                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                       
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
                                                           POLLUTION PREVENTION


MEMORANDUM

Date:		11-NOV-2011

Subject:	Spirodiclofen.  Human-Health Risk Assessment for Proposed Uses in/on Sugar Apple, Cherimoya, Atemoya, Custard Apple, Ilama, Soursop, Biriba, Lychee, Longan, Spanish Lime, Rambutan, Pulasan, Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, Persimmon, and Acerola.

PC Code:  124871
DP Barcode:  D386201
Decision No.:  443557
Registration No.:  264-831
Petition No.:  0E7820
Regulatory Action:  Section 3 
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  7443
TXR No.:  not applicable
CAS No.:  148477-71-8
MRID No:  none
40 CFR:  §180.608

From:	Jennifer R. Tyler, Chemist
	Tom Bloem, Chemist
	Chester E. Rodriguez, Ph.D., Toxicologist
	Lata Venkateshwara, Environmental Protection Specialist
            Risk Assessment Branch 1 (RAB1)
            Health Effects Division (HED; 7509P)

Through:	Dana M. Vogel, Branch Chief
	George F. Kramer, Ph.D., Senior Chemist 
            RABI/HED (7509P)

To:	Barbara Madden/Laura Nollen (RM 05)
            Registration Division (RD; 7505P)


The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from proposed uses of spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate) on sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, biriba, lychee, longan, Spanish lime, rambutan, pulasan, guava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, persimmon, and acerola.

A summary of the findings and an assessment of human risk resulting from the proposed uses of spirodiclofen is provided in this document.  The risk assessment was provided by Jennifer Tyler (RAB1); the residue chemistry review and dietary exposure assessment by Tom Bloem (RAB1); the hazard characterization by Chester Rodriguez (RAB1); the occupational/residential exposure assessment by Lata Venkateshwara (RAB1); and the drinking water assessment by Larry Liu of the Environmental Fate and Effects Division (EFED).

NOTE:  A human-health risk assessment was completed on 28-JULY-2010 by RAB1 in conjunction with a request for the use of spirodiclofen on the bushberry subgroup 13-07B (Memo, T. Bloem; DP#371469).  In this memo, toxicology, dietary, occupational, and aggregate risks were re-evaluated based on the addition of the proposed uses to the spirodiclofen use pattern.

HED Recommendation:  Provided revised Sections B and F are submitted (as specified in Section 9.0), HED concludes that the toxicological, residue chemistry, and occupational/residential exposure databases support a conditional registration for application of spirodiclofen to the proposed crops and establishment of the following permanent tolerances for residues of spirodiclofen (180.608(a)(1)):  lychee - 4.0 ppm; longan - 4.0 ppm; Spanish lime - 4.0 ppm; rambutan - 4.0 ppm; pulasan - 4.0 ppm; sugar apple - 0.40 ppm; atemoya - 0.40 ppm; custard apple - 0.40 ppm; cherimoya - 0.40 ppm; ilama - 0.40 ppm; soursop - 0.40 ppm; biriba - 0.40 ppm; guava - 0.50 ppm; feijoa - 0.50 ppm; jaboticaba - 0.50 ppm; wax jambu - 0.50 ppm; starfruit - 0.50 ppm; passionfruit - 0.50 ppm; acerola - 0.50 ppm; and persimmon - 0.50 ppm.  Unconditional registration may be established upon submission of an immunotoxicity study, which adequately addresses the data requirements specified in 40 CFR Part 158, and a 28-day rat inhalation toxicity study (TXR 0052518, 16-JUN-2004).  


                               Table of Contents
1.0  Executive Summary	4
2.0  Ingredient Profile	9
2.1  Summary of Registered/Proposed Uses	9
2.2  Structure and Nomenclature	9
3.0  Hazard Characterization/Assessment	10
3.1  Mode of Action	11
3.2  Toxicology Studies Available for Analysis	11
3.3  Absorption, Distribution, Metabolism, & Elimination (ADME)	11
3.3.1  Dermal Absorption	11
3.4  Toxicological Effects	11
3.5  FQPA Considerations	13
3.6  Toxicity Endpoint Selection	14
4.0  Dietary Exposure/Risk Characterization	15
4.1  Metabolism in Primary Crops, Livestock, and Rotational Crops	15
4.2  Analytical Methodology	16
4.3  Comparative Metabolic Profile	16
4.4  Drinking Water Residue Profile	16
4.5  Food Residue Profile	17
4.6  International Residue Limits and HED-Recommended Tolerances	17
4.7  Dietary Exposure and Risk	18
5.0  Residential (Non-Occupational) Risk Assessment	19
6.0  Aggregate Risk Assessment	20
7.0  Cumulative Risk Characterization/Assessment	20
8.0  Occupational Exposure/Risk Pathway	20
8.1  Handler Non-Cancer Exposure and Risk Estimates	21
8.2  Post-application Non-Cancer Exposure and Risk Estimates	22
8.3  Cancer Exposure and Risk Estimates	23
8.3.1  Handler Cancer Exposure and Risk  Estimates	23
8.3.2  Post-application Cancer Exposure and Risk Estimates	24
8.4  REI	25
9.0  Data Needs and Label Requirements	25
9.1  Toxicology	25
9.2  Residue Chemistry	25
9.3  Occupational and Residential Exposure	26
Attachment 1:  Chemical Names and Structures.	27
Attachment 2:  Spirodiclofen Toxicity Profile.	28


1.0  EXECUTIVE SUMMARY

Background:  Spirodiclofen is a tetronic acid acaricide.  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).  Spirodiclofen is currently registered for application to several raw agricultural commodities (RACs) with tolerances for residues of spirodiclofen per se of 0.10-30 ppm; milk and ruminant meat, meat byproducts, and fat tolerance for the combined residues of spirodiclofen and BAJ 2510 are also established at 0.02-0.1 ppm (see Attachment 1 for structures).  Spirodiclofen is also registered for application to Christmas tree plantations. 

Interregional Research Project Number 4 (IR-4) has proposed a Section 3 registration for application of Envidor[(R)] 2 Suspension Concentrate (SC) Miticide [2 pounds (lbs) active ingredient (ai)/gallon; EPA Reg. No. 264-831] to sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, biriba, lychee, longan, Spanish lime, rambutan, pulasan, guava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, persimmon, and acerola [1 x 0.31 lbs ai/acre (A); preharvest interval (PHI) = 7 days; restricted-entry interval (REI) = 12 hours].  In conjunction with the request, the petitioner has proposed the establishment of tolerances for residues of spirodiclofen per se in/on these RACs.

Hazard Characterization, Dose Response Assessment, and Food Quality Protection Act (FQPA) Safety Factor (SF):  The toxicological database for spirodiclofen is adequate for FQPA evaluation, selection of points of departure (PODs) for the various routes of exposure, and for dose-response evaluation.  Spirodiclofen was rapidly and extensively absorbed via the oral route of administration in rat studies.  Female rats absorbed a greater fraction of the administered dose at approximately 74% versus 57-62% estimated for male rats.  Extensive metabolism was noted and excretion (approximately complete by 48 hours) was primarily urinary followed by fecal.  There was no evidence of bioaccumulation in any specific organs or tissues.

The primary target organs identified across different studies and species tested with spirodiclofen are the adrenal glands in both sexes and testes in males.  Increased cytoplasmic vacuolation in the Zona fasciculata of the adrenal cortex was observed across different subchronic and chronic studies with spirodiclofen in rats, mice, and dogs of both sexes.  The dog was the most sensitive species and, at least in rat and dog studies, females appear to be the more sensitive sex.  The effect(s) on the adrenal glands generally coincided with increased adrenal weight.  Other organs with histopathology findings reported in male dogs included the testes (vacuolation and hypertrophy/activation of Leydig cells), epididymis (degeneration and/or immaturity of germinal epithelium, oligo- and aspermia), prostate (immaturity signs), and thymus (atrophy).  Increased liver weights were also reported in male dogs along with decreases in prostate weights.

The effects reported in chronic studies in dogs were similar and generally occurred at lower doses of spirodiclofen.  Other effects reported in chronic studies include decreases in cholesterol and triglycerides (rats), decreased body weights and body-weight gains (rats), increased alkaline phosphatase (APh) levels, increased vacuolated jejunum enterocytes (rats), and increased incidences of Leydig cell hyperplasia (rats and mice).

No evidence of increased quantitative or qualitative susceptibility was observed in developmental toxicity studies in rats or rabbits or in a reproduction toxicity study in rats.  Developmental toxicity with no indication of maternal toxicity in the rat prenatal developmental study consisted of an increased incidence of slight dilatation of the renal pelvis only at the limit dose, and in the absence of dose-response or statistical significance.  Furthermore, there was no evidence of dilation of the renal pelvis or any other developmental effect in the rabbit prenatal developmental toxicity study.  In the two-generation reproductive toxicity study, effects were observed in F1 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 F1 females (i.e., increased severity of ovarian luteal cell vacuolation/degeneration], but at a higher dose than the systemic effects seen for parents and offspring.

