was excreted in the urine
and feces respectively, by 48 hours.  At 100 mg/kg approximately 35 and
61% of the radioactivity from a single bolus gavage dose was excreted in
the urine and feces respectively, at 48 hours.  The metabolic profile of
the feces revealed that approximately 1.8% and 16% of the unchanged
parent compound was present after exposure to 2 mg/kg and 100 mg/kg,
respectively; indicating absorption is a limiting factor at high doses. 
Negligible amounts of parent compound and intact enol metabolite were
detected in the bile cannulation study suggesting that the excretion of
the parent and unchanged enol in the feces is due to unabsorbed dose
indicating that saturation of absorption has occurred.  In the rat
metabolism study both the parent and enol metabolites were excreted in
the feces which provides indirect evidence of conversion of parent to
the enol metabolite in the gastrointestinal tract.  This also could
indicate absorption is the limiting factor for both parent and enol
metabolite.  Therefore, these differences support and provide the
explanation of the differences in acute toxicity of the parent and enol
metabolites.  

In summary, in the rat metabolism study, intact parent and enol
metabolite were detected in the feces.  In the bile cannulated rats,
very limited intact parent and enol metabolite were excreted. 
Indicating that the absorption may be a limiting factor since parent and
unchanged enol metabolite were detected in the feces.  In the rat
metabolism study both parent and enol metabolite was excreted in the
feces which provides indirect evidence of conversion of parent to enol
in the gastrointestinal tract.  This also could indicate saturation of
absorption as the limiting factor for both parent and enol metabolite.  

Acute dietary exposure is likely to occur at very low doses.  As such,
the results of the acute LD50 enol metabolite study may not be relevant
for acute dietary exposure to spirodiclofen.  

For the purposes of this risk assessment, EPA considers the enol
metabolite and the parent spirodiclofen to be of similar toxicity for
short-, intermediate and chronic exposure assessment. 

3.6  Summary of Residues for Tolerance Expression and Risk Assessment tc
\l2 "3.6  Summary of Residues for Tolerance Expression and Risk
Assessment 

Based on metabolism and environmental fate studies, HED made the
following conclusions concerning the residues of concern in plants,
livestock, rotational crops, and drinking water (the toxicity of all
metabolites/degradates indicated below are considered to be identical to
parent).

Table 3.6.	Proposed Residues for Tolerance Expression and Risk
Assessment.

Matrix	

Residues included in Risk Assessment	

Residues included in Tolerance Expression

Citrus fruit, Pome Fruit, Stone Fruit, Tree Nut 1	

spirodiclofen	

Spirodiclofen

Grape1	

spirodiclofen	

spirodiclofen, BAJ 2510

Livestock - Ruminants	

spirodiclofen, BAJ 2510	

spirodiclofen, BAJ 2510

Livestock - Poultry	

no data submitted

Rotational Crops	

no data submitted

Drinking Water	

spirodiclofen, BAJ 2510, BAJ 2740-dihydroxy, BAJ 2740-ketohydroxy	

not applicable

1See reference: T. Bloem, D341847, 25-Oct-2007.   

International Harmonization

Although adequate U.S. field trial data are available supporting a
minimum PHI of either 21 or 28 days, IR-4 is requesting a 14-day PHI for
hops in order to harmonize the U.S. and German use patterns.  In
addition, IR-4 is requesting a 30-ppm tolerance on dried hop cones to
harmonize with the established German maximum residue limit (MRL). 
Considering similarity in climatic conditions between the hops growing
regions in the U.S. and Germany and the German MRL of 30 ppm being
higher than the maximum residue values from the other two submitted
field trial data sets having similar application rates, but longer PHIs
(21 and 28 day), HED recommends establishing a permanent tolerance for
spirodiclofen on hops at 30 ppm to promote free trade between NAFTA and
non-NAFTA countries.  

4.0  Hazard Characterization/Assessment tc \l1 "4.0  Hazard
Characterization/Assessment 

4.1  Hazard and Dose-Response Characterization tc \l2 "4.1  Hazard and
Dose-Response Characterization 

4.1.1  Database Summary tc \l3 "4.1.1  Database Summary 

The toxicological database for spirodiclofen is complete.  The HED HIARC
requested a 28-day inhalation toxicity study as a condition of
registration.  However, based on the low volatility and low inhalation
toxicity (Category IV) of spirodiclofen and inhalation MOEs of at least
1000 for the proposed handler uses, spirodiclofen qualifies for a waiver
of the 28-day inhalation toxicity study for the proposed uses (HED
Standard Operating Procedure (SOP) 2002.01: Guidance: Waiver Criteria
for Multiple-Exposure Inhalation Toxicity Studies, 08/15/02).  The
requirement for the 28-day inhalation toxicity study is waived for this
action only.  If in the future, requests for new uses or formulations
are submitted that may result in a significant change in either the
toxicity profile or exposure scenarios, HED will reconsider this data
requirement.

4.1.1.1  Studies Available and Considered tc \l4 "4.1.1.1  Studies
Available and Considered 

Acute - Acute neurotoxicity study in rats

Subchronic neurotoxicity study in rats

Developmental neurotoxicity in rats (2 studies)

Subchronic - 90-day oral studies in rats, mice and dogs

Chronic - One-year dog, 2-year rat and mouse cancer studies

Repro/developmental - Rat and rabbit developmental; 2-generation rat
reproductive studies

Other - mutagenicity screens

4.1.1.2  Mode of Action, Metabolism, Toxicokinetic Data tc \l4 "4.1.1.2 
Mode of Action, Metabolism, Toxicokinetic Data 

Spirodiclofen is a foliar-applied acaricide belonging to a new chemical
class of tetronic acids.  Its mode of action in animal models is
described as inhibitory to lipid biosynthesis which interferes with
steroid biosynthesis, resulting in direct and indirect
endogenously-mediated toxicological response.  Following oral
administration, spirodiclofen is rapidly absorbed, metabolized, and
excreted via urine and feces.  A rat whole body autoradiography study
showed no accumulation in any specific organs or tissues following oral
administration.  A dermal-absorption study in monkeys suggested a
dermal-absorption factor of 2%.

4.1.1.3  Sufficiency of Studies/Data tc \l4 "4.1.1.3  Sufficiency of
Studies/Data 

Data are adequate for each exposure scenario, FQPA evaluation, and for
selection of endpoints and the dose-response evaluation.

4.1.2  Toxicological Effects tc \l3 "4.1.2  Toxicological Effects 

Spirodiclofen has a low acute toxicity via oral, dermal, or inhalation
route. It is not an eye or dermal irritant.  However, it is a potential
skin sensitizer.  Following oral administration, spirodiclofen is
rapidly absorbed, metabolized, and excreted via urine and feces.  A rat
whole body autoradiography study showed no accumulation in any specific
organs or tissues following oral administration. Evidence of
developmental toxicity was not observed in the rat and rabbit
developmental studies.  In the two-generation reproductive toxicity
study, effects were observed in males [i.e., delayed sexual maturation,
decreased testicular spermatid and epididymal sperm counts
(oligospermia); and atrophy of the testes, epididymides, prostate, and
seminal vesicles] and females (i.e., increased severity of ovarian
luteal cell vacuolation/degeneration).  Spirodiclofen did not show any
evidence of neurotoxicity in the acute and subchronic neurotoxicity
studies.  In a developmental neurotoxicity study (DNT), a decrease in
retention was observed in the memory phase of the water maze for PND 60
females at all doses.  In this DNT study, the morphometric measurements
were not performed at the low- and mid-dose; therefore, the registrant
conducted a new study using identical experimental condition as the
previous study.  The results of the new study demonstrated no treatment
related maternal or offspring toxicity at the highest dose tested. 
Therefore, it can be concluded that spirodiclofen is unlikely to be a
neurotoxic or developmentally-neurotoxic compound.  Mutagenicity studies
conducted on technical spirodiclofen formulation and its major
metabolites did not demonstrate any mutagenic potential.  Spirodiclofen
has been shown to have endocrine disruptive effects resulting in direct
and indirect endogenously-mediated toxicological responses.  Testicular
effects were observed in dogs, rats and mice, manifest as Leydig cell
vacuolation in dogs, hypertrophy in dogs and mice and hyperplasia,
progressing to adenomas in rats following chronic exposure.  In female
rats, increased incidence of uterine nodules and uterine adenocarcinoma
were observed at terminal sacrifice in the chronic study.  Cytoplasmic
vacuolation in the adrenal cortex, accompanied by increased adrenal
weight, was consistently observed in rats, dogs, and mice of both sexes.

Chronic toxicity and carcinogenicity studies showed increased incidence
of uterine adenocarcinoma in female rats, Leydig cell adenoma in male
rats, and liver tumors in mice.  The CARC classified spirodiclofen as
“likely to be carcinogenic to humans” by the oral route based on
evidence of testes Leydig cell adenomas in male rats, uterine adenomas
and/or adenocarcinoma in female rats, and liver tumors in mice. 

4.1.3  Dose-Response tc \l3 "4.1.3  Dose-Response 

The critical effect for the overall risk assessment is based on the
toxic effects on the most sensitive target organ, the adrenal gland,
observed in rats, dogs, and mice with dogs as the most sensitive
species. 

For oral exposure, no appropriate single-dose endpoint was available for
the acute oral exposure of the general population, including infants and
children.  A subchronic (90-day) oral toxicity study in dogs was chosen
for the short-term incidental oral exposure scenario.  A one-year oral
toxicity study in dogs was selected for the intermediate-term oral
exposure chronic RfD.  The dog was the most sensitive species and the
selected endpoints provide the more protective limits for human effects
potential.

A dermal-absorption factor of 2% based on a monkey dermal-absorption
study is used for all dermal exposure assessments.  The dermal exposure
limits for short-term exposure were based on a subchronic oral toxicity
study in dog.  For intermediate and chronic exposure, chronic oral
toxicity in dogs was selected.  An oral study was selected because the
endpoint of concern (i.e., adrenal, testes, etc.) was not measured in
the 28-day dermal toxicity study.  

The inhalation exposure limits parallel the determinations made for the
dermal exposure assessments above and use a 100% default assumption in
the absence of a 21/28 day inhalation study.

Quantification of cancer risk was performed using a Q1*(mg/kg/day)-1 of
1.49 x 10-2 in human equivalents based on male rat testes Leydig cell
adenoma.

The uncertainty factors used in determining RfD exposure limits were 100
(10x for intraspecies variation and 10x for interspecies extrapolation).

Table 4.1.   Acute Toxicity of Spirodiclofen.

OPPTS Guideline	Study Type	Results	Toxicity Category

870.1100	Acute oral toxicity / rat	LD50 => 2000 mg/kg (males and
females)	III

870.1200	Acute dermal toxicity / rat	LD50 => 2000 mg/kg (males and
females)	III

870.1300	Acute inhalation toxicity / rat	LC50 => 5.03 mg/L (males and
females)	IV

870.2400	Primary eye irritation / rabbit 	Non-irritating	IV

870.2500	Primary dermal irritation / rabbit	Non-irritating	IV

870.2600	Dermal sensitization / guinea pig	Sensitizer	–

4.2  Food Quality Protection Act (FQPA) Considerations tc \l3 "4.1.4 
FQPA 

4.2.1  FQPA Hazard Considerations tc \l2 "4.2   FQPA Hazard
Considerations 

The database is adequate in terms of endpoint studies and dose response
information to characterize any potential for prenatal or postnatal risk
for infants and children.

4.2.2  Adequacy of the Toxicity Database tc \l3 "4.2.1  Adequacy of the
Toxicity Database 

HED determined that the toxicology database for spirodiclofen is
adequate for FQPA consideration. The following studies are available: 

- Developmental toxicity studies in rats and rabbits

- Two-generation reproduction study in rats

- Acute and subchronic neurotoxicity studies in rats

- Developmental neurotoxicity study in rats (2 studies)

4.2.3  Evidence of Neurotoxicity tc \l3 "4.2.2  Evidence of
Neurotoxicity 

In a subchronic neurotoxicity study, functional-observational-battery
(FOB) effects and decreased motor and locomotor activities were observed
in females at the high dose only (above the limit dose).  The effects
were considered to be due to the large decrease of body weight in these
animals.  In a developmental neurotoxicity study in rats, a decrease in
retention (memory) was observed in the PND 60 females in the water maze
test.

4.2.3.1  Acute Neurotoxicity tc \l4 "4.2.2.1  Acute Neurotoxicity 

In an acute neurotoxicity study (MRID 45696725), groups of fasted, nine
weeks old Wistar (Crl:WI(HAN)BR) rats (12/sex/group) were given a single
oral dose of Technical Grade Spirodiclofen (97.7 to 97.9%, Mixed batch
number 06480/0002) in 0.5% methylcellulose/0.4% Tween 80 in deionized
water at doses of 0, 200, 500 or 2000 mg/kg bw and observed for 14 days.
 A neurobehavioral assessment (functional observational battery and
motor activity testing) was performed one week prior to treatment,
approximately 4 hours after administration of the dose, and 7, and 14
days following treatment.  At study termination, 6 animals/sex/group
were euthanized and perfused [in situ] for neuropathological
examination.  Of the perfused animals, 6/sex from the control and high
dose group were subjected to histologic evaluation of brain and
peripheral nervous system tissues. 