Spirodiclofen did not show any evidence of neurotoxicity in the acute and subchronic neurotoxicity studies and the results of a developmental neurotoxicity (DNT) study suggest that spirodiclofen is unlikely to be a developmentally neurotoxic compound.  

Chronic/carcinogenicity studies showed an increased incidence of uterine adenocarcinoma in female rats, Leydig cell adenoma in male rats, and liver tumors in mice.  The HED Cancer Assessment Review Committee (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 adenocarcinomas in female rats and liver tumors in mice.

Several immunotoxicity parameters were measured in a rat subchronic toxicity study including macrophage activity and antibody titers.  However, upon review of the study, several deficiencies were noted and the study was deemed unacceptable by the Agency to fulfill the immunotoxicity data requirement.

Spirodiclofen was ranked low (Category IV) for acute inhalation toxicity.  However, there is no information to evaluate inhalation exposures of longer durations.  A 28-day rat inhalation toxicity study was requested by the Hazard Identification Assessment Review Committee (HIARC) in 2004 to characterize potential effects on the pulmonary system (HIARC 2004, TXR# 0052618).  However, no additional inhalation toxicity studies have been submitted to the Agency for evaluation.

Risk assessments were conducted for the specific exposure scenarios listed below.  An acute dietary assessment was not conducted as an appropriate endpoint attributable to a single dose was not identified.  The chronic reference dose (cRfD) was calculated by dividing the no-observed-adverse-effect-level (NOAEL) by 100 (10X for interspecies extrapolation, 10X for intraspecies variation).  For short-term dermal and inhalation occupational exposure scenarios, a database uncertainty factor (UFD) of 3X has been applied due to the use of a lowest-observed-adverse-effect-level (LOAEL; no NOAEL was established in the subchronic dog study).  Since an oral study was selected for the short- and intermediate-term durations of dermal exposure, an estimated 2% dermal-absorption factor was used in the route-to-route extrapolation.  Since no inhalation absorption data are available, toxicity by the inhalation route is considered to be equivalent to toxicity by the oral route of exposure.  The level of concern for occupational dermal and inhalation exposures are for margins of exposure (MOEs) >100 (10X for interspecies extrapolation, 10X for intraspecies variation) and >300 (10X for interspecies extrapolation, 10X for intraspecies variation, 3X UFD), respectively.  Since the same study/effect was selected for assessment of short-term dermal/inhalation exposure, exposure via these routes can be aggregated.

The toxicology database for spirodiclofen is adequate for FQPA consideration.  Although there are two toxicity studies pending for spirodiclofen, the spirodiclofen risk assessment team recommends that the FQPA SF be reduced from 10X to 1X for all dietary exposure scenarios for the following reasons:  (1) the concern for increased susceptibility following in utero and/or post-natal exposure of spirodiclofen in the developmental toxicity studies (rat and rabbit) or in the rat reproduction toxicity study is low; (2) there was no evidence of neurotoxicity in the acute, subchronic, and developmental neurotoxicity studies; (3) although an immunotoxicity study is currently lacking, there is no evidence in the current toxicology database that the immune system may be a target at the dose levels being used for risk assessment (mild atrophy in the thymus was noted in the dog subchronic toxicity study, but such effect was considered indirect and was not seen the dog chronic toxicity study or any other study in the database); and (4) there are no additional residual uncertainties with respect to exposure data, and there is no potential for residential exposure.  Since the FQPA SF has been reduced to 1X, the chronic population-adjusted dose (cPAD) is equal to the cRfD.
  
                               Exposure Scenario
                                     Dose
                                   Endpoint
                                 Study/Effect
Chronic dietary (all populations)
NOAEL = 1.38 mg/kg/day
cRfD and cPAD = 0.014 mg/kg/day
Chronic Oral Toxicity Study in Dogs/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 (1-30 days) Dermal
LOAEL = 8.4 mg/kg/day
LOC for MOE <300 (occupational)
Subchronic Oral Toxicity Study in Dogs/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 (1-6 months) and Long-term (>6 months) Dermal
NOAEL = 1.38 mg/kg/day
LOC for MOE <100 (occupational)
Chronic Oral Toxicity Study in Dogs/See description above.
Short-term (1-30 days) Inhalation
LOAEL = 8.4 mg/kg/day
LOC for MOE <300 (occupational)
Subchronic Oral Toxicity Study in Dogs/See description above.
Intermediate (1-6 months) and Long-term (>6 months) Inhalation
NOAEL = 1.38 mg/kg/day
LOC for MOE <100 (occupational)
Chronic Oral Toxicity Study in Dogs/See description above.
Cancer; Oral, Dermal, and Inhalation
Classification:  "Likely to be Carcinogenic to Humans"; Q1* (mg/kg/day)[-1] = 1.49 x 10[-2].

Dietary (Food + Drinking Water) Risk Assessment:  Chronic and cancer dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 2.03), which incorporates consumption data from United States Department of Agriculture (USDA) Continuing Survey of Food Intake by Individuals (CSFII; 1994-1996 and 1998).  An acute dietary risk assessment was not conducted since an appropriate endpoint attributable to a single dose was not identified for the general U.S. population or any population subgroup.  The chronic and cancer analyses assumed the following:  (1) average field trial residues (food and feed commodities); (2) experimentally determined processing factors for citrus fruit, pome fruit, and grape [DEEM (ver. 7.81) defaults assumed for the remaining processed commodities]; (3) Biological and Economic Analysis Division (BEAD) new use percent crop treated estimates for hops and blueberry and BEAD Screening Level Usage Analysis (SLUA) data for almonds; apples; apricots; cherries; grapefruit; grapes, raisins; grape, table; grape, wine; hazelnuts; lemons; nectarines; oranges; peaches; pears; pecans; pistachios; plum/prunes; and walnuts; (4) livestock residues which incorporated average field trial residues for determination of the livestock dietary burdens; and (5) drinking water estimates derived from the Pesticide Root Zone Modeling/Exposure Analysis Modeling System (PRZM/EXAMS) model.  
The resulting chronic risk estimates (food and water) were <=3.2% of the cPAD and are not of concern to HED (children 1-2 years old were the most highly exposed population subgroup).  The cancer dietary risk estimate (food and water) for the U.S. population was 3 x 10[-6].  HED is generally concerned when the cancer risk exceeds 10[-6].  Based on a critical commodity analysis conducted in DEEM-FCID, the major contributors to the risk were hops (44% of the total exposure) and water (21% of the total exposure).  HED notes the following concerning the assumptions incorporated into the cancer analysis for hops and water:  (1) hops - DEEM-FCID assumes that 100% of the residue in hops are transferred to beer during the brewing process (no residues remain in/on the spent hops); based on the spirodiclofen log KOW of 5.83, this is a conservative assumption; in addition, the assessment assumed 92% crop treated for hops (new-use percent crop treated estimates which are designed to provide a conservative estimate of actual percent crop treated) and (2) water - the water residue estimate assumed 87% of the basin is cropped with 100% of the crops treated at the maximum labeled rate.  Therefore, HED concludes that the cancer risk estimate provided in this assessment is conservative and actual cancer risk will be lower than the estimate provided in this document.

Aggregate Risk Assessment:  In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources:  food, drinking water, and residential exposures.  As there are no registered or proposed residential uses of spirodiclofen, aggregate risk assessment takes into consideration dietary (food + drinking water) exposure only.  Therefore, chronic and cancer aggregate (food + drinking water) risk assessment were conducted.  An acute aggregate risk assessment was not performed because an endpoint of concern attributable to a single oral dose was not selected for any population subgroup (including infants and children).  Short- and intermediate-term aggregate risk assessments were not performed because there are no registered or proposed residential non-food uses.  The chronic and cancer aggregate exposure and risk estimates are not of concern (see Dietary Risk Assessment Section). 

Occupational Risk Assessment:  Based on the proposed use, short-/intermediate-term handler exposure (airblast application), and short-term post-application exposure are expected.  As no chemical-specific handler exposure data were submitted in support of this Section 3 registration, the handler exposure estimates are based on surrogate data currently available from various sources provided in the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; September 2011).  The post-application exposure estimates are based on previously submitted dislodgeable foliar residue (DFR) data for apple and citrus and HED Science Advisory Council for Exposure (ExpoSAC) Policy 3: Agricultural Transfer Coefficients (June 2011).  All short-term non-cancer risks for occupational handlers are not of concern (i.e., MOEs >300) with the label-required personal protective equipment (PPE) (i.e., long-sleeve shirt, long pants, waterproof gloves and shoes plus socks); and intermediate-term non-cancer risks for occupational handler are not of concern (i.e., MOEs >100) with the label-required PPE.  With the label-required PPE, the cancer risk estimates are at or below 4.0 x 10[-6] for commercial applicators and at or below 1.3 x 10[-6] for private farmers.  The assumptions made in these calculations are conservative in nature.  The maximum application rate is used in all calculations.  For the commercial handler calculation, it is assumed an applicator is applying the pesticide 30 days of the year for 35 years.  For the private handler calculation, it is assumed an applicator is applying the pesticide for 10 days a year for 35 years.  Because of these conservative assumptions, the risks are not under estimated and there is no risk of concern.  HED recommends that RD ensure the correct language for gloves is on the label (chemical-resistant vs. waterproof).    

All dermal short-term non-cancer estimated risks for post-application activities do not exceed HED's level of concern (i.e., MOEs >300).  The estimated dermal post-application cancer risks on the day of application ranged from 2.8 x 10[-7] to 1.7 x 10[-6] for the activities associated with tropical fruit.  The interim Worker Protection Standard (WPS) restricted entry interval (REI) of 12 hours is adequate to protect agricultural worker from post-application exposures.  

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

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

Human Studies:  The occupational exposure/risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ARTF) Database.  EPA has reviewed all the studies in these multi-pesticide generic exposure databases, and based on available evidence, has found them to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted.  There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied.

HED Recommendation:  Provided revised Sections B and F are submitted (as specified in Section 9.0), HED concludes that the toxicological, residue chemistry, and occupational/residential exposure databases support a conditional registration for application of spirodiclofen to the proposed crops and establishment of the following permanent tolerances for residues of spirodiclofen (180.608(a)(1)):   lychee - 4.0 ppm; longan - 4.0 ppm; Spanish lime - 4.0 ppm; rambutan - 4.0 ppm; pulasan - 4.0 ppm; sugar apple - 0.40 ppm; atemoya - 0.40 ppm; custard apple - 0.40 ppm; cherimoya - 0.40 ppm; ilama - 0.40 ppm; soursop - 0.40 ppm; biriba - 0.40 ppm; guava - 0.50 ppm; feijoa - 0.50 ppm; jaboticaba - 0.50 ppm; wax jambu - 0.50 ppm; starfruit - 0.50 ppm; passionfruit - 0.50 ppm; acerola - 0.50 ppm; and persimmon - 0.50 ppm.  Unconditional registration may be established upon submission of an immunotoxicity study which adequately addresses the data requirements specified in 40 CFR Part 158 and a 28-day rat inhalation toxicity study (TXR 0052518, 16-JUN-2004).  

2.0  Ingredient Profile

Spirodiclofen is a tetronic acid acaricide.  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).  

2.1  Summary of Registered/Proposed Uses

Registered:  Spirodiclofen is currently registered for application to citrus fruit, grape, pome fruit, stone fruit, tree nuts, avocado, black sapote, canistel, mamey sapote, mango, papaya, sapodilla, star apple, hops, and the bushberry crop subgroup (13-07B) with tolerances for residues of spirodiclofen per se of 0.10-30 ppm (1 x 0.16-0.53 lbs ai/A; PHI = 7-14 days).  Spirodiclofen is also registered for application to Christmas tree plantations (1 x 0.28-0.39 lbs ai/A). 

Proposed:  Table 2.1.1 is a summary of the petitioner proposed use directions for application of Envidor[(R)] 2 SC Miticide (suspension-concentrate; 2 lbs ai/gallon; EPA Reg. No. 264-831) to sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, biriba, lychee, longan, Spanish lime, rambutan, pulasan, guava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, persimmon, and acerola.  HED requests a revised Section B which prohibits the addition of an adjuvant to the spray solution for the proposed crops (the field trial data did not include an adjuvant).  

Table 2.1.1.  Summary of Proposed Application Scenarios.
                         App. Timing; Type; and Equip.
                          Formulation (EPA Reg. No.)
                                   App. Rate
                                   (lb ai/A)
                            Max. #. App. per Season
                       Max. Seasonal App. Rate (lb ai/A)
                                    PHI[1]
                                    (days)
                        Use Directions and Limitations
Sugar Apple, Cherimoya, Atemoya, Custard Apple, Ilama, Soursop, Biriba, Lychee, Longan, Spanish Lime, Rambutan, Pulasan, Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, Persimmon, and Acerola
postemergence; foliar broadcast
                                2 lb ai/gal  SC
                                   (264-831)
                                   0.28-0.31
                                       1
                                     0.31
                                       1
-Apply in a minimum of 50 GPA with ground equipment.
-Application through irrigation equipment and in enclosed structures is prohibited.
1.  PHI = preharvest interval.

2.2  Structure and Nomenclature

Tables 2.2.1 and 2.2.2 are summaries of spirodiclofen nomenclature and physical chemical properties, respectively.
Table 2.2.1.  Nomenclature.
Spirodiclofen

Common name
Spirodiclofen
Company experimental name
BAJ 2740
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 FlC (ENVIDOR[(R)] 2 SC Miticide; EPA Reg. No. 264-831)

Table 2.2.2.  Physicochemical Properties of Spirodiclofen.
Melting point
94.8ºC
                             D315459, S. Mathur, 
                                  20-Apr-2005
pH
4.2

Density (20ºC)
1.29 g/cm[3]

Water solubility (20ºC at pH 4)
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 (2.25 x 10[-9] mm Hg)

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

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


3.0  Hazard Characterization/Assessment

The toxicological database for spirodiclofen is adequate for FQPA evaluation, selection of PODs for the various routes of exposure, and for dose-response evaluation.  The following is a summary of the spirodiclofen toxicological database.  For a complete review of these data, please refer to the human-health risk assessment dated 01-APR-2008 (Memo, M. Clock-Rust et al.; DP#339672).  Attachment 2 includes a tabular summary of the spirodiclofen acute, subchronic, and chronic toxicity profile.  Attachment 3 includes a rationale for toxicology endpoint selection, and a summary of toxicological doses and endpoints.

HED notes that based on the available toxicity database and the Agency's current practices, the inhalation risk for spirodiclofen was assessed using an oral toxicity study.  The Agency sought expert advice and input on issues related to this route-to-route extrapolation approach (i.e., the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhalation risk assessments, including route-to-route extrapolation of toxicity data.  If any new policies or procedures are developed, then the Agency may revisit the need for an inhalation toxicity study for spirodiclofen and/or a re-examination of the inhalation toxicity risk assessment.

3.1  Mode of Action

Spirodiclofen is a foliar acaricide belonging to the class of tetronic acids.  Its pesticidal mode of action presumably involves inhibition of lipid biosynthesis which interferes with mite development.  There is no evidence from the available toxicity database that a similar mode of action operates in mammals.

3.2  Toxicology Studies Available for Analysis

The toxicological database for spirodiclofen is adequate for evaluation. In the last risk assessment (Memo, T. Bloem et al., 02-JUL-2010; DP#371469), the only database deficiencies noted were an immunotoxicity study, as specified in 40 CFR Part 158 requirements, and a 28-day rat inhalation toxicity study, as requested by the HIARC to characterize potential effects on the pulmonary system (HIARC 2004, TXR# 0052618).  A waiver for the immunotoxicity study requirement was received by the Agency on the basis primarily of an amended rat subchronic toxicity study where some immunotoxicity parameters were measured.  Evaluation of this waiver request is included in this hazard characterization.  No new inhalation toxicity information is available for spirodiclofen since the last risk assessment.

3.3  Absorption, Distribution, Metabolism, & Elimination (ADME)

Following oral administration, radiolabeled spirodiclofen was rapidly and extensively absorbed from the gastrointestinal tract into the systemic circulation.  Based on the radioactivity quantified at 48 hours, females absorbed a greater fraction of approximately 74% versus 57-62% estimated for males.  Spirodiclofen underwent extensive metabolism and excretion was primarily urinary followed by fecal.  Female rats metabolized spirodiclofen to a urinary enol metabolite more extensively than did males (39.65-52.42% versus 4.88-5.41% of the administered dose, respectively).  Parent compound was detected only in small quantities in the feces (probably reflecting unabsorbed compound), but not in the urine or bile.  Excretion was approximately 90% complete at 48 hours post dosing.  Results of biliary excretion experiments showed that approximately 11% of the administered dose appeared in the bile as biotransformation products.  There was no evidence of accumulation in any specific organs or tissues based on rat whole-body autoradiography taken at 1, 4, 8, 24, and 48 hours post-dose.

3.3.1  Dermal Absorption

A dermal-absorption factor of 2% was previously estimated based on the results of two dermal-absorption studies in monkeys.  The dermal-absorption factor has been deemed appropriate for estimating dermal risk for all time durations (HIARC 2004, TXR# 0052618).