There were no treatment-related effects on mortality, clinical signs,
body weight, brain weight or gross and histologic pathology or
neuropathology.  FOB and motor activity testing revealed no effects that
were considered treatment related.

Based on the absence of effects in this study, the NOAEL for
spirodiclofen in rats is the limit dose of 2000 mg/kg bw.  The LOAEL was
not identified.

4.2.3.2  Subchronic Neurotoxicity tc \l4 "4.2.2.2  Subchronic
Neurotoxicity  

In a subchronic neurotoxicity study (MRID 45696726), groups of young
adult Wistar rats (12/sex/dose) were fed spirodiclofen in the diet at
doses of 0, 100, 1000 or 12,500 ppm (0, 7.2, 70.3 or 1088.8 mg/kg bw/day
for males and 0, 9.1, 87.3, or 1306.5 mg/kg bw/day for females,
respectively) for 13 weeks.  Neurobehavioral assessment (functional
observational battery and motor activity testing) was performed in all
animals (12/sex/group) with 6/sex/dose used for micropathology. 
Cholinesterase activity was not determined.  Of the perfused animals,
6/sex/dose were subjected to histopathological evaluation of brain and
peripheral nervous system tissues.  The following observations and
measurements were included in the study:  clinical observations,
mortality, body weight, food consumption, automated measurements of
activity (figure-eight maze), functional observational battery,
ophthalmic exams, brain weight, and a gross necropsy.  Skeletal muscle,
peripheral nerves, eyes, (with optic nerves) and tissues from the
central nervous system were also examined microscopically for lesions.

There was no mortality at any dose level prior to scheduled terminal
sacrifice.  At 12,500 ppm clinical signs were limited to urine stain
observed in both sexes.  High-dose females also showed oral stain and
red-tinged stains at locations such as paws, snout, forelimbs and ears. 
Body weights were reduced (p<0.05) 25% for males and 15% for females at
the high dose, but not at lower doses.  Food consumption was reduced
(p<0.05) at the high dose for both sexes.  

For the FOB there were compound-related effects in both sexes at the
high dose, but not at any lower doses.  Clinical observations associated
with treatment were limited to various stains (oral, urine, nasal) and
red-tinged stains in the high-dose females and males (urine stain only).
 The high dose animals of both sexes tended to have slightly lower
landing foot splay and grip strength measurements on some test
occasions. 

No compound-related effects were noted on motor and locomotor activity
in the figure-eight maze at any dose level for males.  High-dose females
showed a consistent slight decrease in motor and locomotor activity
during week 4.  Habituation was not affected by treatment. No changes
were noted in ophthalmic findings.

Under conditions of this study, the LOAEL for spirodiclofen in rats was
12500 ppm (1088.8 and 1306.5 mg/kg bw/day for males and females,
respectively) based on decreased body weights, food consumption, and
increased urine staining in both sexes and decreased motor and locomotor
activity (week 4) in females.  The NOAEL was 1000 ppm (70.3 and 87.3
mg/kg bw /day for males and females). 

4.2.4  Developmental Toxicity Studies tc \l4 "4.2.2.3  Developmental
Toxicity Studies 

4.2.4.1  Developmental Toxicity Study in Rats tc \l5 "4.2.2.3.1 
Developmental Toxicity Study in Rats 

In a developmental toxicity study (MRID 45696906), spirodiclofen was
administered to 28 female Wistar (Hsd Cpb:WU) rats/dose by gavage at
dose levels of 0, 100, 300, or 1000 mg/kg bw/day from days 6 through 19
of gestation.  On gestation day (GD) 20, all surviving dams were
sacrificed and examined grossly.  Each fetus was weighed and examined
externally for abnormalities, including the palate, and for sex
determination.  Approximately one-half of the fetuses in each litter
were examined viscerally by sectioning according to a modified Wilson
technique.  The remaining one-half of the fetuses in each litter were
eviscerated and processed for skeletal (bone and cartilage) examination.

No treatment-related deaths or clinical signs of toxicity were observed
in any animal and gross necropsy was unremarkable.  No treatment-related
effects on maternal absolute body weights, body-weight gains, or food
consumption were found between the treated and control groups at any
time during the study.  Maternal necropsy observations were
unremarkable.

The maternal toxicity LOAEL is not identified and the maternal toxicity
NOAEL is 1000 mg/kg bw/day.

No treatment-related differences were noted between the treated and
control groups for numbers of corpora lutea and implantations, placental
and gravid uterine weights, live fetuses per dam, resorptions, fetal sex
ratios, and pre- or post-implantation losses.  Fetal body weights were
similar between the treated and control groups.  An increased fetal and
litter incidence of slight dilatation of the renal pelvis was observed
at 1000 mg/kg bw/day.  No other dose- or treatment-related external,
visceral, or skeletal malformations or variations were observed.

The developmental toxicity LOAEL is 1000 mg/kg bw/day, based on an
increased incidence of slight dilatation of the renal pelvis, and the
developmental toxicity NOAEL is 300 mg/kg bw/day.

4.2.4.2  Developmental Toxicity Study in Rabbits tc \l5 "4.2.2.3.2 
Developmental Toxicity Study in Rabbits 

In a developmental toxicity study (MRID 45696714), spirodiclofen was
administered to 22 female Himalayan CHBB:HM rabbits/dose by gavage at
dose levels of 0, 100, 300, or 1000 mg/kg bw/day from days 6 through 28
of gestation.  On GD 29, all surviving does were sacrificed and examined
grossly.  Each fetus was weighed and examined for external abnormalities
and for sex determination.  Fetuses were examined viscerally by a
modified Staples technique including a transverse section through the
brain in about 50% of the fetuses.  The eviscerated carcasses were
processed for skeletal examination including cartilage staining.  For
approximately half of the fetuses, the head was examined via a
transverse section through the brain and left intact for skeletal
processing and examination; for the remainder of the fetuses, the heads
were sectioned by a modified Wilson technique for an evaluation of
internal cranial structures.

There were no treatment-related mortalities in maternal animals. 
Reduced feces were observed in 8, 14, and 17 does in the control, low-,
mid-, and high-dose groups, respectively.  In addition, light colored
feces were seen in 14 high-dose animals compared with none of the
control, low-, or mid-dose animals.  Increased incidences of alopecia
and discolored urination were also noted in high-dose does.  No
statistical differences in absolute body weights were found between the
treated and control groups at any time during the study.  However,
marked body-weight loss occurred in the mid- and high-dose groups after
the initiation of treatment.  Weight loss during GD 6-9 was
significantly (p ( 0.05 or 0.01) greater in the mid- (-55.8 g) and
high-dose (-72.7 g) groups compared with the control group (-23.7 g)
with the most pronounced effects on GD 6-7.  Body-weight loss and
reduced feces correlated with decreased food consumption values at the
mid- and high-dose (which were 72% and 58%, respectively, of the control
levels for GD 6-9).  Weight changes and food consumption by the low-dose
group were similar to the control group throughout the study.  Maternal
necropsy was unremarkable.

The maternal toxicity LOAEL for spirodiclofen in rabbits is 300
mg/kg/day based on body-weight loss and decreased food consumption; the
maternal toxicity NOAEL is 100 mg/kg/day.

No statistically significant differences were noted between the treated
and control groups for numbers of corpora lutea, implantations, live
fetuses, or resorptions, fetal sex ratios, placental weight and
appearance, and pre- or post-implantation losses.  Fetal body weights
were similar between the treated and control groups.  No
treatment-related external, visceral, or skeletal malformations or
deviations were observed in fetuses. 

The developmental toxicity LOAEL for spirodiclofen in rabbits was not
determined; the developmental toxicity NOAEL is 1000 mg/kg/day.

4.2.5  Reproductive Toxicity Study tc \l4 "4.2.2.4  Reproductive
Toxicity Study 

In a two-generation reproduction study (MRID 45696802), spirodiclofen
was administered to groups of 25 F0 male and 25 F0 female Wistar
[Crl:WI(WU)BR] rats for 12 weeks before mating and during mating,
gestation and lactation of one litter.  Groups of 25 F1 male and 25 F1
females selected to parent the F2 generation received the same diets as
their F0 parents for 13 weeks before mating, during mating, gestation
and lactation of one litter.  Weight-normalized doses during the
premating period were as follows for the 0-, 70-, 350-, and 1750-ppm
groups, respectively: 0, 5.2, 26.2, and 134.8 mg/kg bw/day for F0 males;
0, 5.5, 27.6, and 139.2 mg/kg bw/day for F0 females; 0, 6.4, 30.2, 177.6
mg/kg bw/day for F1 males; 0, 7.0, 34.4, 192.7 mg/kg bw/day for F1
females.  Dose selection was based on a one-generation study conducted
in Wistar rats administered dietary concentrations of 0, 250, 2500, or
10,000 ppm (MRID 45696709).

No treatment-related clinical signs or deaths occurred in parental male
or female rats of either generation receiving any dose of the test
material.  Mean body weights were significantly (p<0.01 or <0.05)
decreased by 6-8% throughout the study in high-dose F0 males and by 5%
at various time points in mid-dose group F0 males compared with control
weights.  High-dose F1 males weighed 17-23% (p<0.01) less than controls
throughout the study, and low- and mid-dose F1 males had weights similar
to those of controls.  High-dose F0 and F1 males gained 9% and 16% less
weight, respectively, than controls over the entire study.  High-dose F0
females weighed 5-7% (p<0.01 or <0.05) less than controls during a few
premating weeks and gained 19% less weight, whereas high-dose F1 females
showed no toxicologically significant effect on body weights or weight
gain.  No treatment-related effect was observed on premating food
consumption in either sex or generation and food efficiency was only
slightly decreased.  Mean body weights and weight gain for females were
only slightly decreased (up to 10% less than controls) or showed no
toxicologically significant effect during gestation or lactation for
either generation. 

Clinical chemistry parameters were evaluated in a subset of F1 males and
females at the end of the premating period.  Statistically significant
decreases in plasma triglyceride, cholesterol, and/or unesterified fatty
acid levels were observed at all doses in males and at the mid and high
dose in females, and were considered to be indicative of alterations in
lipid metabolism.  Alkaline phosphatase activity was elevated slightly
more than two-fold in high-dose group F1 male and female rats, and was
attributed to significantly increased incidences of vacuolation in the
epithelium of the small intestine in high-dose animals.  Absolute liver
weights were decreased by 12-15% (p<0.01) and relative liver weights
were decreased by 8-9% (p<0.01) at all dose levels in F0 males, and
absolute and relative liver weights were decreased by 26% and 13%
(p<0.01), respectively, in high-dose F1 males.  The severity, but not
the incidence, of adrenal cortical vacuolation was increased in
high-dose F0 males, mid- and high-dose F0 females, and mid- and
high-dose F1 males and females. 

The LOAEL for spirodiclofen systemic parental toxicity in rats was 350
ppm for both sexes (26.2-30.2 mg/kg bw/day for males and 27.6-34.4 mg/kg
bw/day for females) based on the following findings:

in parental males:  decreased body weight in F0 males; decreased
absolute and relative liver weight in F0 males; decreased cholesterol
and triglycerides in F1 males; and increased severity of adrenal
cortical vacuolation in F1 males;

in parental females:  decreased unesterified fatty acids in F1 females,
and increased severity of adrenal cortical vacuolation in F0 and F1
females.

The parental systemic NOAEL is 70 ppm (5.2-6.4 mg/kg bw/day for males
and 5.5-7.0 mg/kg bw/day for females).

Evaluation of reproductive performance and function showed no
treatment-related effects on the fertility index, gestation index, total
number of pups born, number of stillbirths, post implantation loss or
number of live litters produced in either generation, mean gestation
interval, estrous cycle length, the number of females with prolonged or
abnormal cycles, day of vaginal patency in F1 females, percent motile
sperm or percent abnormal sperm in both generations, or testicular
spermatid and epididymal sperm count in high-dose F0 males.  The
insemination (mating) index, testicular spermatid count, and epididymal
sperm count were reduced in high-dose F1 males.  Sexual maturation as
measured by day of preputial separation was delayed by 2 days in
high-dose F1 males.  Postmortem examination of reproductive organs
showed decreases (12%, N.S.) in testes and epididymis (13%, p<0.05)
weights related to atrophy in the testis (4/25) and atrophy and
oligospermia in the epididymis (4/25) in high-dose F1 males compared
with none of the controls.  For two of these males, atrophy of the
prostate and seminal vesicles was also observed.  A small increase in
the severity of vacuolation/ degeneration in the luteal cells of the
ovaries was noted in high-dose F1 females.  All observed adverse
treatment-related effects on the reproductive system in this study were
observed at the highest dose tested (1750 ppm) in second generation (F1)
males and females, but not in first generation (F0) parental animals. 
This would suggest that early life stage (developmental) exposure to
spirodiclofen was a critical factor in eliciting this response, even
though a number of the adverse outcomes were not observed until the
animals were mature.

The LOAEL for spirodiclofen for reproductive effects in rats is 1750 ppm
(134.8-177.6 mg/kg bw/day for males and 139.2-192.7 mg/kg bw/day for
females) based on the following findings:

in F1 males: delayed sexual maturation; decreased testicular spermatid
and epididymal sperm counts (oligospermia); and atrophy of the testes,
epididymides, prostate and seminal vesicles;

in F1 females: increased severity of ovarian luteal cell
vacuolation/degeneration.

The reproductive NOAEL is 350 ppm (26.2-30.2 mg/kg bw/day for males and
27.6 and 34.4 mg/kg bw/day for females).

Evaluation of offspring parameters showed no treatment-related or
adverse effects on survival indices, (live birth, viability, and
lactation), sex ratios, live litter size, clinical signs, relative organ
weights (brain, thymus, and spleen), or gross findings.  During the
28-day lactation period, high-dose F1 and F2 male pups weighed 9-23% and
6-17% less, respectively, than controls and gained 24% and 17% less
weight, respectively, than controls.  Mid-dose F1 male pups weighed 2-6%
(p<0.01 or <0.05) less than controls during lactation, and mid-dose F2
male pups weighed significantly less (5%, p<0.05) than controls only on
the day of birth.  High-dose F1 and F2 female pups weighed 5-21%
(p<0.01) and 12-21% (p<0.01) less than controls, respectively, and
gained 22% and 19% less weight, respectively, than controls during
lactation.  Mid-dose F1 female pups weighed 3-9% (p<0.01) less than
controls, and mid-dose F2 female pups weighed significantly less (7%,
p<0.01) than controls only on the day of birth.

The LOAEL for spirodiclofen for offspring effects in rats is 350 ppm
(26.2-30.2 mg/kg bw/day for males and 27.6-34.4 mg/kg bw/day for
females) based on decreased body weight and weight gain in F1 male and
female pups.  The offspring NOAEL is 70 ppm (5.2-6.4 mg/kg bw/day for
males and 5.5-7.0 mg/kg bw/day for females).

4.2.6  Developmental Neurotoxicity Study tc \l4 "4.2.2.5  Developmental
Neurotoxicity Study 

In a DNT study (MRID 46324901) spirodiclofen (96.8-97.1% ai; Batch #:
06480/0002) was administered in the diet to pregnant Wistar Hannover
rats (30/dose) continuously from gestation day 0 to lactation day 21 at
nominal doses of 0, 70, 350, or 1500 ppm (equivalent to 0/0, 6.5/14.0,
32.1/69.7, and 135.9/273.8 mg/kg/day [gestation/lactation]). 

For maternal toxicity, no treatment-related effects were observed in
mortality, clinical signs, FOB, serum cholesterol level, reproductive
performance and postmortem examinations.  The number of animals with
vocalizations during removal from the home-cage was increased (p(0.05)
at 1500 ppm on GD 20 (10/30 treated vs 2/30 controls); however, this was
the only statistically significant FOB finding, and it was considered
not to be biologically important.  No treatment-related differences were
noted in body weights, body-weight gains, or food consumption during
gestation period.  During lactation, statistically significant
body-weight decrease ((5%, p(0.05) was observed in the 1500 ppm dams on
LD 21.  Food consumption was decreased (p(0.05) by 8% in the 1500 ppm
dams during LD 7-14.  However, body-weight changes within each group did
not show significant difference while compared with the control group. 
The body-weight decrease may be treatment-related but was not considered
biologically significant.

The maternal NOAEL was 1500 ppm (equivalent to 135.9 mg/kg/day).  The
maternal LOAEL was not established.

For offspring, no significant differences were noted between the treated
and control groups in live litter size, sex ratio, or number of deaths
during PND 0 to PND 4 (pre-cull) or PND 4 (post-cull) to PND 21, and the
litter indices (live birth, viability, and lactation).  No
treatment-related clinical signs were observed at any dose in either
sex.

During pre-weaning, body weights were decreased (p(0.05) by 5-8% in the
1500 ppm animals on PNDs 17 and 21.  Body-weight gains were decreased
(p(0.05) by 6-18% at 1500 ppm in both sexes at most intervals, and
overall (PNDs 0-21) body-weight gain was decreased by 9% in each sex at
1500 ppm.  During post-weaning, body weights were recovered in the 1500
ppm group. Post-weaning food consumption was similar between the treated
and control males.

No treatment-related effects were observed on sexual maturation (mean
time to preputial separation or mean time to vaginal patency).  For
behavioral assessment, no treatment-related FOB, motor activity, or
locomotor activity were observed in the treated pups compared to
controls during the pre-weaning and post-weaning periods.  No
treatment-related differences in the passive avoidance tests were
observed at any dose.  The trials to criterion for the retention phase
of the water maze test for PND 60 females showed a treatment-related
effect at all doses (number of animals with < 6 consecutive errorless
trials: 14/16, 8/16, 7/16, and 8/16 for the control, low, mid, and
high-dose groups, respectively).  Four of the high dose females failed
to complete five consecutive errorless trials (criterion for success). 

For postmortem examination, no significant differences in absolute brain
weight or cerebrum and cerebellum lengths were observed at any dose in
either sex at any time-point.  The following morphometric measurement
differences (p(0.05) were noted in the 1500 ppm group:  (i) caudate
putamen ((3%) and (ii) hippocampal gyrus ((7%) in the PND 21 females;
(iii) parietal cortex ((6%) in the terminal males; (iv) caudate putamen
((3%) and (v) hippocampal gyrus ((6%) in the terminal females.  Due to
these findings, along with the effects on memory observed at all doses
in the PND 60 females in the water maze test, morphometric analyses of
the caudate putamen, parietal cortex, hippocampal gyrus, and dentate
gyrus at the mid and low doses are requested for both sexes.

The offspring LOAEL was 70 ppm (equivalent to 6.5 mg/kg/day) based on
effects in memory phase of the water maze test in PND 60 females.  There
was no offspring NOAEL in this study. 

The study classification is reserved for the guideline requirement
(OPPTS 870.6300; OECD 426) for a developmental neurotoxicity study in
rats pending receipt of additional morphometric measurements for the low
and mid dose groups.

In a second DNT study, an abbreviated developmental neurotoxicity study
(MRID 47166501), technical spirodiclofen (97.5-98.3 % ai, batch
06480/0002) was administered in the diet to 30 female Wistar Han Crl:WI
(Han) rats per dose at dose levels of 0, 70, 350 or 1500 ppm (average
daily intake of 0, 5.4, 28.6 and 119.2 mg/kg/day, respectively, during
gestation and 0, 13.0, 65.7 and 262.1 mg/kg/day, respectively, during
lactation) from GD 0 through lactation day (LD) 21.  Because of
increased food consumption during lactation, dietary levels were
adjusted to achieve a more consistent mg/kg/day dosage throughout the
exposure period.  On PND 4, litters were culled to yield four males and
four females (as closely as possible). Offspring were allocated for
clinical observations, body-weight measurements, ophthalmic examinations
and assessment of learning and memory (water maze testing using M-Maze
and Cincinnati Water Maze). Whole-brain tissue was collected from
10/sex/dose level on PND 21 and at study termination (PND 75 ±5) for
morphometry.  The study was conducted to address questions about brain
measurements and M-Maze results in the original developmental
neurotoxicity study.

No deaths or clinical signs of toxicity were observed in parental
females.  The slight decrease in food consumption (4-5% as compared to
controls) during lactation produced a minimal decrease in body-weight
gain (4% as compared to controls) for LDs 0-20.  The findings are not
considered adverse due to the low magnitude of the changes and the lack
of statistical significance.  No treatment-related effects on
reproduction were reported. 

No clinical signs of toxicity were observed in offspring during
lactation or postweaning.  Litter size and viability were not affected
by treatment.  Beginning on PND 17, a decrease in body weight was
observed in the high-dose group, with statistically significant
decreases of 8% and 7% in males and females as compared to controls,
respectively, on PND 21.  Statistically significant decreases in
body-weight gain were observed in high dose males and females for the
periods PND 4-21 (9-10%), PND 11-21 (13%) and PND 17-21 (21%).  During
postweaning, body weight was decreased (5-6% as compared to controls) in
high-dose males on PND 29 through PND 50, which was statistically
significant on PNDs 35 and 42.  No treatment-related effects on learning
and memory were observed in either the M-Maze or the Cincinnati Water
Maze testing.  In the previous study, there was a significant increase
in the trials to criterion observed in females in all dose groups during
session 2 (memory).  A request was made for the submission of positive
control data which has not been received as yet.  Despite the lack of
positive control data, it was observed that the trials to criterion for
both male and female rats ranged from 5.4-7.9 seconds in the previous
and current studies; thus indicating no treatment related changes in
this study.  Therefore, the results of the previous study were not
replicated in this new study.  No treatment-related effects on
ophthalmic examinations, brain weight or postmortem macroscopic and
morphometric findings were observed. 

The maternal LOAEL for spirodiclofen in rats was not established.  The
maternal NOAEL is 1500 ppm (119.2 and 262.1 mg/kg/day during gestation
and lactation, respectively).

The offspring LOAEL for spirodiclofen in rats is 1500 ppm (119.2 and
262.1 mg/kg/day during gestation and lactation, respectively) based on
decreased preweaning body weight and body-weight gain in males and
females and decreased post-weaning body weight in males.  The offspring
NOAEL is 350 ppm (28.6 and 65.7 mg/kg/day during gestation and
lactation, respectively).

4.2.7  Additional Information from Literature Sources tc \l3 "4.2.3 
Additional Information from Literature Sources 

No additional hazard information from published literature was
identified.

4.2.8  Pre- and/or Postnatal Toxicity tc \l3 "4.2.4   Pre- and/or
Postnatal Toxicity 

4.2.9  Determination of Susceptibility tc \l4 "4.2.4.1  Determination of
Susceptibility 

The database is adequate to evaluate the potential increased
susceptibility of infants and children. The HIARC determined that there
is no evidence (qualitative or quantitative) of increased susceptibility
in the rabbit developmental toxicity study and the rat reproduction
toxicity study following in utero and/or pre-/post-natal exposure of
spirodiclofen.  However, evidence for quantitative susceptibility was
observed in a rat developmental toxicity study where an increased
incidence of slight dilatation of the renal pelvis was observed at a
dose (1000 mg/kg/day) which did not cause any maternal toxicity. 
Previously, the HIARC concluded that there is evidence of increased
susceptibility of rat offspring in the first DNT study (second DNT study
was not available) because the toxicity in the offspring was observed in
the absence of maternal toxicity, indicating increased susceptibility. 
In this study, there was no maternal toxicity was observed (135.9
mg/kg/day; HDT; highest dose tested).  The offspring toxicity LOAEL was
6.5 mg/kg/day based on marginal effects in the memory phase of the water
maze test in female offspring on post natal day 60 and differences in
morphometric measurements at the HDT (135.9 mg/kg/day).  Additionally,
treatment-related changes were seen at the HDT (135.9 mg/kg/day) in
several brain morphometric parameters (caudate putamen, parietal cortex,
hippocampal gyrus, and dentate gyrus).  Consequently, evaluations were
requested for these parameters at the mid- and low-dose groups. 
However, the registrant has informed that the brain tissues were not
appropriately preserved; therefore, additional brain morphometric
analyses at the mid and low doses are not possible.  Therefore, the
registrant conducted the second study.  In a second DNT study, there is
evidence for increased susceptibility of rat offspring due to exposure
to spirodiclofen.  In this study, the offspring toxicity such as
decreased pre-weaning body weight and body-weight gain in males and
females and decreased post-weaning body weights in males at the LOAEL of
119.2 mg/kg/day and NOAEL was 28.6 mg/kg/day.  There was no maternal
toxicity at the doses up to and including 119.2 mg/kg/day. 

4.2.10  Degree-of-Concern Analysis for Pre and/or Post-natal
Susceptibility tc \l4 "4.2.4.2  Degree-of-Concern Analysis for Pre
and/or Post-natal Susceptibility 

The HIARC determined that the degree of concern is low for the
quantitative susceptibility seen in rats. The increased incidence of
slight renal pelvic dilation in the rat developmental toxicity was
observed at the limit-dose only without statistical significance and
dose response.  Renal pelvic dilation was considered to be a
developmental delay and not a severe effect for developmental toxicity. 
The low background incidences in this study may be idiosyncratic to this
strain (Wistar) of rats since renal pelvis dilations are commonly seen
at higher incidences in other strains (Sprague-Dawley or Fisher) of
rats. In addition, doses selected for risk assessment of spirodiclofen
are much lower than the dose that caused these developmental delays. 
The two DNT studies suggest increased evidence of susceptibility of
offspring due to exposure to spirodiclofen.  However, there is no
concern for the increased susceptibility seen the first DNT study
because the results were not reproduced in the second DNT study
conducted using the identical doses and experimental conditions in a
second study.  The concern for increased susceptibility in a second DNT
study is low because there is a well established NOAEL, marginal
toxicity (slight changes in body weights), and all
developmental/functional parameters were comparable to controls.  In
addition, doses selected for risk assessment of spirodiclofen are much
lower than the dose that caused these marginal changes in the body
weights of offspring in the second DNT study.  There is no concern for
increased susceptibility in the developmental toxicity in rabbits,
two-generation reproduction study in rats.  The FQPA factor of 3X has
been applied for use LOAEL instead of NOAEL for short-term oral,
short-term dermal and inhalation exposure scenarios.  HIARC determined
that a 3x (as opposed to a 10x) uncertainty factor is adequate (for the
use of a LOAEL) since the extrapolated NOAEL (8.4/3= 2.8 mg/kg/day) is
comparable to the NOAEL (1.38 or 1.52 mg/kg/day for males or females,
respectively) in the chronic study.