3.4  Toxicological Effects

The effects observed following repeated oral exposures to spirodiclofen have been remarkably consistent across different studies and species tested.  The primary target organs identified are the adrenal glands in both sexes and testes in males.  Increased cytoplasmic vacuolation in the Zona fasciculate of the adrenal cortex has been consistently observed across different subchronic and chronic studies with spirodiclofen in rats, mice, and dogs of both sexes.  The dog was the most sensitive species and, at least in rat and dog studies, females appear to be the more sensitive sex.  The effect(s) on the adrenal glands generally coincided with increased adrenal weight.  Other organs with histopathology findings reported in male dogs included the testes (vacuolation and hypertrophy/activation of Leydig cells), epididymis (degeneration and/or immaturity of germinal epithelium, oligo- and aspermia), prostate (immaturity signs), and thymus (atrophy).  Increased liver weights were also reported in male dogs along with decreases in prostate weights.

The effects reported in chronic studies in dogs were similar and occurred at lower administered oral doses of spirodiclofen.  The effects consisted of dose-related increases in adrenal glands of both sexes, kidney (females only), testes, epididymis, and prostates in males.  As with subchronic studies, histopathology of the adrenal gland revealed an increased incidence of cortical vacuolation in the zona fasciculata of both sexes.  In the testes, increased incidences of Leydig cell vacuolation, slight Leydig cell hypertrophy, and tubular degeneration were observed in males.  Other effects reported in chronic studies include decreases in cholesterol and triglycerides (rats), decreased body weights and body-weight gains (rats), increased APh levels, increased vacuolated jejunum enterocytes (rats), and increased incidences of Leydig cell hyperplasia (rats and mice). 

Developmental toxicity with no indication of maternal toxicity in the rat prenatal developmental study consisted of an increased incidence of slight dilatation of the renal pelvis only at the limit dose and in the absence of dose-response or statistical significance.  Furthermore, there was no evidence of dilatation of the renal pelvis or any other developmental effect in the rabbit prenatal developmental toxicity study.  In the two-generation reproductive toxicity study, developmental effects were observed in F1 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 F1 females (i.e., increased severity of ovarian luteal cell vacuolation/degeneration), but at a higher dose (1750 ppm) than the systemic effects seen for parents and offspring (350 ppm).  There was no evidence of developmental toxicity in the rabbit prenatal developmental toxicity study.

Spirodiclofen did not show any evidence of neurotoxicity in the acute and subchronic neurotoxicity studies.  In a DNT study, a decrease in retention was observed in the memory phase of the water maze for postnatal day (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 conditions as the previous study.  The results of the new study demonstrated no treatment-related neurotoxicity.  Therefore, it can be concluded that spirodiclofen is unlikely to be a neurotoxic or developmentally neurotoxic compound.  

In a dermal toxicity study, spirodiclofen did not exhibit toxicity at the highest dose tested.  However, the study was deemed unacceptable since potential target organs (uterus, prostate, etc.) were not examined for histopathology.  A dermal-absorption factor of 2% was previously estimated based on the results of two dermal-absorption studies in monkeys.

In rat subchronic toxicity study, several immunotoxicity parameters were measured including macrophage activity and antibody titers.  However, upon review of the study, several deficiencies were noted and the study was deemed unacceptable to fulfill the immunotoxicity data requirement.  Spirodiclofen was ranked low (Category IV) for acute inhalation toxicity.  There is no information to evaluate inhalation exposures of longer duration.  A 28-day rat inhalation toxicity study was requested by the HIARC in 2004 to characterize potential effects on the pulmonary system (HIARC 2004, TXR# 0052618).  However, no additional inhalation toxicity studies have been submitted for evaluation. 

Chronic/carcinogenicity studies showed an increased incidence of uterine adenocarcinoma in female rats, Leydig cell adenoma in male rats, and liver tumors in mice.  The HED 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.  Results of genotoxicity testing were negative.

3.5  FQPA Considerations

The toxicology database for spirodiclofen is adequate for FQPA consideration.  The following acceptable studies are available:  developmental toxicity studies in rats and rabbits; a two-generation reproduction study in rats; and acute, subchronic, and developmental neurotoxicity studies.  The spirodiclofen risk assessment team recommends that the FQPA SF be reduced from 10X to 1X for all dietary exposure scenarios for the following reasons:

   * The concern for increased susceptibility following prenatal or postnatal exposure is low.  Although increased 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, the increased incidence of slight renal pelvic dilation was observed at the limit-dose in the absence of statistical significance or 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 also be idiosyncratic to this strain (Wistar) of rats since renal pelvis dilations are commonly seen at higher incidences in other rat strains (e.g., Sprague-Dawley or Fisher).  Furthermore, there is a well-established NOAEL at which all developmental/functional parameters were comparable to controls and much lower doses are being used for risk assessment of spirodiclofen.  There was no evidence of increased susceptibility in the developmental toxicity study in rabbits or the two-generation reproduction study in rats (For more discussion, see Memo, T. Bloem et al., 28-JUL-2010; DP#371469).  
   * There was no evidence of neurotoxicity or neuropathology in the acute and subchronic neurotoxicity studies.  In the acute neurotoxicity study, a decrease in motor activity was observed on the first day of dosing at the limit dose (2000 mg/kg/day) in males only.  The finding was not accompanied by any other neuropathological changes and was considered a reflection of a mild and transient general systemic toxicity and not a substance-specific neurotoxic effect.  Additionally, it was not corroborated in the subchronic neurotoxicity study where systemic toxicity was seen at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) ppm in males and females, respectively.  There is also no other indication of neurotoxicity in any study in the database.  
   * The overall weight of evidence suggests that this chemical does not directly target the immune system. Although an immunotoxicity study is currently lacking, there is no indication in the current database that the immune system may be a target at the dose levels being used for risk assessment.  Mild atrophy in the thymus was noted in the dog subchronic toxicity study, but such effect was considered indirect and was not seen the dog chronic toxicity study or any other study in the database.  Thus, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently used for overall risk assessment, and therefore, a UFD is not needed to account for the lack of this study.
   * There are also no additional residual uncertainties with respect to exposure data.  The chronic and cancer dietary (food and drinking water) exposure assessment was refined, utilizing average field trial residues (food and feed commodities); experimentally determined processing factors for citrus fruit, pome fruit, and grape (DEEM (ver. 7.81) and defaults for the remaining processed commodities; BEAD new use percent crop treated estimates for hops and blueberry and BEAD SLUA data for several commodities (see Section 4.7); livestock residues which incorporated average field trial residues for determination of the livestock dietary burdens; and drinking water estimates derived from the PRZM/EXAMS model.  The chronic assessment is somewhat refined and based on reliable data and will not underestimate exposure/risk The drinking water assessment utilizes water concentration values generated by model and associated modeling parameters which are designed to provide conservative, health-protective, high-end estimates of water concentrations which will not likely be exceeded.  There is no potential for residential exposure.  

3.6  Toxicity Endpoint Selection

Table 3.6.1 summarizes the toxicological doses and endpoints selected for residential dietary and occupational risk assessment.  The rationale for the dose/endpoint selection is described in Appendix 3.  It should be noted that a UFD factor of 3X has been applied for short-term dermal and inhalation exposure scenarios due to the use of a LOAEL (no NOAEL was established) as the POD.  In a HIARC 2004 report (HIARC 2004, TXR# 0052618), it was determined that a 3X uncertainty factor would be adequate (for the use of a LOAEL) since the extrapolated NOAEL (8.4/3= 2.8 mg/kg/day) in the subchronic dog study is comparable to the NOAEL (1.38 or 1.52 mg/kg/day for males or females, respectively) in the chronic dog study.  Since the same study/effect was selected for assessment of short-term dermal/inhalation exposure, exposure via these routes can be aggregated.  

Table 3.6.1.  Summary of Toxicological Doses and Endpoints for Residential and Dietary Risk Assessments.
                                   Exposure
                                   Scenario
                       Dose Used in Risk Assessment, UF
               FQPA SF and Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary
An appropriate endpoint attributable to a single dose was not identified.  
Chronic Dietary
(All populations)
NOAEL= 1.38 mg/kg/day
                                   UF = 100 
                              (10X interspecies,
                              10X intraspecies,)
cRfD = 0.014 mg/kg/day
FQPA SF = 1x
cPAD = cRfD / FQPA SF = 0.0138 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.
Summary of Toxicological Doses and Endpoints for Occupational Risk Assessment.
Short-term (1-30 days) Dermal 
LOAEL = 8.4 mg/kg/day
dermal-absorption rate = 2%
UFD = 3x
Residential LOC for MOE <300 (10X interspecies,
10X intraspecies,
3X for no NOAEL)
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 (1-6 months) and Long-term (>6 months) Dermal 
NOAEL = 1.38 mg/kg/day
dermal-absorption rate = 2%
Residential/Occupational LOC for MOE <100 (10X interspecies,
10X intraspecies)
Chronic Oral Toxicity Study in Dogs; LOAEL= 4.7 mg/kg/day
(See description above)
Short-term (1-30 days) Inhalation 
LOAEL = 8.4 mg/kg/day
100% absorption assumed
UFD = 3x
Residential LOC for MOE <300 (10X interspecies,
10X intraspecies, 3X for no NOAEL)
Subchronic Oral Toxicity Study in Dogs; LOAEL= 8.4 mg/kg/day (See description above)
Intermediate (1-6 months) and Long-term (>6 months) Inhalation
NOAEL = 1.38 mg/kg/day
100% absorption assumed
Residential/Occupational LOC for MOE <100 (10X interspecies,
10X intraspecies)
Chronic Oral Toxicity Study in Dogs; LOAEL= 4.7 mg/kg/day
(See description above)
Cancer; Oral, Dermal, and Inhalation
Classification:  "Likely to be Carcinogenic to Humans"; Q1* (mg/kg/day)[-1] = 1.49 x 10[-2].
UF = uncertainty factor; UFD = database uncertainty factor RfD = reference dose.  LOC = level of concern.  MOE = margin of exposure = NOAEL / exposure.  