4.3  Hazard Identification and Toxicity Endpoint Selection tc \l2 "4.4 
Hazard Identification and Toxicity Endpoint Selection 

4.3.1  Acute Reference Dose (aRfD) - All Populations tc \l3 "4.4.1 
Acute Reference Dose (aRfD) - All Populations 

An endpoint of concern attributable to a single dose was not identified
in the hazard database.  The increased incidence of slight dilation of
the renal pelvis, observed only at the limit dose was not considered to
be a single dose effect and therefore was not selected for establishing
the aRfD.

  

In the first developmental neurotoxicity study, offspring effects (brain
morphometry and learning and memory) were noted in the absence of
toxicity in the dams.  However, these effects were not observed in the
repeat study using the same doses and identical experimental conditions.
 

4.3.2  Chronic Reference Dose (cRfD) tc \l3 "4.4.2  Chronic Reference
Dose (cRfD) 

A cRfD was determined based on increased relative adrenal weights in
both sexes, increased relative testis weight in male dogs and
histopathology findings in the adrenal gland of both sexes of dogs seen
at the LOAEL of 4.33 mg/kg/day.  The NOAEL was 1.38 mg/kg/day. The
chronic oral toxicity study in dogs (MRID 45696810) was selected for
chronic dietary risk assessment because, while the effects were seen in
rats, dogs and mice, dogs were considered the most sensitive species. 
These endpoints will provide the most protective limits for human
effects.  This study is of the appropriate duration and route of
exposure. 

In a chronic toxicity study (MRID 45696810), spirodiclofen was
administered to beagle dogs (4/sex/dose) in the diet at dose levels of
0, 20, 50, 150, or 500/600 ppm (equivalent to 0, 0.56, 1.38, 4.33, or
16.1 mg/kg bw/day for males and 0, 0.59, 1.52, 4.74, or 17.7 mg/kg
bw/day for females, respectively) for 52 weeks.  The highest dose was
increased from 500 ppm to 600 ppm in study week 4. 

There were no compound related effects on mortality, clinical signs,
food consumption, body-weight gains, urinalysis, hematology, clinical
chemistry, and ophthalmoscopic examinations.  Liver enzyme activities
showed dose-dependent increases of N-DEM, and O-DEM activities which
indicated an induction of hepatic metabolic activity in response to
spirodiclofen administration.

The relative organ weight showed dose-related increases in adrenal
glands of both sexes, in kidneys (females only), and in testes,
epididmydes and prostates of males.  Histopathology of the adrenal gland
revealed an increased incidence of cortical vacuolation in the zona
fasciculata of both sexes at 150 and 500/600 ppm.  In the testes,
increased incidences of Leydig cell vacuolation, slight Leydig cell
hypertrophy, and tubular degeneration were observed in males at 500/600
ppm.

Under the conditions of this study, the NOAEL is 50 ppm (1.38 mg/kg
bw/day for males and 1.52 mg/kg bw/day for females) and the LOAEL is 150
ppm (4.33 mg/kg bw/day for males and 4.74 mg/kg bw/day for females)
based on increased relative adrenal weights in both sexes, increased
relative testis weight in males and histopathology findings in the
adrenal gland of both sexes.

The dose and endpoint for establishing the cRfD are the NOAEL = 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).  An
uncertainty factor of 100X has been incorporated into the cRfD (10x for
interspecies extrapolation and 10x for intraspecies variations). 

Chronic RfD = 1.38 mg/kg (NOAEL) = 0.014 mg/kg/day

4.3.3  Incidental Oral Exposure:  Short-Term (1-30 days) tc \l3 "4.4.3 
Incidental Oral Exposure:  Short-Term (1-30 days) 

The endpoint for short-term incidental oral risk assessment was chosen
based on the results of a subchronic oral toxicity study in dogs (MRID
45696803).  The endpoints are increased adrenal gland weight (two out of
four animals) which corroborated with histopathology findings
(cytoplasmic vacuoles in the Zona fasciculata of the adrenal glands) in
females and the study and results are summarized below.  The study and
endpoint are of the appropriate duration and route of exposure for
short-term incidental oral risk assessment.   

In a 90-day oral toxicity study spirodiclofen was administered to beagle
dogs (4/sex/dose) via diet at dose levels of 0, 200, 630, or 2000 ppm
(equivalent to 0, 7.7, 26.6, or 84.7 mg/kg bw/day for males and 0, 8.4,
28.0, 81.0 mg/kg bw/day for females, respectively) for 14 weeks. 

There were no compound related effects on mortality, clinical signs,
food consumption, hematology, urinalysis, and ophthalmoscopic
examinations.  There was a dose-dependent decrease of body-weight gain
in both sexes.  A significant decrease of body-weight gain was observed
in males at doses of 630 ppm and above compared with the controls. 
Increased plasma transaminase activities (ASAT, ALAT) and increased APh
and GLDH levels were seen at doses of 630 ppm and above of both sexes. 
A trend to lower cholesterol was observed in the 630 and 2000 ppm groups
of both sexes.  The activities of liver enzymes showed an induction of
phase I enzymes (cytochrome p-450-dependent monooxygenases (ECOD, EROD,
ALD)) in response to spirodiclofen administration.  There were no
effects on the phase II enzyme activities (GS-T and GLU-T).  The EH was
induced at the high dose in females only.  Dose-dependent increases of
N-DEM, O-DEM, ECOD and ALD levels were seen in both sexes.  The changes
of liver enzyme activities suggest an induction of hepatic metabolic
activity in response to administration of spirodiclofen.  These changes
are considered adaptive effects and not regard as adverse effects.

Based on dose-dependent relationship, increased relative organ weights
were observed in the liver at 630 and 2000 ppm of both sexes, kidney at
2000 ppm of both sexes, pituitary at 630 and 2000 ppm of males, and
adrenal gland at 630 and 2000 ppm of both sexes.  Decreased relative
prostate weight also was observed in males at 630 and 2000 ppm. 
Histopathological examination revealed treatment-related findings in the
liver, kidney, adrenal gland, prostate, testis, and thymus. 
Hepatocellular cytoplasmic changes, inflammatory infiltrates, and single
cell necrosis were seen in females only at the highest dose.  Dilation
of the proximal tubules of the renal cortex was seen in both sexes at
the 2000 ppm.  The dilation is considered an adaptive effect since no
degenerative changes were seen.  In testes, vacuolation and
hypertrophy/activation of Leydig cells was observed in males at 630 and
2000 ppm.  In addition, degeneration and/or immaturity of the testicular
germinal epithelium, oligo- and aspermia of the epididmydes, and
immature prostates were detected at doses of 630 ppm and above.  A
dose-dependent increase of cytoplasmic vacuolation of the adrenal cortex
was observed in females at all doses and in males at the 630 ppm and
above.  The adrenal effects were also observed in rat and mouse studies
and were considered significant.

The LOAEL for males was 630 ppm (26.6 mg/kg bw/day) based on decreased
body-weight gains, decreased relative prostate weight, increased
relative liver and adrenal weights and histopathology findings in the
adrenal glands, testes, and prostates; the NOAEL was 200 ppm (7.7 mg/kg
bw/day).  The LOAEL for females was 200 ppm (8.4 mg/kg bw/day) based on
increased adrenal gland weight (two out of four animals) which
corroborated with histopathology findings (cytoplasmic vacuoles in the
Zona fasciculata of the adrenal glands); the NOAEL for females was not
established.

The dose and endpoint for risk assessment are the LOAEL of 8.4 mg/kg/day
based on increased adrenal gland weight (two out of four animals) which
corroborated with histopathology findings (cytoplasmic vacuoles in the
Zona fasciculata of the adrenal glands) in females; a NOAEL for females
was not established. 

The dose/endpoint is appropriate for the population (infants and
children) of concern.  The HIARC selected the 90-day study for this
duration (short-term) since similar target organ toxicity (adrenal
glands) was also seen in the chronic study in dogs as well as in mice. 
The Committee determined that a 3x (as opposed to a 10x) uncertainty
factor is adequate (for the use of a LOAEL) since the extrapolated NOAEL
(8.4/3= 2.8 mg/kg/day) is comparable to the NOAEL (1.38 or 1.52
mg/kg/day for males or females, respectively) in the chronic study.

4.3.4  Incidental Oral Exposure:  Intermediate-Term (1-6 Months) tc \l3
"4.4.4  Incidental Oral Exposure:  Intermediate-Term (1 - 6 Months) 

The dose and endpoint for intermediate-term incidental oral risk
assessment was chosen based on the results of the chronic oral toxicity
study in dogs (MRID 45696810).  The endpoints are increased relative
adrenal weights in both sexes, increased relative testis weight in male
dogs and histopathology findings in the adrenal gland of both sexes of
dogs.  The study is summarized above in Section 4.3.2.  This study and
endpoint are of the appropriate duration and route of exposure for
intermediate-term incidental oral risk assessment.

The dose and endpoint for risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

4.3.5  Dermal Absorption

A dermal-absorption factor of 2% was determined based on the results of
two dermal-absorption studies in monkeys.  The dermal-absorption rate is
appropriate for estimating dermal risk for all time durations.

4.3.6  Short-Term Dermal Exposure (1-30 days) tc \l3 "4.4.6  Short-Term
Dermal Exposure: (1-30 days) 

The dose and endpoint for short-term dermal risk assessment were chosen
based on the results of a subchronic oral toxicity study in dogs (MRID
45696803).  The endpoint is increased adrenal gland weight (two out of
four animals) which corroborated with histopathology findings
(cytoplasmic vacuoles in the Zona fasciculata of the adrenal glands) in
females.  The study and results are summarized in Section 4.3.3.  The
study and endpoint are of the appropriate duration and route of exposure
for short-term dermal risk assessment.   

The dose and endpoint for risk assessment are the LOAEL of 8.4 mg/kg/day
based on increased adrenal gland weight (two out of four animals) which
corroborated with histopathology findings (cytoplasmic vacuoles in the
Zona fasciculata of the adrenal glands) in females; a NOAEL for females
was not established. 

The HIARC did not select the 28-day dermal toxicity study because the
target organs (i.e., adrenal, testes, etc.) were not evaluated in this
study.  The HIARC selected the 90-day study for this duration
(short-term) since similar target organ toxicity (adrenal glands) was
also seen in the chronic study in dogs as well as in mice.  The
Committee determined that a 3x (as opposed to a 10x) uncertainty factor
is adequate (for the use of a LOAEL) since the extrapolated NOAEL (8.4(3
= 2.8 mg/kg/day) is comparable to the NOAEL (1.38 or 1.52 mg/kg/day for
males or females, respectively) in the chronic study.  Since an oral
LOAEL was selected, 2% dermal-absorption factor should be used for
route-to-route extrapolation.

4.3.7  Intermediate-Term Dermal (1-6 Months) tc \l3 "4.4.7 
Intermediate-Term Dermal (1 - 6 Months) 

The dose and endpoint for intermediate-term dermal risk assessment were
chosen based on the results of a chronic oral toxicity study in dogs
(MRID 45696810).  The endpoints are increased relative adrenal weights
in both sexes, increased relative testis weight in males and
histopathology findings in the adrenal gland of both sexes.  The study
and results are summarized above in Section 4.3.2.  The study and
endpoint are of the appropriate duration and route of exposure for
intermediate-term dermal risk assessment.   

The dose and endpoint for use in risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

This dose/endpoint/study was selected for establishing the chronic RfD. 
Since an oral NOAEL was selected, 2% dermal-absorption factor should be
used for route-to-route extrapolation.

4.3.8  Long-Term Dermal (>6 Months) Exposure tc \l3 "4.4.8  Long-Term
Dermal (> 6 Months) Exposure 

The dose and endpoint selected for long-term dermal risk assessment were
chosen based on the results of a chronic oral toxicity study in dogs
(MRID 45696810).  The endpoints are increased relative adrenal weights
in both sexes, increased relative testis weight in males and
histopathology findings in the adrenal gland of both sexes.  The study
and results are summarized above in Section 4.3.2.  The study and
endpoint are of the appropriate duration and route of exposure for
long-term dermal risk assessment.   

The dose and endpoint for use in risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

This dose/endpoint/study was selected for establishing the chronic RfD. 
Since an oral NOAEL was selected, 2% dermal-absorption factor should be
used for route-to-route extrapolation.

4.3.9  Short-Term Inhalation (1-30 days) Exposure tc \l3 "4.4.9 
Short-Term Inhalation (1-30 days) Exposure 

The dose and endpoint for short-term inhalation risk assessment were
chosen based on the results of a subchronic oral toxicity study in dogs
(MRID 45696803).  The endpoints are increased adrenal gland weight (two
out of four animals) which corroborated with histopathology findings
(cytoplasmic vacuoles in the Zona fasciculata of the adrenal glands) in
females.  The study and results are summarized in Section 4.3.3.  The
study and endpoint are of the appropriate duration and route of exposure
for short-term inhalation risk assessment.   

The dose and endpoint for risk assessment are the LOAEL of 8.4 mg/kg/day
based on increased adrenal gland weight (two out of four animals) which
corroborated with histopathology findings (cytoplasmic vacuoles in the
Zona fasciculata of the adrenal glands) in females; a NOAEL for females
was not established. 

The dose and endpoint for use in risk assessment are the LOAEL of 8.4
mg/kg/day based on increased adrenal gland weight (two out of four
animals) which coincided with histopathology findings (cytoplasmic
vacuoles in the Zona fasciculata of the adrenal glands) in females; a
NOAEL for females was not established. 

The HIARC selected the 90-day study for this duration (short-term) since
similar target organ toxicity (adrenal glands) was also seen in the
chronic study in dogs as well as in mice.  The Committee determined that
a 3x (as opposed to a 10x) uncertainty factor is adequate (for the use
of a LOAEL) since the extrapolated NOAEL (8.4/3 = 2.8 mg/kg/day) is
comparable to the NOAEL (1.38 or 1.52 mg/kg/day for males or females,
respectively) in the chronic study.  In the absence of a repeated
exposure inhalation study, the HIARC selected an oral study.  Inhalation
absorption is assumed to be equivalent to oral (i.e., 100%).

4.3.10  Intermediate-Term Inhalation (1-6 months) Exposure tc \l3
"4.4.10  Intermediate-Term Inhalation (1-6 months) Exposure 

The dose and endpoint for intermediate-term inhalation risk assessment
were chosen based on the results of a chronic oral toxicity study in
dogs (MRID 45696810).  The endpoints are increased relative adrenal
weights in both sexes, increased relative testis weight in males and
histopathology findings in the adrenal gland of both sexes.  The study
and results are summarized above in Section 4.3.2.  The study and
endpoint are of the appropriate duration and route of exposure for
intermediate-term inhalation risk assessment.   

The dose and endpoint for use in risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

This dose/endpoint/study was selected for establishing the chronic RfD.

The dose and endpoint for use in risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

In the absence of a repeated exposure inhalation study, the HIARC
selected an oral study.  Inhalation absorption is assumed to be
equivalent to oral (i.e., 100%).

4.3.11  Long-Term Inhalation (>6 months) Exposure tc \l3 "4.4.11 
Long-Term Inhalation (>6 months) Exposure 

The dose and endpoint for long-term inhalation risk assessment were
chosen based on the results of a chronic oral toxicity study in dogs
(MRID 45696810).  The endpoints are increased relative adrenal weights
in both sexes, increased relative testis weight in males and
histopathology findings in the adrenal gland of both sexes.  The study
and results are summarized above in Section 4.3.2.  The study and
endpoint are of the appropriate duration and route of exposure for
long-term dermal risk assessment.   

The dose and endpoint for use in risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

This dose/endpoint/study was selected for establishing the chronic RfD.

The dose and endpoint for use in risk assessment are the NOAEL of 1.38
mg/kg/day based on increased relative adrenal weights in both sexes,
increased relative testis weight in males and histopathology findings in
the adrenal gland of both sexes at 4.33 mg/kg/day (LOAEL).

In the absence of a repeated exposure inhalation study, the HIARC
selected an oral study.  Inhalation absorption is assumed to be
equivalent to oral (i.e., 100%).

 

4.3.12  Margins of Exposure tc \l3 "4.4.12  Margins of Exposure 

Table 4.3.12.  Summary of Target MOEs for Risk Assessment.

Route	Duration	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	 Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	300	100	100

Inhalation	300	100	100

Residential (Non-Dietary) Exposure

Oral	300	100	100

Dermal	300	100	100

Inhalation	300	100	100

For Occupational Exposure:  For short-term dermal and inhalation
exposure risk assessments, a MOE of 300 is required.  For intermediate
and long-term dermal and inhalation exposure risk assessments, a MOE of
100 is required.  This includes the conventional 100x and an additional
3x for the use of a LOAEL for short-term dermal and inhalation risk
assessment.  For intermediate– and long-term dermal and inhalation
risk assessments, the conventional 100x UF is used. 

For Residential Exposure:  Not applicable for this action.  There are no
residential uses proposed.  

4.3.13  Recommendation for Aggregate Exposure Risk Assessments tc \l3
"4.4.13  Recommendation for Aggregate Exposure Risk Assessments 

Chronic and cancer aggregate risk estimates include exposure from
drinking water and from food sources.  Short- and intermediate-term
aggregate risk assessments are not required since there are no
residential uses proposed at this time.  

4.3.14  Carcinogenicity

4.3.14.1  Combined Chronic Toxicity/Carcinogenicity Study in Rats tc \l4
"4.4.14.1  Combined Chronic Toxicity/Carcinogenicity Study in Rats 

In a combined chronic toxicity/carcinogenicity study (MRID 45696808),
spirodiclofen was administered to Wistar rats (50/sex/dose) via diet at
dose levels of 0, 50, 100, 350, or 2500 ppm (0, 2.0, 4.1, 14.7, or 110.1
mg/kg bw/day for males and 0, 2.9, 5.9, 19.9, or 152.9 mg/kg bw/day for
females, respectively) for two years.  Additional groups of rats
(10/sex/dose) were treated likewise with spirodiclofen for interim
sacrifice after one year. 

No significant treatment-related effects were observed in clinical signs
and mortality.  Significant decreases in body weights were observed in
the 2500 ppm group of both sexes compared to controls ((8-10% for males
up to weeks 101; (6-7% for females up to weeks 53).  Body-weight gains
were decreased at 2500 ppm of both sexes up to week 3 and recovered
thereafter.  Blood analyses showed no significant effects in
hematological examinations; however, significant increases of alkaline
phosphatase (APh) and decreases of cholesterol and triglyceride levels
(not statistically significant) were observed in both sexes at 2500 ppm
at all test points.  Significantly increased thyroxine (T4) levels were
observed in 2500 ppm males at weeks 53 and 105.  Increased thyroid
stimulating hormone was observed at 2500 ppm of both sexes but the
statistical significance was observed only in females at weeks 79 and
105.  Gross and histopathology examinations showed an increased
incidence of vacuolated enterocytes in the jejunum (both sexes),
increased incidence and severity of vacuolation in Zona fasciculata
cells of the adrenal cortex (males only), increased portion of ovarian
stroma, and increased incidence of uterus nodules (females) at 2500 ppm.
 Increased incidence of Leydig cell hyperplasia was observed in males at
350 ppm and above with a positive trend.

Under conditions of this study, the LOAEL is 350 ppm for males (14.7
mg/kg bw/day) based on increased incidence of Leydig cell hyperplasia. 
The LOAEL is 2500 ppm (152.9 mg/kg/day) for females is based on
decreased body weights, decreased body-weight gain, increased APh
levels, increased thyroid stimulating hormone (TSH), uterus nodules, and
increased vacuolated jejunum enterocytes.  The NOAEL is 100 ppm for
males (4.1 mg/kg/day) and 350 ppm for females (19.9 mg/kg/day).

Neoplastic pathology showed an increased incidence of treatment related
neoplastic findings in reproductive organs of males (testes) and females
(uterus).  In males, a significantly increased frequency of Leydig cell
adenoma (4%, 2%, 0%, 8%, or 20% at dose levels of 0, 50, 100, 350, or
2500 ppm, respectively) was observed at 350 ppm and above with a
positive trend.  Concurrently, increased incidence of Leydig cell
hyperplasia (8%, 8%, 8%, 14%, or 38%, respectively) was observed at 350
ppm and above with a positive trend.  The majority of Leydig cell
adenomas and focal hyperplasias were found in males at the termination
of the study suggesting a late onset of these alterations.  In females,
increased incidence of uterine adenocarcinoma (8%, 10%, 6%, 4%, or 28%,
respectively) was observed at 2500 ppm.  The majority of the uterine
adenocarcinoma (11 out of 14) was found in females which died or had to
be sacrificed before the termination of the study.  The pathology report
also indicated that many of the adenocarcinomas had metastasized by
invasion and intra-abdominal spread into various organs of the abdominal
cavity such as ovaries, liver, spleen, pancreas, mesenteric lymph node,
kidney, lung, and bone marrow.  Slightly increased incidences of C-cell
adenoma in thyroid gland were observed in males (8%, 12%, 10%, 8%, or
14%, respectively) and in females (4%, 4%, 6%, 10%, or 12%,
respectively) at 2500 ppm; however, the incidences were within the
historical control ranges (6-24% in males and 6-22% in females).

Discussion of Tumor Data:  Male rats had a significant increasing trend
at p<0.01, and a significant difference in the pair-wise comparison of
the 2500 ppm dose group with the controls at p< 0.05, for testicular
Leydig cell adenomas.  The incidence of Leydig cell adenomas of 20% for
the high dose group is outside the historical control range of the
performing laboratory (2-8%).  The incidence of Leydig cell adenomas for
the 350 ppm dose group of 8%, although not statistically significant,
was just within the boundary of the historical control range (2-8%) and
was considered to be biologically significant.  This is supported by an
increase (not statistically significant) in focal Leydig cell
hyperplasia at 350 ppm.

Female rats had significant increasing trends, and significant
differences in the pair-wise comparisons of the 2500 ppm dose group with
the controls, for uterine adenocarcinomas and combined adenomas and/or
adenocarcinomas, all at p<0.01.  The incidence of adenocarcinomas of 28%
at the high dose was outside the laboratory historical control range of
2-10% for adenocarcinomas.

Adequacy of the Dose Levels Tested:  Dosing was considered adequate
based on body-weight decrease, clinical chemistry, and histopathological
findings.  Significant decreases in body weights were observed in the
2500 ppm group of both sexes compared to controls ((8-10% for males up
to weeks 101; (6-7% for females up to weeks 53).  Body-weight gains were
decreased at 2500 ppm of both sexes up to week 3 and recovered
thereafter.  Significant increases of APh and decreases of cholesterol
and triglyceride levels (not statistically significant) were observed in
both sexes at 2500 ppm at all test points.  Significantly increased
thyroxine (T4) levels were observed in 2500 ppm males at weeks 53 and
105.  Increased TSH was observed at 2500 ppm of both sexes but the
statistical significance was observed only in females at weeks 79 and
105.  Gross and histopathology examinations showed an increased
incidence of vacuolated enterocytes in the jejunum (both sexes),
increased incidence and severity of vacuolation in Zona fasciculata
cells of the adrenal cortex (males only), increased portion of ovarian
stroma, and increased incidence of uterus nodules (females) at 2500 ppm.
 Increased incidence of treatment related neoplastic findings in
reproductive organs of males (testes) and females (uterus) were observed
at the 2500 ppm group.

4.3.14.2  Carcinogenicity Study in Mice tc \l4 "4.4.14.2 
Carcinogenicity Study in Mice 

In a carcinogenicity study (MRID 45696724), spirodiclofen (97.6-98.6%
ai, batch/lot # 06480/0002) was administered to CD-1 mice (50/sex/dose)
via diet at dose levels of 0, 25, 3500, or 7000 ppm (equivalent to 0,
4.1, 610, or 1216 mg/kg bw/day for males, and 0, 5.1, 722, or 1495 mg/kg
bw/day for females, respectively) for 18 months. 

There were no compound-related effects on mortality, clinical signs,
body weight, food consumption, and hematology examinations.  Increased
organ weights were observed in livers and adrenal glands at 3500 and
7000 ppm of both sexes.  Increased testis weights were observed in males
at 7000 ppm.  Decreased absolute and relative kidney weights were
observed in 3500 ppm and 7000 ppm of both sexes.  Gross pathology showed
enlarged adrenal glands at 3500 and 7000 ppm of both sexes. 
Histopathology examination revealed increases of incidence and severity
of vacuolation in the adrenal cortex at 3500 and 7000 ppm of both sexes.
 In the liver, dose-dependent increases of incidence and severity of
hepatocytomegaly were observed in males only.  In the testis, increases
of incidence and severity on hypertrophy and hyperplasia of the
interstitial cell were noted in 3500 and 7000 ppm males.  A dose-related
increased incidence of amyloid was observed in various organs of both
sexes.  The lesion in the testis consisted of increased cell size as
well as numbers of cells.  Additional histopathology findings included
discolored testis in mid dose males, epididymis aspermia in high dose
males, lymphocytic infiltrate in high dose females and increased
incidence of focal opacity in high dose males.

Under conditions of this study, the NOAEL is 25 ppm (4.1 mg/kg bw/day
for males and 5.1 mg/kg bw/day for females).  The LOAEL is 3500 ppm (610
mg/kg bw/day) for males based on increased absolute and relative liver
and adrenal weights, decreased absolute and relative kidney weight,
enlarged adrenal gland, discolored testis, adrenal gland vacuolization,
interstitial cell degeneration of the testes and amyloid.  The LOAEL is
3500 ppm (722 mg/kg bw/day) for females based on increased absolute and
relative adrenal weight, decreased absolute and relative kidney weight,
increased incidences of adrenal gland pigmentation, adrenal
vacuolization and amyloid.