4.0  Dietary Exposure/Risk Characterization

4.1  Metabolism in Primary Crops, Livestock, and Rotational Crops

Based on the currently available data, HED concluded that the residues of concern in proposed/registered crops, ruminants, and drinking water are as defined in Table 4.1.1.  In addition, HED concluded that the metabolites/degradates included in the spirodiclofen risk assessment are not likely to be more toxic than parent (Memo, M. Clock-Rust et al., 22-JUN-2005; DP#285047).  It is noted that the currently available plant metabolism data (citrus, grape, and apple) indicate that the majority of spirodiclofen residues are surface residues or associated with the peel.  The text below provides a summary of these decisions.  

Table 4.1.1.  Residues of Concern for Tolerance Expression and Risk Assessment.
                                    Matrix
                             Residues included in
                                Risk Assessment
                             Residues included in
                             Tolerance Expression
Pome Fruit, Tree Nut, and Hops
                                 spirodiclofen
                                 spirodiclofen
Grape, Citrus Fruit, Stone Fruit, Berry (CG 13), and Tropical Fruit[1]
                            spirodiclofen, BAJ 2510
                                 spirodiclofen
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
[1]  BAJ 2510 is included as a residue of concern in grape, citrus fruit, stone fruit, berry (CG 13), and tropical fruit due to the demonstrated (grape and citrus fruit) degradation of parent to BAJ 2510 during processing or due to the lack of data eliminating this possibility (stone fruit, berry (CG-13), and tropical fruit).  BAJ 2510 is only a residue of concern in the processed commodities of grape, citrus fruit, stone fruit, berry (CG 13), and tropical fruit.  If processing data for the combined residues of spirodiclofen and BAJ 2510 are not available, then the dietary analysis should incorporate default processing factors.

Primary Crops:  Based on the results of the citrus, grape, and apple metabolism studies (Risk Assessment Document:  D285047, M Clock-Rust et al., 22-JUN-2005); the apple, grape, and orange processing studies (D341847, T. Bloem, 22-JUN-2005; D359773, T. Bloem, 24-JUN-2009; D390192, T. Bloem, 20-JUN-2011); and previous conclusions relating to the residues of concern in hops (D346710, M. Sahafeyan, 3-JAN-2008); HED concludes that the residues of concern in the currently-registered/proposed crops are as follows (see Table 4.1.1 for a summary):  pome fruit, tree nut, and hops - the residue of concern for risk assessment and tolerance enforcement is spirodiclofen per se and grape, citrus fruit, stone fruit, berry (crop group (CG) 13), and tropical fruit - the residue of concern for tolerance enforcement is spirodiclofen per se and residues of concern for risk assessment are spirodiclofen and BAJ 2510.  HED notes that following:  (1) BAJ 2510 is included as a residue of concern in grape, citrus fruit, stone fruit, berry (CG 13), and tropical fruit due to the demonstrated (grape and citrus fruit) degradation of parent to BAJ 2510 during processing or due to the lack of data eliminating this possibility (stone fruit, berry CG 13, and tropical fruit); (2) BAJ 2510 is only a residue of concern in the processed commodities of grape, citrus fruit, stone fruit, berry (CG 13), and tropical fruit; and (3) if processing data for the combined residues of spirodiclofen and BAJ 2510 are not available, then the dietary analysis should incorporate default processing factors.  Based on the results of the grape and orange processing studies, HED requests that all future processing studies monitor for residues of spirodiclofen, BAJ 2510, 3-OH-enol, and 4-OH-enol.  

Livestock:  The petitioner has not submitted data concerning the nature of the residues in poultry. Since there are no poultry feed commodities associated with the proposed/registered crops, these data are unnecessary.  

The goat metabolism study indicated that the metabolism of spirodiclofen in ruminants proceeds via hydrolysis of the parent ester linkage resulting in the formation of BAJ 2510 followed by hydroxylation of the 4-position of the cyclohexyl ring (4-OH-enol).  BAJ 2510 accounted for the majority of the radioactivity in all matrices (81-95% TRR in tissue and milk).  The 4-OH-enol metabolite was the only other metabolite identified, accounting for <=8.7% in kidney, liver, and milk (not detected in muscle and fat).  Spirodiclofen was not detected in any of the matrices; however, it was identified as the major residue in fat samples collected from the ruminant feeding study.  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. 

Rotational Crops:  The petitioner has not submitted data concerning the nature of the residue in rotational crops.  Since none of the proposed/registered crops are rotated, these data are unnecessary.  

4.2  Analytical Methodology

HED determined that the Bayer analytical method 109351 was appropriate for enforcement of the currently established tolerances and forwarded this method to Food and Drug Administration (FDA) for inclusion in the Pesticide Analytical Manual (PAM; D368434, T. Bloem, 23-Sep-2009).  Based on the similarities of the data collection method and the tolerance enforcement method and since the tolerance enforcement method has been validated on a fruit crop and adequate validation data were submitted with the field trial studies, HED concludes that the current enforcement method is appropriate for enforcement of the tolerances recommended as part of this petition.  

4.3  Comparative Metabolic Profile

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

4.4  Drinking Water Residue Profile

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 dissipates rapidly from aquatic environments (half-life of 1-7 days).  The major residue identified in the aerobic soil and anaerobic/aerobic aquatic degradation studies was BAJ 2510 (52-95% of 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 30 days), and DCB-acid (40% of the applied dose at 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.  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.

Surface and ground estimated drinking water concentrations were previously generated by EFED using PRZM-EXAMS and the Screening Concentration in Ground Water Model (SCI-GROW), respectively (Memo, F. Kahn, 4-JAN-2005; DP#311291).  The SCI-GROW model was run using the highest application rate (1 x 0.53 lb ai/A) and resulted in a point estimate of 0.44 ppb.  Multiple crop scenarios were modeled using PRZM-EXAMS (citrus, pecan, apple, peach, and grape; 87% cropped and 100% crop treated assumed) with citrus (1 x 0.31 lb ai/A) resulting in the highest 1-in-10-year peak concentration (23.86 ppb), 1-in-10-year yearly average (4.99 ppb), and 30-year average (1.67 ppb).  Since the application rates proposed as part of the current petition (1 x 0.31 lb ai/A) are equal to the citrus application rate, EFED concluded that the previously generated water estimates remain relevant (Memo, L. Liu, 14-APR-2011; DP#386204).  Therefore, the chronic and cancer analyses employed the citrus 1-in-10-year yearly average (4.99 ppb) and 30-year average (1.67 ppb), respectively.

4.5  Food Residue Profile
D387339, T. Bloem, 15-October-2011

Primary Crops:  In support of the proposed registration, the petitioner submitted lychee, sugar apple, and guava field trial studies.  Provided the label is revised to prohibit the addition of adjuvants to the spray solution, the application scenario employed in the field trials supports the proposed application scenario.  HED has determined that these data are adequate to support registration to the proposed crops.  Based on the available residue data and the Organization for Economic Cooperation and Development (OECD) tolerance/ maximum residue limit (MRL) calculator, HED concludes that the following tolerances for residues of spirodiclofen per se are appropriate (a revised Section F is requested):  lychee - 4.0 ppm; longan - 4.0 ppm; Spanish lime - 4.0 ppm; rambutan - 4.0 ppm; pulasan - 4.0 ppm; sugar apple - 0.40 ppm; atemoya - 0.40 ppm; custard apple - 0.40 ppm; cherimoya - 0.40 ppm; ilama - 0.40 ppm; soursop - 0.40 ppm; biriba - 0.40 ppm; guava - 0.50 ppm; feijoa - 0.50 ppm; jaboticaba - 0.50 ppm; wax jambu - 0.50 ppm; starfruit - 0.50 ppm; passionfruit - 0.50 ppm; acerola - 0.50 ppm; and persimmon - 0.50 ppm.  

Livestock:  Based on the revised Table 1 feedstuffs (OPPTS 860.1000), none of the proposed crops have feed commodities; therefore, a discussion concerning the magnitude of the residue in livestock is unnecessary.  

Rotational Crops:  Since all of the requested crops are perennials, a discussion concerning the nature/magnitude of the residue in rotational crops is unnecessary.  

4.6  International Residue Limits and HED-Recommended Tolerances

Table 4.6.1 is a summary of the proposed and recommended tolerance for residues of spirodiclofen per se.  There are no Codex, Canadian, or Mexican MRLs in/on the requested crops.  Therefore, harmonization is not an issue for this petition.  

In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 180.608(a)(1) and 180.6(a)(2) be changed as indicated below.  HED notes that this alteration in the tolerance expression does not necessitate a change in the currently established or recommended tolerance levels.  A revised Section F specifying the new tolerance expression, the currently established commodity/tolerance levels, and the HED-recommended tolerances should be submitted.  

   180.608(a)(1):  Tolerances are established for residues of spirodiclofen, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the following tolerance levels is to be determined by measuring only spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate).

   180.608(a)(2):  Tolerances are established for residues of spirodiclofen, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the following tolerance levels is to be determined by measuring only spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate) and its metabolite 3-(2,4-dichlorophenyl)-4-hydroxy-1-oxaspiro[4.5] dec-3-en-2-one, calculated as the stoichiometric equivalent of spirodiclofen.

Table 4.6.1.  Tolerance Summary.
                                   Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments
Lychee
                                      3.5
                                      4.0
Based on the field trial data and the OECD tolerance calculator, the appropriate tolerance for residues of spirodiclofen per se in/on these crops is 4.0 ppm.
Longan
                                      3.5
                                      4.0

Spanish lime
                                      3.5
                                      4.0

Rambutan
                                      3.5
                                      4.0

Pulasan
                                      3.5
                                      4.0

Sugar apple
                                     0.45
                                     0.40
Based on the field trial data and the OECD tolerance calculator, the appropriate tolerance for residues of spirodiclofen per se in/on these crops is 0.40 ppm.
Atemoya
                                     0.45
                                     0.40

Custard apple
                                     0.45
                                     0.40

Cherimoya
                                     0.45
                                     0.40

Ilama
                                     0.45
                                     0.40

Soursop
                                     0.45
                                     0.40

Biriba
                                     0.45
                                     0.40

Guava
                                     0.45
                                     0.50
Based on the field trial data and the OECD tolerance calculator, the appropriate tolerance for residues of spirodiclofen per se in/on these crops is 0.50 ppm.
Feijoa
                                     0.45
                                     0.50
                                       
Jaboticaba
                                     0.45
                                     0.50
                                       
Wax jambu
                                     0.45
                                     0.50
                                       
Starfruit
                                     0.45
                                     0.50
                                       
Passionfruit
                                     0.45
                                     0.50

Acerola
                                     0.45
                                     0.50

Persimmon
                                     0.45
                                     0.50


4.7  Dietary Exposure and Risk
D387338, T. Bloem, in preparation

Chronic and cancer dietary risk assessments were conducted using DEEM-FCID (ver. 2.03) which incorporates consumption data from USDA CSFII (1994-1996 and 1998).  The chronic and cancer analyses assumed the following:  (1) average field trial residues (food and feed commodities); (2) experimentally determined processing factors for citrus fruit, pome fruit, and grape (DEEM (ver. 7.81) defaults assumed for the remaining processed commodities); (3) BEAD new use percent crop treated estimates for hops (92%) and blueberry (2%) and the following SLUA data also provided by BEAD:  almond - 5%; apple - 5%; apricot - 5%; cherry - 2%; grapefruit - 50%; grapes, raisin - 10%; grape, table - 30%; grape, wine - 5% - ; hazelnuts - 2%; lemon - 1%; nectarine - 10%; orange - 10%; peach - 5%; pear - 10%; pecan - 2%; pistachio - 1%; plum/prune - 5%; and walnuts - 5%; (4) livestock residues, which incorporated average field trial residues for determination of the livestock dietary burdens; and (5) drinking water estimates derived from the PRZM/EXAMS model (citrus application scenario; 1 x 0.31 lb ai/acre; citrus yielded the highest chronic/cancer drinking water estimates).  The resulting chronic risk estimates (food and water) were <=3.2% of the cPAD and are not of concern to HED (children 1-2 years old were the most highly exposed population).  The cancer risk estimate (food and water) for the U.S. population was 3 x 10[-6].  The major contributors to the cancer analysis were hops (44%; assumes 100% transfer of residues from hops to beer; spirodiclofen Log KOW = 5.83) and water (21%; 87% of the basin cropped and 100% crop treated at the maximum labeled rate).  Table 4.7.1 and 4.7.2 are summaries of the chronic and cancer exposure and risk estimates, respectively.

Table 4.7.1.  Summary of Chronic Dietary Exposure and Risk.
Population Subgroup
                               cPAD (mg/kg/day)
                             Exposure (mg/kg/day)
                                   %cPAD[1]
General U.S. Population
                                     0.014
                                   0.000241
                                      1.7
All Infants (<1 year old)

                                   0.000434
                                      3.1
Children 1-2 years old

                                   0.000444
                                      3.2
Children 3-5 years old

                                   0.000348
                                      2.5
Children 6-12 years old

                                   0.000193
                                      1.4
Youth 13-19 years old

                                   0.000136
                                      1.0
Adults 20-49 years old

                                   0.000268
                                      1.9
Adults 50+ years old

                                   0.000198
                                      1.4
Females 13-49 years old

                                   0.000183
                                      1.3
	[1]  The bolded %cPAD represents the population with highest risk.

Table 4.7.2.  Summary of Cancer Dietary Exposure and Risk.
Population Subgroup
                                      Q1*
                             Exposure (mg/kg/day)
                                     Risk
General U.S. Population
                                    0.0149
                                   0.000171
                                 2.6 x 10[-6]

5.0  Residential (Non-Occupational) Risk Assessment

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

5.1  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 (see the Agency's Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical-by-chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT[(R)] 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.
5.2  Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application inhalation exposure assessment was not performed for spirodiclofen at this time.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for spirodiclofen.

6.0  Aggregate Risk Assessment

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources:  food, drinking water, and residential exposures.  As there are no registered or proposed residential uses of spirodiclofen, aggregate risk assessment takes into consideration dietary (food + drinking water) exposure only.  Therefore, chronic and cancer aggregate (food + drinking water) risk assessments were conducted.  An acute aggregate risk assessment was not performed because an endpoint of concern attributable to a single oral dose was not selected for any population subgroup (including infants and children).  Short- and intermediate-term aggregate risk assessments were not performed because there are no registered or proposed residential non-food uses.  The chronic and cancer aggregate exposure and risk estimates are not of concern (See Section 4.7; acute dietary analysis is unnecessary).  

7.0  Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 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 assumed that spirodiclofen does not have a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

8.0  Occupational Exposure/Risk Pathway
D387337, L. Venkateshwara, in preparation

Spirodiclofen is proposed for a single application to sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, biriba, lychee, longan, Spanish lime, rambutan, pulasan, guava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, persimmon, and acerola at 0.31 lbs ai/A (PHI = 1 day; REI = 12 hours; see Section 2.1).  Based on the proposed application scenario and toxicological considerations, non-cancer and cancer handler (dermal and inhalation) and post-application (dermal and inhalation) risk assessments were conducted.  

8.1  Handler Non-Cancer Exposure and Risk Estimates

There is potential for the following occupational handler exposure from the proposed uses:  (1) mixing/loading liquids for airblast applications, and (2) applying sprays via airblast equipment.  HED notes that airblast application is protective of all ground applications.  

No chemical-specific data were available with which to assess potential exposure to pesticide handlers.  To assess handler exposures for regulatory actions when chemical-specific monitoring data are not available, HED relies on the most scientifically reliable surrogate data currently available from various sources provided in the OPHED.

For pesticide handlers, HED presents estimates of dermal exposure for "baseline" (i.e., workers wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as for "baseline" and the use of protective gloves or other PPE, as might be necessary.  The spirodiclofen product label directs mixers, loaders, applicators, and other handlers to wear a long-sleeve shirt, long pants, waterproof gloves and shoes plus socks.  HED notes the PPE on the label is waterproof gloves.  RD should ensure this is the correct PPE for this product (chemical-resistant versus waterproof gloves.

Since only a single application is allowed per crop season, only short-term handler exposure is expected (1-30 days); however, it is HED policy to assess both short-term and intermediate-term exposure for handlers.  Typically, HED completes short- and intermediate-term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate-term scenarios.  HED believes that occupational exposures may occur over a single day or up to weeks at a time for many use-patterns and that intermittent exposure over several weeks may also occur.  Some applicators may apply these products over a period of weeks, because they are commercial applicators who are completing multiple applications for multiple clients.  