Neoplastic pathology examination showed increases of neoplastic lesions
in the liver.  The incidences of hepatocellular adenoma were 0/50, 0/50,
5/50, or 6/50 for males and 0/50, 0/50, 3/50, or 1/50 for females at 0,
25, 3500, or 7000 ppm, respectively. The incidences of hepatocellular
carcinoma were 1/50, 1/50, 3/50 or 5/50 for males and 0/50, 0/50, 2/50,
or 2/50 for females at 0, 25, 3500, or 7000 ppm, respectively.  The
combined frequencies of hepatocellular neoplasm (hepatocellular adenoma
and carcinoma) were 1/50 (2%), 1/50 (2%), 8/50 (16%), or 10/50 (20%) for
males and 0/50, 0/50, 5/50 (10%), or 3/50 (6%) for females at 0, 25,
3,500 or 7,000 ppm, respectively.  Comparing with historical control,
the combined frequencies of hepatocellular adenoma and carcinoma at 3500
ppm (16% in males and 10% in females) and 7000 ppm (22% in males and 6%
in females) are higher than the ranges seen in either in-house control
(4-14% in males and 0-2% in females) or literature historical data
(0-9.6% in males and 0-2.7% in females).

Discussion of Tumor Data:  Male mice had significant increasing trends
in liver adenomas and adenomas and/or carcinomas combined, both at
p<0.01.  There was a significant increasing trend in liver carcinomas at
p<0.05.  There were significant differences in the pair-wise comparisons
of the 3500 and 7000 ppm dose groups with the controls for liver
adenomas, both at p< 0.05.  There were significant differences in the
3500 ppm dose group at p<0.05 and in the 7000 ppm dose group at p<0.01
with the controls for liver adenomas and/or carcinomas combined.  The
incidences of combined liver adenomas and carcinomas of 16% and 22% for
the 3500 ppm and 7000 ppm dose groups, respectively, are outside the
historical control range of the performing laboratory (4-14%).

Female mice had a significant increasing trend, and a significant
difference in the pair-wise comparison of the 3500 ppm dose group with
the controls, for liver adenomas and/or carcinomas combined, both at
p<0.05.  The incidences of combined liver adenomas and carcinomas of 10%
(statistically significant) and 6% (not statistically significant) for
the 3500 ppm and 7000 ppm dose groups, respectively, are outside the
historical control range of the performing laboratory (0-2%).

Adequacy of the Dose Levels Tested:  Dosing was considered adequate and
not excessive based on observations of increased organ weights and
histopathological findings.  A limit dose of 7000 ppm was used in this
study.  Increased organ weights were observed in livers and adrenal
glands at 3500 and 7000 ppm of both sexes.  Increased testis weights
were observed in males at 7000 ppm. Gross pathology showed enlarged
adrenal glands at 3500 and 7000 ppm of both sexes.  Histopathology
examination revealed increases of incidence and severity of vacuolation
in the adrenal cortex at 3500 and 7000 ppm of both sexes.  In the liver,
dose-dependent increases of incidence and severity of hepatocytomegaly
were observed in males only.  In the testis, increases of incidence and
severity on hypertrophy and hyperplasia of the interstitial cell were
noted in 3500 and 7000 ppm males.

4.3.14.3  Classification of Carcinogenic Potential tc \l3 "4.4.14 
Classification of Carcinogenic Potential 

The CARC met on May 5, 2004 to evaluate the carcinogenic potential of
spirodiclofen.  In accordance with the EPA Draft Guidelines for
Carcinogen Risk Assessment (July 1999), the CARC classified
spirodiclofen as “likely to be carcinogenic to humans” by the oral
route.  This classification was based on evidence of testes Leydig cell
adenomas in male rats, uterine adenomas and/or adenocarcinoma in female
rats, and liver tumors in mice.  The CARC recommended using a linear
low-dose extrapolation approach for the quantification of human cancer
risk (TXR No. 0052552).  The unit risk, Q1*(mg/kg/day)-1 for
spirodiclofen is 1.49 x 10-2 based on male rat testes Leydig cell
adenoma (TXR No. 0052535).

4.3.15  Mutagenicity tc \l3 "4.4.15 	Mutagenicity 

HED concluded that there is no concern for mutagenicity.  Neither
technical spirodiclofen, a formulation, nor major metabolites (BAJ 2740
enol, BAJ 2740 - MA-3OH-cyclohexylester,  BAJ 2740-ketohydroxy, BAJ
2740-hexylester or C6-hydroxyester) were mutagenic in Salmonella
typhimurium when tested up to the limit dose (5000 µg/plate +/- S9)
(MRID Nos. 45696702, 45696817, 45696805, 45696818, 45696819, 45696921 or
45696909), respectively.  Technical spirodiclofen was also not mutagenic
in mammalian cells (MRID 45696614) or clastogenic in cultured mammalian
cells (MRID 45696615) and was not clastogenic or aneugenic in the mouse
micronucleus assay up to an overtly toxic dose (800 mg/kg) (MRID
45696701).  Similarly, the spirodiclofen formulation, spirodiclofen 240
SC was not clastogenic in cultured Chinese hamster lung (V79) cells
(MRID 45696821). 



Table 4.3.	Summary of Toxicology Endpoint Selection for Spirodiclofen.

Exposure

Scenario	Dose Used in Risk Assessment, UF	FQPA SF and Level of Concern
for Risk Assessment	Study and Toxicological Effects

Acute Dietary

	Acute RfD = 

Not established.	An appropriate endpoint attributable to a single dose
was not identified.  Assessment not necessary/

Chronic Dietary

(All populations)	NOAEL= 1.38 mg/kg/day

UF = 100

Chronic RfD = 

0.014 mg/kg/day	FQPA SF = 1X

cPAD = 

Chronic RfD

FQPA SF

= 0.014 mg/kg/day	Chronic Oral Toxicity Study in Dogs

LOAEL= 4.7 mg/kg/day based on increased relative adrenal weights in both
sexes, increased relative testis weight in males and histopathology
findings in the adrenal gland of both sexes.

Short-term Incidental Oral;

Short-term Dermal;

Short-term Inhalation

(1-30 Days)	LOAEL = 8.4 mg/kg/day

(dermal-absorption rate= 2%)

	Residential LOC for MOE = 300

Occupational LOC for MOE = 300	Subchronic Oral Toxicity Study in Dogs

LOAEL= 8.4 mg/kg/day based on  increased adrenal gland weight (two out
of four animals) which corroborated with histopathology findings
(cytoplasmic vacuoles in the Zona fasciculata of the adrenal glands) in
females; a NOAEL for females was not established. 

Intermediate-term Incidental Oral;

Intermediate-term Dermal; 

Intermediate-term Inhalation

(1-6 Months)	NOAEL = 1.38 mg/kg/day

(dermal-absorption rate = 2%) 

	Residential LOC for MOE = 100	Chronic Oral Toxicity Study in Dogs

See above under Chronic Dietary.

Long-term Dermal; Long-term Inhalation

(>6 Months)	Oral

NOAEL= 1.38

mg/kg/day

(dermal-absorption rate = 2%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Chronic Oral Toxicity Study in Dogs

See above under Chronic Dietary.

Cancer 

(Oral, dermal, inhalation)	Classification: “Likely to be Carcinogenic
to Humans”

with Q1* (mg/kg/day)-1 = 1.49 x 10-2.

4.4  Endocrine Disruption tc \l2 "4.6  Endocrine Disruption 

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

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

5.0  Exposure Characterization/Assessment tc \l1 "6.0  Exposure
Characterization/Assessment 

5.1  Dietary Exposure/Risk Pathway  

 tc \l2 "6.1  Dietary Exposure/Risk Pathway   

5.1.1  Residue Profile tc \l3 "6.1.1  Residue Profile 

Magnitude of the Residue - Plants:  Adequate field trial data on hops
are available from 3 trials conducted in the U.S. in Zones 11 and 12
during 2004.  In each trial, spirodiclofen (2 lb/gal FlC) was applied to
hops as a single foliar-directed application at 0.387-0.412 lb ai/A (1x
rate) during cone development and maturation.  Applications were made
using ground equipment at volumes of 43-175 gal/A, and did not include
the use of any spray adjuvants.  The resulting residues of spirodiclofen
were 1.97-13.1 ppm in/on 6 samples of dried hop cones harvested 21 days
after treatment (DAT) and 2.85-5.72 ppm in/on 6 samples harvested at 28
DAT.  Average spirodiclofen residues were 6.42 and 3.99 ppm at 21 and 28
DAT, respectively.

The petitioner also submitted supplemental hops field trial data from 8
trials conducted in Germany during 2003 and 2004.  In each of these
trials, spirodiclofen (240 g/L FlC) was applied to hops as a single
foliar application at 0.34-0.43 kg ai/ha (0.30-0.38 lb ai/A, ~1x
proposed U.S. rate) during cone development and maturation (BBCH 71-87),
using ground equipment at volumes of 2100-3547 L/ha (225-380 gal/A). 
Residues of spirodiclofen were 3.9-24.0 ppm in/on 8 samples of dried
hops harvested at the proposed PHI of 14 days.  Residues were 3.9-10.9
ppm in/on 4 samples by 21 DAT and 3.1-10.0 ppm in/on 6 samples by 28
DAT.  Average residues were 11.6, 7.23, and 7.07 ppm at 14, 21 and 28
DAT, respectively, indicating that residues declined slowly from 14-28
DAT.

As there are no regulated processed commodities associated with hops, no
processing studies are required for this petition.  Data pertaining to
residues in rotational crops are also not required as hops are a
perennial crop.  

The submitted U.S. field trial data supports a minimum PHI of either 21
or 28 days; however, IR-4 is requesting a 14-day PHI for hops in order
to harmonize the U.S. and German use patterns.  In addition, IR-4 is
requesting a 30-ppm tolerance on dried hop cones to harmonize with the
established German maximum residue limit (MRL).  Considering similarity
in climatic conditions between the hops growing regions in the U.S. and
Germany and the German MRL of 30 ppm being higher than the maximum
residue values from the other two submitted field trial data sets having
similar application rates, but longer PHIs (21 and 28 day), HED
recommends establishing a permanent tolerance for spirodiclofen on hops
at 30 ppm to promote free trade between North-American Free Trade
Agreement (NAFTA) and non-NAFTA countries.

Magnitude of the Residue - Livestock:  As there are no livestock
feedstuffs associated with the proposed use on hops, data requirements
pertaining to meat, milk, poultry, and eggs are not relevant to this
tolerance petition.

Analytical Enforcement Method :  Samples from the U.S. hops field trials
were analyzed for residues of spirodiclofen using a liquid
chromatography (LC)/mass spectrometry (MS)/MS method, which was derived
from the proposed enforcement method.  The proposed enforcement method
has undergone a successful independent laboratory validation (ILV)
trial, and has been reviewed by the Analytical Chemistry Branch (ACB). 
ACB determined that the method would be adequate for tolerance
enforcement provided that a revised copy of the method was submitted
incorporating the changes and clarifications recommended by ACB
(D308566, E. Kolbe, 5/18/05).  

The LC/MS/MS method used for determining residues of spirodiclofen in/on
dried hops in the field trials was adequately validated prior to and in
conjunction with the analysis of field trial samples.  Given the
similarity between the data collection method and the LC/MS/MS
enforcement method (nutmeats), the enforcement method will be adequate
for regulating residues in/on dried hops. 

Hop, dried cones1	30 ppm

1 Tolerance expression includes residues of spirodiclofen
(3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl
2,2-dimethylbutanoate) per se.

5.1.2  Dietary Exposure and Risk tc \l3 "6.1.2  Dietary Exposure and
Risk 

Dietary (food + water) chronic and cancer dietary risk assessments for
spirodiclofen were conducted using the DEEM-FCID (ver. 2.03).  

DEEM-FCID uses food consumption data from the USDA’s Continuing
Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998). 
Acute dietary risk assessment was not conducted since an appropriate
endpoint attributable to a single dose was not identified for U.S.
general population and its population subgroups.

The chronic and cancer analyses incorporated average field trial
residues, experimental and DEEM default processing factors, and
projected average %CT information and EDWCs.  

es is not likely to exceed 4.99 and 1.67 μg/L, respectively. 

For chronic dietary risk assessments, HED is concerned when dietary risk
exceeds 100% of cPAD.  

The results are summarized in Tables 5.1.2.1 and 5.1.2.2 below for
chronic and cancer dietary analyses, respectively.  

The resulting chronic (food + water) exposure estimates were not of
concern to HED (<100% of the cPAD) for U.S. general population (1.8 %
cPAD) and all population sub-groups; the most highly exposed population
subgroup was all infants (<1 year old) at 3.2% cPAD.

The cancer risk estimates for the U.S. general population with and
without drinking water were 3 x 10-6 and 2 x 10-6, respectively, and are
not of concern.  HED also notes that the cancer risk estimates were
generated using average residues derived from crop field trial studies
(maximum application rate and minimum PHI), incorporated maximum
theoretical processing factors for juice, and incorporated surface
drinking water estimates which assumed 87% of the basin was cropped and
100% of the cropped area was treated at the maximum rate.  Based on a
critical commodity analysis conducted in DEEM-FCID(, the major
contributors to the cancer risk were hops (41% of the total exposure),
water (19% of the total exposure), and orange juice (17% of the total
exposure).