Table 8.1.1 presents the short- and intermediate-term estimated risks for handlers with baseline attire and with additional PPE.  HED has determined that risks are not of concern for short-term exposures (i.e., MOEs >300) and intermediate-term exposures (i.e., MOEs >100) with the PPE required on the label.

Table 8.1.1.  Occupational Handler Dermal and Inhalation Exposures and Risk Estimates.
                                  Dermal and
                           Inhalation Unit Exposures
                                  (ug/lb ai)
                               Application Rate
                                 (lb ai/A)[1]
                           Area Treated Daily (A)[2]
             Short-term and Intermediate-term Doses (mg/kg/day)[3]
                              Short-term MOEs[4]
                           Intermediate-term MOEs[4]
                     Mixer/Loader  -  Airblast Application
                                    Dermal
                               Baseline[5]:  220
                                       
                                  Inhalation
                              Baseline[6]:  0.219
                                     0.31
                                      40
                                    Dermal
                                  Baseline: 
                                    0.0008
                              Combined Baseline: 
                                    0.0008
                                    Dermal
                                  Baseline: 
                                    11,000
                              Combined Baseline: 
                                    10,000
                                    Dermal
                                Baseline: 1,800
                           Combined Baseline: 1,700
                                       
                                       
                                       
                                  Inhalation
                                  Baseline: 
                                   0.000039
                                       
                                  Inhalation
                                  Baseline: 
                                    220,000
                                       
                                  Inhalation
                               Baseline: 36,000
                                       
                      Applicator  - Airblast Application
                                    Dermal
                                Baseline:  1770
                       Single layer w/ gloves[2]:  1590
                                       
                                  Inhalation
                                Baseline:  4.71
0.31
40
Dermal Baseline: 
0.0063 

Single layer w/ gloves: 
0.0056
Combined Baseline: 
0.0071

Single layer w/gloves:0.0064
Dermal
Baseline: 
1,300

Single layer w/glove: 1,500
Combined Baseline:  1,200

Single layer w/glove: 1,300
Dermal
Baseline: 220

Single layer w/gloves: 240
Combined Baseline:  190


Single layer w/ gloves:
210
                                       
                                       
                                       
                          Inhalation Baseline: 0.0008
                                       
                                  Inhalation
                                  Baseline: 
                                    10,000
                                       
                                  Inhalation
                                  Baseline: 
                                     1,700
                                       
1.  Application rates are the maximum (single) recommended rates provided on the spirodiclofen product labels.
2.  Area treated per day values are HED estimates based on ExpoSAC Policy #9 "Standard Values for Daily Acres Treated in Agriculture," industry sources, and HED estimates.
3.  Dose (mg/kg/day) = Unit Exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x % Absorption (2% dermal and 100% inhalation assumed) / Body Weight.  The body weight is 70 kg for the inhalation and dermal dose. 
4.  MOE = NOAEL or LOAEL/Dose; where the short-term dermal and inhalation LOAEL =  8.4 mg/kg/day and intermediate-term dermal and inhalation NOAEL is 1.38 mg/kg/day
5.  Baseline Dermal:  Long-sleeve shirt, long pants, shoes, socks and no gloves.
6.  Baseline Inhalation:  no respirator.

8.2  Post-application Non-Cancer Exposure and Risk Estimates

Inhalation:  Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for spirodiclofen at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (2.25 x 10[-9] mm Hg), and the low proposed use rate (0.31 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for spirodiclofen.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

Dermal:  Based on the proposed use, there is a possibility for agricultural workers to have short-term post-application dermal exposure to spirodiclofen.  Post-application data have been submitted previously for the use of spirodiclofen on citrus and apple.  Post-application dermal exposures have been assessed using the submitted DFR data as well as dermal transfer coefficients from the ExpoSAC Policy Number 3 (http://www.epa.gov/ pesticides/science/ exposac_policy3.pdf).  This policy reflects adoption of all ARTF data.  Use of the data in this policy requires compensation to the ARTF under FIFRA.

For the proposed crop uses, the relevant post-application activities and transfer coefficients are hand pruning, scouting (580 cm[2]/hr); hand harvesting (1,400 cm[2]/hr); and thinning fruit (3,600 cm[2]/hr).  HED has determined that short-term non-cancer risk estimates are not of concern (i.e., MOEs >300) on the day of treatment (i.e., Day 0) for all post-application exposure activities.  Table 8.2.1 presents a summary of occupational post-application risks associated with use of spirodiclofen.

Table 8.2.1.  Post-application Risk Estimates for Spirodiclofen.
                                     Crop
                         Application  Rate(lb ai/A)[1]
                             Transfer Coefficient
                                  (cm[2]/hr)
                               DFR (ug/cm[2])[2]
                             Days After Treatment
                                 Daily Dose[3]
                                  (mg/kg/ay)
                                    MOE[4]
                                Tropical Fruit
                                     0.31
                          580 (Hand pruning, scouting)
                                     0.476
                                       0
                                  (12 hours)
                                    0.0006
                                    14,000
                                       
                                       
                              1400 (Hand harvest)
                                       
                                       
                                    0.0015
                                     5,600
                                       
                                       
                             3600 (Thinning fruit)
                                       
                                       
                                    0.0039
                                     2,000
The information in the table is based on proprietary and non-proprietary data.
1.  Proposed application rate = 0.31 lb ai/A.
2.  Day 0 adjusted for application rate difference between study and proposed use.  DFR value is from MRID 456973-13, June 29, 2004.
3.  Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x Dermal Absorption (2%) x 8 hrs/day] / Body Weight (70 kg)
4.  LOAEL/Daily Dose (Short-term LOAEL = 8.4 mg/kg/day).

8.3  Cancer Exposure and Risk Estimates 

Occupational handler and post-application cancer risk estimates were calculated using a linear low-dose extrapolation approach in which a lifetime average daily dose (LADD) is calculated and then multiplied by the Q1* to obtain a cancer risk estimate.

8.3.1  Handler Cancer Exposure and Risk  Estimates

Based on the proposed use scenario, it is anticipated that commercial applicators would handle spirodiclofen approximately 30 days per year and individual farmers would handle spirodiclofen approximately 10 days per year.  The combined handler inhalation and dermal ADD exposure estimates (see Table 8.1.1), amortized over a 35-year career and a 70-year lifespan, were used as the basis for the LADD.  Estimated spirodiclofen cancer risks for handlers are summarized below in Table 8.3.1.1.  With required PPE, the cancer risk estimates are at or below 4.0 x 10[-6] for commercial applicators and at or below 1.3 x 10[-6] for private farmers.  The assumptions made in these calculations are conservative in nature.  The maximum application rate is used in all calculations.  For the commercial handler calculation, it is assumed an applicator is applying the pesticide 30 days of the year for 35 years.  For the private handler calculation, it is assumed an applicator is applying the pesticide for 10 days a year for 35 years.  Because of these conservative assumptions, the risks are not under estimated and there is no risk of concern.

Table 8.3.1.1.  Handler Cancer Risk Estimates for Commercial/Private Spirodiclofen Handlers.
                                   Scenario
                                  Mitigation
                          Dermal Dose[1] (mg/kg/day)
                        Inhalation Dose[1] (mg/kg/day)
                          Combined ADD[2] (mg/kg/day)
                                    LADD[3]
                                  (mg/kg/day)
                                    Cancer
                                    Risk[4]
                              Commercial Handlers
                Mixing/loading liquids airblast application (1)
                        Baseline Dermal and Inhalation
                                    0.00078
                                   3.88E-05
                                    0.00082
                                    3.4E-05
                                    5.0E-07
                                       
                  Single layer w/gloves + Baseline Inhalation
                                    0.00013
                                       
                                    0.00017
                                    7.1E-06
                                  1.1E-07[5]
                                       
                  Double layer w/gloves + Baseline Inhalation
                                    0.00001
                                       
                                    0.0014
                                    5.8E-06
                                    8.7E-08
                                       
                             Engineering controls
                                    0.00027
                                       
                                    0.00031
                                    2.8E-06
                                    4.2E-08
                       Applying spray using airblast (3)
                        Baseline Dermal and Inhalation
                                    0.0063
                                    0.00083
                                    0.0072
                                    2.9E-04
                                    4.4E-06
                                       
                  Single layer w/gloves + Baseline Inhalation
                                    0.0056
                                       
                                    0.0065
                                    0.00027
                                    4.0E-06
                                       
            Single layer w/gloves + Head gear + Baseline Inhalation
                                    0.00076
                                       