Table 5.1.2.1.	Summary of Chronic Dietary Exposure and Risk for
Spirodiclofen (drinking water included).

Population Subgroup	cPAD (mg/kg/day)	Exposure (mg/kg/day)	%cPAD

General U.S. Population	

0.014	0.000253	1.8

All Infants (< 1 year old)

0.000452	3.2

Children 1-2 years old

0.000424	3.0

Children 3-5 years old

0.000345	2.5

Children 6-12 years old

0.000210	1.5

Youth 13-19 years old

0.000160	1.1

Females 13-49 years old

0.000197	1.4

Adults 20-49 years old

0.000280	2.0

Adults 50+ years old

0.000211	1.5

The bolded %cPAD is the highest.

Table 5.1.2.2.  Summary of Cancer Dietary Exposure and Risk for
Spirodiclofen.

Population Subgroup	Q1*	Exposure (mg/kg/day)	Risk

With drinking water

General U.S. Population	0.0149	0.000183	3 x 10-6

without drinking water

General U.S. Population	0.0149	0.000148	2 x 10-6

5.2  Residential (Non-Occupational) Exposure/Risk Pathway tc \l2 "6.3 
Residential (Non-Occupational) Exposure/Risk Pathway 

Spirodiclofen has no existing or proposed residential or recreational
uses. Therefore, a residential or recreational risk assessment was not
performed.

5.3  Spray Drift

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
spirodiclofen.  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 data base submitted by the Spray Drift Task Force, a membership
of  U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT( computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

6.0  Aggregate Risk Assessments and Risk Characterization tc \l1 "7.0 
Aggregate Risk Assessments and Risk Characterization  

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

For spirodiclofen, no residential uses are proposed.  Therefore,
aggregate risk consists of exposure from food and drinking water
sources.  Since an effect of concern attributable to a single dose was
not identified in the database, acute aggregate risk was not addressed. 
Chronic and cancer aggregate risks were calculated and are discussed in
detail below. 

Drinking water quality model output concentrations were incorporated
directly into dietary risk assessments. 

6.1  Acute Aggregate Risk tc \l2 "7.1  Acute Aggregate Risk 

Since an effect of concern attributable to a single dose was not
identified in the hazard database, acute aggregate risk was not
calculated.  Therefore, an acute aggregate risk assessment was not
performed. 

6.2  Short-Term Aggregate Risk tc \l2 "7.2  Short-Term Aggregate Risk 

Since there are no existing or proposed residential uses for
spirodiclofen, short-term aggregate risk was not performed. 

6.3  Intermediate-Term Aggregate Risk tc \l2 "7.3  Intermediate-Term
Aggregate Risk 

Since there are no existing or proposed residential uses for
spirodiclofen, intermediate-term aggregate risk was not performed. 

6.4  Chronic Aggregate Risk tc \l2 "7.4  Chronic/Long-Term Aggregate
Risk 

Since there are no residential uses, chronic aggregate risk consists of
food and drinking water exposure only.  Chronic dietary risk is
presented in Table 5.1.2.1 and represents chronic aggregate risk. 
Drinking water estimates were incorporated directly into the dietary
analysis. The chronic analyses incorporated average field trial
residues, experimental and DEEM default processing factors, and
projected average %CT estimates and surface drinking water estimates
using PRZM/EXAMS model.  The DEEM-FCID( chronic aggregate risk estimates
(including drinking water) were not of concern to HED [≤3.2% cPAD; all
infants (<1 year old) were the most highly exposed population].   

  

6.5  Aggregate Cancer Risk tc \l2 "7.5  Aggregate Cancer Risk 

Since there are no residential uses, aggregate cancer risk consists of
food and drinking water exposure only.  Dietary cancer risk is presented
in Table 5.1.2.2 and represents aggregate cancer risk.  Cancer aggregate
risk was calculated for the U.S. population only.  Drinking water
estimates were incorporated directly into the dietary analysis.  The
cancer analyses incorporated average field trial residues, experimental
and DEEM default processing factors, and projected average %CT estimates
and surface drinking water estimates using PRZM/EXAMS model.  The cancer
risk estimate (food + water) for the U.S. population was 3 x 10-6 for
the general U.S. population, and is not of concern to HED.

7.0  Cumulative Risk Characterization/Assessment tc \l1 "8.0  Cumulative
Risk Characterization/Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to spirodiclofen and any other
substances and spirodiclofen 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 spirodiclofen 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 OPP concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

8.0  Occupational Exposure/Risk Pathway tc \l1 "9.0  Occupational
Exposure/Risk Pathway 

Spirodiclofen is to be applied to hops once per crop season by airblast
equipment.  It may not be applied aerially or through any type of
irrigation equipment or in any type of enclosed structures such as green
houses or plant houses.  

The use pattern summary is taken from proposed draft labeling for
Envidor® 2 SC Miticide (EPA Reg. No. 264-831).  Envidor® is formulated
as a liquid soluble concentrate and contains 2.0 lb active ingredient
(ai) (22.3 %) spirodiclofen per gallon.  The target pests on hops are
twospotted spider mites.

The rate of application to hops is 18.0-24.7 fl oz formulation/A
(0.28-0.39 lb ai/A).  It is to be applied in a minimum of 50 gallons of
spray per acre in conventional ground airblast sprayer.  The PHI is 14
days.  The REI is 12 hours.

8.1  Short- and Intermediate-term Occupational Handler Risk tc \l2 "9.1
 Short- and Intermediate-term Occupational Handler Risk 

Based upon the proposed use pattern, HED believes the most highly
exposed occupational pesticide handlers (i.e., mixers, loaders,
applicators) will be mixer/loaders using liquid, open pour technique and
applicators using open-cab, air-blast equipment. 

With a single application on proposed labels, commercial and private
(i.e., grower operators) pesticide handlers are typically expected to be
exposed over the short-term duration (i.e., 1-30 days).  The acreage
involved with hops using an airblast sprayer (40 acres/day) is
relatively small as compared to high acreage field crops such as cotton,
corn or soybeans (more than 1000 acres/day with aerial application).  

No chemical-specific data are 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 PHED (v. 1.1,
1998).   

For pesticide handlers, it is HED policy to present estimates of dermal
exposure for “baseline;” that is, with a single layer of work
clothing consisting of a  long sleeved shirt, long pants, shoes plus
socks and no protective gloves as well as “baseline” and the use of
protective gloves or other PPE as might be necessary.  The proposed
Envidor® label directs mixers, loaders and other handlers to wear a
long-sleeved shirt and long pants, waterproof gloves and shoes plus
socks.  

Table 8.1. Spirodiclofen Handler Risk for Proposed Use on Hops.

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/A	Units Treated3 Acres Per Day	Average Daily

Dose4

mg ai/kg bw/day	Combined

MOE5

Mixer/Loader - Liquid - Open Pour for Airblast Application

Dermal:

SLNG       2.9    

SLWG      0.023 

Inhal         0.0012 	0.39	40	Dermal:

No Gloves      0.013

With Gloves   0.000103

Inhal               0.00027	No Gloves

630

With Gloves

23,000

Applicator - Air-blast - Open Cab

Dermal:

SLNG       0.36 

SLWG      0.24 

Inhal         0.0045	0.39	40	Dermal:

NG                  0.0016

WG                 0.00107

Inhal               0.001	No Gloves 

3,200

With Gloves

4,100

1. Unit Exposures are taken from “PHED Surrogate Exposure Guide”,
from The Pesticide Handler Exposure Database Version 1.1, August 1998.
Dermal: SLNG = Single layer of work clothing with no gloves; SLWG =
Single layer of work clothing with gloves; Inhal. = Inhalation. 

2. Application Rate. = Taken from proposed Envidor® 2 SC label. 

3. Units Treated are taken from ExpoSAC SOP No. 9.1; 5/7/2000.

4. Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated * Absorption Factor (2% dermal; 100 % inhalation) ( Body Weight
(70 kg).  

5. MOE = LOAEL ( ADD.  In this case, dermal exposure and inhalation
exposures are combined (summed) since the dose and endpoint for these
risk assessments are from the same study.  The LOAEL is 8.4 mg ai/kg
bw/day for (short-term duration exposures).

A MOE of 300 is adequate to protect occupational pesticide handlers. 
All MOEs are above 300; therefore, the proposed use is not of concern.

8.2  Short- and Intermediate-term Post-Application Risk tc \l2 "9.2 
Short/Intermediate/Long-Term Postapplication Risk 

Post-application exposure is assumed to consist of dermal exposure only;
inhalation exposure is assumed to be negligible.  

Typically, there are possibilities for agricultural workers to
experience post-application exposures to pesticides.  In this case,
there were no compound specific data with which to estimate
post-application exposures to agricultural workers.  Assumptions
regarding transfer of residues were obtained in the Science Advisory
Council for Exposure (ExpoSAC) SOP 003.1 (Revised 7 August 2000) and
amended by “ExpoSAC meeting Notes - 9/13/01").  The SOP lists a number
of possible post-application agricultural activities relative to the
proposed use on hops that might result in post-application or
“re-entry” exposure.    

Post-application activities in hops include training vines, scouting,
stripping vines and harvesting.  However, hops are typically
mechanically harvested.  In addition, there is a 14 day PHI.  Therefore,
HED believes harvesting is not likely to result in the highest dermal
post-application exposures.  However, training vines with a TC of 2,000
cm2/hr was used as it is the highest TC identified for any
post-application activity in hops.  

Post-application, re-entry exposure may be estimated using the following
convention.

PDRt = DFRt * CF1 * TC * ET where:

PDRt = potential dose rate on day “t” (mg/day)

DFRt = dislodgeable foliar residue on day “t” (ug/cm2)

CF1 = weighted unit conversion factor changing µg to mg (0.001 mg/µg)

TC   =  transfer coefficient (cm2/hr) (2,000 cm²/hr)

ET = Exposure Time (hr/day)

where

DFRt = (AR * F) * (1 - D)t * CF2 * CF3 where:

AR = application rate (lb ai/ft2 or lb ai/Acre) (0.39 lb ai/A)

F     = fraction of ai retained on foliage (unitless =  20%)

D    = fraction of residue that dissipates daily (unitless) (10%)

t      = post-application day on which exposure is being assessed

CF2= conversion factor lb ai to µg for DFR (4.54 x 108 µg/lb)

CF3 = conversion factor to convert surface area units (ft2) in
application rate to cm2 for DFR value (1.08 x 10-3 ft2/cm2 or 2.47 x
10-8 acre/cm2 if rate is per acre).

In this case, the DFRt is calculated as:

0.39 lb ai/A * 0.2 * (1 - D)0 * 4.54 x 108 µg/lb * 2.47 x 10-8A/cm2 =
0.87 µg ai/cm2  and

PDRt = 0.87 µg ai/cm2 * 0.001 mg/µg * 2,000 cm2/hr * 8 hr/day  = 14
mg/day.

14 mg/day * 0.02 (% dermal absorption) ( 70 kg bw = 0.0039 mg ai/kg
bw/day.

MOE = NOAEL ( Dose; therefore:        8.4 mg ai/kg bw/day =							      
                                  0.0039 mg ai/kg bw/day

MOE = 2,200

A MOE of at least 300 is not of concern for agricultural workers.  Since
the calculated MOE is above 300, the proposed use is not of concern.  

8.3  Occupational Handler and Post-Application Cancer Risk tc \l2 "9.3 
Occupational Handler and Postapplication Cancer Risk 

There are no definitive data regarding the numbers of exposures per year
or numbers of years “worked” per lifetime of pesticide handlers or
of agricultural workers.  Therefore, HED calculated risk for handlers
and post-application workers assuming 10 and 30 days of exposure per
year over a 35-year “working” lifetime and a 70-year lifespan.  As
can be seen below in Tables 8.3.1 and 8.3.2, risks are not of concern
even for 30 days of exposure per year.  

An estimate of cancer risk is calculated by multiplying the Q1* value by
a Lifetime Average Daily Dose (LADD).  The LADD is calculated using the
following convention:

(Average Daily Dose (mg ai/kg bw/day [dermal + inhalation]) * 10 day/yr
* 35 year

                                         70 year * 365 day/yr

The ADD is taken from Table 8.1 for occupational handlers and from the
post-application discussion in Section 8.2 for agricultural workers.  A
sample calculation for a mixer/loader using protective gloves is as
follows:

(0.000103 mg ai/kg bw/day dermal + 0.00027 mg ai/kg bw/day inhalation )
* 10 day/yr * 35 yr                                                     
                       				70 year * 365 day/yr

5.1 x 10-6 mg ai/kg bw/day.

Cancer risk is calculated by Q1* * LADD and in the example 

1.49 x 10-2 mg ai/kg bw/day * 5.1 x 10-6 = 7.6 x 10-8.

See Table 8.3.1 and 8.3.2 below for a summary of cancer risks assuming
10 and 30 work days per year.



Table 8.3.1.  Handler and Post-Application Cancer Risks From Exposure to
Spirodiclofen Assuming 10 work days per year.

Lifetime Average Daily Dose

(mg ai/kg bw/day)	Q1*

(mg ai/kg bw/day)

	Mixer/loader Using Gloves

5.1 x 10-6	

1.49 x 10-2

	7.6 x 10-8

Airblast Applicator Using Gloves

2.8 x 10-5

4.2 x 10-7

Airblast Applicator Not Using Gloves

3.6 x 10-5

5.4 x 10-7

Hops

Training vines 

5.3 x 10-5

8.0 x 10-7

Table 8.3.2.  Handler and Post-Application Cancer Risks From Exposure to
Spirodiclofen Assuming 30 work days per year.

Lifetime Average Daily Dose

(mg ai/kg bw/day)	Q1*

(mg ai/kg bw/day)

	Mixer/loader Using Gloves

1.5 x 10-5	

1.49 x 10-2

	2.0 x 10-7

Airblast Applicator Using Gloves

8.5 x 10-5

1.2 x 10-6

Airblast Applicator Not Using Gloves

1.2 x 10-4

1.5 x 10-6

Hops

Training vines 

8.4 x 10-4

1.2 x 10-5

Since the estimated cancer risks are below 10-5 for all scenarios, HED
does not have a concern for the proposed use on hops.  

REI

Spirodiclofen is classified in Acute Toxicity Category III for acute
oral and acute dermal toxicity and Acute Toxicity Category IV for acute
inhalation, primary eye irritation and primary skin irritation.  It is a
dermal sensitizer.  The interim Worker Protection Standard (WPS) REI of
12 hours is adequate to protect workers training hops vines after
treatment.  The proposed labels are in compliance with the WPS REI.

9.0  Data Needs and Label Requirements tc \l1 "10.0  Data Needs and
Label Requirements 

Toxicology tc \l2 "10.1  Toxicology 

The toxicological database for spirodiclofen is complete.  The HED HIARC
requested a 28-day inhalation toxicity study as a condition of
registration.  However, based on the low volatility and low inhalation
toxicity (Category IV) of spirodiclofen and inhalation MOEs of at least
1000 for the proposed handler uses, spirodiclofen qualifies for a waiver
of the 28-day inhalation toxicity study for the proposed uses (HED SOP
2002.01: Guidance: Waiver Criteria for Multiple-Exposure Inhalation
Toxicity Studies, 08/15/02).  The requirement for the 28-day inhalation
toxicity study is waived for this action only.  If in the future,
requests for new uses or formulations are submitted that may result in a
significant change in either the toxicity profile or exposure scenarios,
HED will reconsider this data requirement.

Attachments follow (2)

Attachment 1: Chemical Names and Structures of Spirodiclofen and its
Metabolites

Attachment 2: Toxicity Profile for Spirodiclofen

Attachment 1: Chemical Names and Structures of Spirodiclofen and its
Metabolites

Chemical Name	Structure

Spirodiclofen; BAJ2740

3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutanoate	

BAJ 2510

 

3-OH-enol

 

4-OH-enol

 

Attachment 2: Toxicity Profile for Spirodiclofen tc \l1 "Attachment 2:
Toxicology Data Requirements  

Subchronic, Chronic and Other Toxicity Profile for Spirodiclofen

Guideline No./ Study Type/	

MRID Nos.

Doses/Classification	

Results

870.3100

Subchronic Oral

- Rat	

45696715, 45696716 (1998,2003)

(0,100,500,2500,12500 ppm)

M:0,6.6,32.1,166.9,851.4 mg/kg/day

F:0,8.1,47.1 215.3995.8 mg/kg/day

Acceptable/guideline	

For males, NOAEL = 32.1 mg/kg/day, LOAEL = 166.9 mg/kg/day based on
increased incidence and severity of small cytoplasmic vacuolation in the
cortex of adrenal glands, decreased cholesterol (week 5 and 13), and
decreased triglycerides (week 5).  

For females, NOAEL= 8.1 mg/kg/day, LOAEL= 47.1 mg/kg/day based on
increased incidence of small cytoplasmic vacuolation in the cortex of
adrenal glands.

870.3100

Subchronic Oral

- Mouse	

45696711,45696712,45696713(1997)

(0,100,1000,10,000 ppm)

M:0,15,164,1640 mg/kg/day 

F: 0,30,234,2685 mg/kg/day 

Acceptable/guideline	

For males, NOAEL= 15 mg/kg/day, LOAEL= 164 mg/kg/day based on an
increased incidence of hypertrophic Leydig cells in the testes. 

For females, NOAEL = 30 mg/kg/day, LOAEL= 234mg/kg/day based on an
increased incidence of cytoplasmic vacuolation of the adrenal cortex.

870.3150

Subchronic Oral

- Dog	

45696803,45696804 (2000)

(0,200,630,2000 ppm)

0,7.7,26.6,84.7 mg/kg/day (M)

0,8.4,28.0,81.0 mg/kg/day(F)

Acceptable/guideline	

For males, NOAEL= 7.7 mg/kg/day, LOAEL = 26.6 mg/kg/day based on
decreased body-weight gains, increased liver and adrenal weights,
decreased prostate weights, and histopathology findings in the adrenal
glands, testes, epididymis, thymus, and prostates.

For females, NOAEL (8.4 mg/kg/day. LOAEL=8.4 mg/kg/day based on
increased adrenal gland weight (two out of four animals) which coincided
with histopathology findings (cytoplasmic vacuoles in the Zona
fasciculata of the adrenal glands).

870.3200

28-Day dermal toxicity

- Rat	

45696806 (1999)

0, 1000 mg/kg/day

Unacceptable/Guideline	

The NOAEL=1000 mg/kg/day (HDT; highest dose tested); however, the
histopathology was not appropriately conducted as required by the
guideline. The study did not examine all of the tissues, especially the
possible target organs (i.e., uterus, prostate, etc).

870.3700a

Prenatal developmental  

- Rat 	

45696906 (2000)

0,100,300,1000 mg/kg/day

Acceptable/Guideline	

Maternal: NOAEL =1000 mg/kg/day (HDT)

Developmental:NOAEL= 300 mg/kg/day, LOAEL =1000 mg/kg/day based on an
increased incidence of slight dilatation of the renal pelvis.

870.3700b

Prenatal developmental  

- Rabbit	

45696714 (1998)

0,100,300,1000 mg/kg/day

Acceptable/guideline	

Maternal: NOAEL = 100 mg/kg/day, LOAEL =300 mg/kg/day based on
body-weight loss and decreased food consumption. 

Developmental: NOAEL =1000 mg/kg/day (HDT)

870.3800

Reproduction and fertility effects

- Rat

	

45696802,45696709 (2000)

(0,70,350,1750 ppm)

M: 0,5.2,26.2,134.8 mg/kg/day

F: 0,5.5,27.6,139.2 mg/kg/day

Acceptable/guideline	

Parental/system:

For males: NOAEL= 5.2-6.4 mg/kg/day, LOAEL =26.2-30.2 mg/kg/day based on
decreased body weight in F0 males; decreased absolute and relative liver
weight in F0 males; decreased cholesterol and triglycerides in F1 males;
and increased severity of adrenal cortical vacuolation in F1 males. For
females, NOAEL= 5.5-7.0 mg/kg/day, LOAEL= 27.6-34.4 mg/kg/day based on
decreased unesterified fatty acids in F1 females, and increased severity
of adrenal cortical vacuolation in F0 and F1 females.

Reproductive:

For males: NOAEL= 26.2-30.2 mg/kg/day, LOAEL=134.8-177.6 mg/kg/day based
on delayed sexual maturation; decreased testicular spermatid and
epididymal sperm counts (oligospermia); and atrophy of the testes,
epididymides, prostate and seminal vesicles. For females: NOAEL=
27.6-34.4 mg/kg/day, LOAEL= 139.2-192.7 mg/kg/day based on increased
severity of ovarian luteal cell vacuolation/ degeneration.

Offspring:

NOAEL= 5.2-6.4 (M)/5.5-7.0 (F) mg/kg/day, LOAEL= 26.2-30.2 (M)/
27.6-34.4(F) mg/kg/day based on decreased body weight and weight gain in
F1 male and female pups.  

870.4300

Chronic toxicity 

-Rat	

45696808,45696809 (2000)

(0,50,100,350,2500 ppm)

M: 0,2.0,4.1,14.7,110.1 mg/kg/day

F: 0,2.9,5.9,19.9,152.9 mg/kg/day

Acceptable/guideline	

For males: NOAEL= 14.7 mg/kg/day, LOAEL= 110.1 mg/kg/day based on
decreased body weights, decreased body-weight gain, increased APh
levels, decreased cholesterol and triglyceride levels, increased
vacuolated jejunum enterocytes, and increased incidences of Leydig cell
hyperplasia.

For females: NOAEL= 19.9 mg/kg/day, LOAEL= 152.9 mg/kg/day based on
decreased body weights, decreased body-weight gain, increased APh
levels, increased TSH, uterus nodules, and increased vacuolated jejunum
enterocytes.

(testes Leydig cell adenoma in males, (uterine adenoma and/or
adenocarcinoma in females.

870.4100b

Chronic toxicity

- dog	

45696810,45696811 (2001)

(0,20,50,150,500/600 ppm)

M: 0,0.56,1.38,4.33,16.1 mg/kg/day

F: 0,0.59,1.52,4.74,17.7 mg/kg/day

Acceptable/guideline	

NOAEL= 1.38 (M)/1.52(F) mg/kg/day, LOAEL= 4.33(M)/4.74 (F) mg/kg/day
based on increased relative adrenal weights in both sexes, increased
relative testis weight in males and histopathology findings in the
adrenal gland of both sexes.

870.4200b

Carcinogenicity 

- mouse	

45696724 (2000)

(0,25,3500,7000 ppm)

M: 0,4.1,610,1216 mg/kg/day

F: 0,5.1,722,1495 mg/kg/day

Acceptable/guideline	

NOAEL= 4.1(M)/5.1(F) mg/kg/day, LOAEL= 610 (M) mg/kg/day based on
increased absolute and relative liver and adrenal weights, decreased
absolute and relative kidney weight, enlarged adrenal gland, discolored
testis, adrenal gland vacuolization, interstitial cell degeneration of
the testes. For females, LOAEL= 722 mg/kg/day based on increased
absolute and relative adrenal weight, decreased absolute and relative
kidney weight, increased incidences of adrenal gland pigmentation, and
adrenal vacuolization.

(Hepatocellular adenoma and carcinoma.

870.5100

Gene mutation

Salmonella typhimurium	

45696702

Acceptable/guideline	

There was no evidence of increased revertant colonies above control in 5
Salmonella strains
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at concentrations up to 300 ug/mL -S9 and +S9. Cytotoxicity was observed
at (15 ug/mL -S9 and 80 ug/mL +S9.

870.5375

In vitro Mammalian Chromosome Aberration 	

45696615 (1996)

Acceptable/guideline	

Negative, tested in Chinese hamster lung (V79) cells at concentrations
5-80 ug/mL or 0.75-12 ug/mL -S9 or 10-160 ug/mL +S9.

870.5395

In vivo Mouse Bone Morrow Micronucleus	

45696701 (1996)

Acceptable/guideline	

Negative, tested at a dose 800 mg/kg (MTD).  Clinical signs and
cytotoxicity were seen at 800 mg/kg.

870.6200

Acute Neurotoxicity

- Rat	

45696725 (2000)

0,200,500,2000 mg/kg

Acceptable/guideline	

NOAEL = 2000 mg/kg/day, no neurotoxicity observed.

870.6200

Subchronic neurotoxicity

- Rat  	

45696726 (2001)

(0,100,1000,12500 ppm)

M: 0,7.2,70.3,1088.8 mg/kg/day

F: 0,9.1,87.3,1306.5 mg/kg/day

Acceptable/guideline	

NOAEL= 70.3(M)/87.3(F) mg/kg/day. LOAEL= 1088.8(M)/ 1306.5(F) mg/kg/day
based on decreased body weights, food consumption, and increased urine
staining in both sexes and decreased motor and locomotor activity (week
4) in females only.

870.6300

Developmental neurotoxicity	

46324901 (2004)

(0, 70, 350 or 1500 ppm)

0/0, 6.5/14.0, 32.1/69.7 or 135.9/273.8 mg/kg/day (gestation/lactation)

The study classification is reserved for the guideline requirement
pending receipt of additional morphometric measurements for the low and
mid dose groups.

	

Maternal NOAEL = 135.9/273.8 mg/kg/day

LOAEL = Not established.

Offspring NOAEL = Not established

LOAEL = 6.5/14.0 mg/kg/day based on effects in memory phase of the water
maze test in PND 60 females.

870.6300

Developmental neurotoxicity	47166501 (2007)

(0, 70, 350 or 1500 ppm)

0/0, 5.4/13.0, 28.6/65.7 and 119.2/262.1 mg/kg/day (gestation/lactation)
Maternal NOAEL=119.2/262.1 mg/kg/day

LOAEL= Not established

Offspring NOAEL = 119.2/262.1 mg/kg/day

LOAEL= Not established

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