                                    0.0016
                                   0.000066
                                    9.8E-07
                                       
                             Engineering controls
                                   0.000064
                                       
                                    0.0009
                                   0.000036
                                    5.4E-07
                               Private Handlers
                Mixing/loading liquids airblast application (1)
                        Baseline Dermal and Inhalation
                                    0.00078
                                   3.88E-05
                                    0.00082
                                    1.1E-05
                                    1.7E07
                                       
                  Single layer w/gloves + Baseline Inhalation
                                    0.00013
                                       
                                    0.00017
                                   0.0000024
                                    3.5E-08
                                       
                 Double layer w/ gloves + Baseline Inhalation
                                    0.00001
                                       
                                    0.00014
                                       
                                   0.0000019
                                    2.9E-08
                                       
                             Engineering controls
                                   0.000045
                                       
                                   0..00008
                                  0.00000095
                                    1.4E-08
                       Applying spray using airblast (3)
                        Baseline Dermal and Inhalation
                                    0.0063
                                    0.00083
                                    0.0071
                                    9.7E-05
                                    1.5E-06
                                       
                  Single layer w/gloves + Baseline Inhalation
                                    0.0056
                                       
                                    0.0065
                                   0.000089
                                    1.3E-06
                                       
           Single layer w/ gloves +  Head gear + Baseline Inhalation
                                    0.00076
                                       
                                    0.0016
                                   0.000022
                                    3.3E-07
                                       
                             Engineering controls
                                   0.000064
                                       
                                    0.00089
                                   0.000012
                                    1.8E-07
[1]  Dermal and inhalation ADD; See Table 8.1.1.
[2]  Combined ADD (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day).
[3]  LADD (mg/kg/day) = combined ADD x ((30 days/yr (commercial); 10 days/year (private)) / (365 days/yr)) x (35 yrs / 70yrs).
[4]  Cancer Risk = LADD x Q1* (1.49 x 10[-2] mg/kg/day).  
[5]  Bolded values represent cancer risk estimates for scenarios that correspond to label required PPE.   

8.3.2  Post-application Cancer Exposure and Risk Estimates

Based on the proposed use scenario, it is anticipated that individuals employed by multiple establishments (i.e., commercial or migratory farmworkers) could have post-application exposure up to 30 days per year.  Since only a single application is allowed per year and since residues are assumed to dissipate over time, HED used the average DFR value calculated over 30 days (calculated using chemical-specific data) for determination of the daily dose (DD) rather than the 0-day DFR used in the non-cancer post-application assessment.  The resulting DD was then amortized over a 35-year career and a 70-year lifespan for calculation of the LADD.  Estimated spirodiclofen cancer risks for post-application exposure are summarized in Table 8.3.2.1.  The estimated cancer risks on the day of application ranged from 2.8 x 10[-7] to 1.7 x 10[-6].

 Table 8.3.2.1.  Cancer Exposure/Risk Estimates for Spirodiclofen Post-application Workers.
                                      Crop
                                     DAT[1]
                                     DFR[2]
                                   (ug/cm[2])
                        Transfer Coefficient (cm[2]/hr)
                            Daily Dose3 (mg/kg/day)
                                    LADD[4]
                                 Cancer Risk[5]
                                 Tropical Fruit
                                      0-30
                                      0.34
                          580 (Hand pruning, scouting)
                                    0.00045
                                   0.000019
                                    2.8E-07
                                        
                                        
                                        
                              1400 (Hand harvest)
                                    0.0011
                                   0.000045
                                    6.7E-07
                                        
                                        
                                        
                             3600 (Thinning fruit)
                                    0.0028
                                    0.00011
                                    1.7E-06
1.  DAT = 30 day residue average.
2.  DFR value used is based the 30 day average of submitted chemical-specific DFR data.
3.  Daily Dose (mg/kg/day) = DFR (ug/cm2) x 0.001 mg/ug x Tc (cm2/hr) x DA (2%) x ET (8 hr/day)/70 kg.
4.  LADD (mg/kg/day) = DD x [(30 days/yr)/ (365 days/yr)] x (35 yrs/70yrs).
5.  Cancer Risk = LADD x Q1* [1.49 x 10[-2] (mg/kg/day)-1].
 
8.4  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 WPS REI of 12 hours is adequate to protect workers performing thinning and harvesting activities in the proposed crops.  The proposed label is in compliance with the WPS REI.

9.0  Data Needs and Label Requirements

9.1  Toxicology

   * Immunotoxicity study as specified in 40 CFR Part 158.
   * 28-day rat inhalation toxicity study (TXR 0052618, 16-Jun-2004).  

9.2  Residue Chemistry

   * Revised Section B which prohibits the addition of an adjuvant to the spray solution for the proposed crops.  
   * In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 180.608(a)(1) and 180.6(a)(2) be changed as indicated below.  A revised Section F specifying the new tolerance expression, the currently established commodity/tolerance levels, and the following HED-recommended tolerances should be submitted:  lychee - 4.0 ppm; longan - 4.0 ppm; Spanish lime - 4.0 ppm; rambutan - 4.0 ppm; pulasan - 4.0 ppm; sugar apple - 0.40 ppm; atemoya - 0.40 ppm; custard apple - 0.40 ppm; cherimoya - 0.40 ppm; ilama - 0.40 ppm; soursop - 0.40 ppm; biriba - 0.40 ppm; guava - 0.50 ppm; feijoa - 0.50 ppm; jaboticaba - 0.50 ppm; wax jambu - 0.50 ppm; starfruit - 0.50 ppm; passionfruit - 0.50 ppm; acerola - 0.50 ppm; and persimmon - 0.50 ppm..  

            180.608(a)(1):  Tolerances are established for residues of spirodiclofen, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the following tolerance levels is to be determined by measuring only spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate.
            
            180.608(a)(2):  Tolerances are established for residues of spirodiclofen, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the following tolerance levels is to be determined by measuring only spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate) and its metabolite 3-(2,4-dichlorophenyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one, calculated as the stoichiometric equivalent of spirodiclofen.
   
9.3  Occupational and Residential Exposure

   * RD should ensure the correct language for gloves is listed on the label (chemical-resistant versus waterproof).


10.0  Attachments

Attachment 1:  Chemical Names and Structures.
Attachment 2:  Spirodiclofen Toxicity Profile.
Attachment 3:  Toxicology Endpoint Rationale and Summary of Toxicological Doses and Endpoints.




























RDI: RAB1 review (11/2/11); G. Kramer (10/28/11); D. Vogel (11/11/11)
J. Tyler:S10943:PY1:(703)-851-5825(7509P)
Attachment 1:  Chemical Names and Structures.

                                 Chemical Name
                                   Structure
Spirodiclofen; BAJ 2740

3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate
                                       
BAJ 2510; BAJ 2740-enol

3-(2,4-dichlorophenyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one
                                       
BAJ 2740-ketohydroxy

3-(2,4-Dichlorophenyl)-3-hydroxy-1-oxaspiro[4.5]decane-2,4-dione
                                       
BAJ 2740-dihydroxy

3-(2,4-Dichlorophenyl)-3,4-dihydroxy-1-oxaspiro[4.5]decane-2-one
                                       
BAJ 2740-dioxoketone
                                       
2,4-dichloromandelic acid hydroxycyclohexyl ester
                                       
2,4-dichloromandelic acid
                                       
DCB-acid

2,4-dichlorobenzene acetic acid; 2,4-dichlorobenzoic acid
                                       

Attachment 2:  Spirodiclofen Toxicity Profile.

Acute Toxicity for 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
                                       - 

Subchronic, Chronic, and Other Toxicity 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: 0,8.1,47.1,215.3,995.8 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); 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 body-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 (TA1535, TA1537, TA1538, TA100, TA98) +- S9 at concentrations up to 5000 ug/plate.
870.5300
In vitro Mammalian Cell Gene Mutation
45696614
Acceptable/guideline
Negative, tested in Chinese Hamster lung fibroblast V79 cells 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.

Attachment 3:  Toxicology Endpoint Rationale and Summary of Toxicological Doses and Endpoints.

Acute Dietary Endpoint (general population including infants and children):  An acute dietary endpoint was not established for this population group since an appropriate endpoint attributable to a single dose was not identified.  Studies evaluated for this endpoint include the acute neurotoxicity study for which a NOAEL was only established at the highest dose tested (2000 mg/kg bw). 

Acute Dietary Endpoint (females 13-49 years old):  An acute dietary endpoint was not established for this subpopulation group due to developmental effects resulting from a single dose could be identified in the database.  Effects such as incidence of slight dilatation of the renal pelvis observed in the rat developmental toxicity study or effects in memory phase of the water maze test in PND 60 females noted in a developmental neurotoxicity study are most likely reflective of repeated daily exposures. 

Chronic Dietary Endpoint:  This endpoint was based on increased relative adrenal weights in both sexes, increased relative testis weight in males and histopathology findings (cytoplasmic vacuolation) in the adrenal gland of both sexes in a chronic dog study at the LOAEL of 4.7 mg/kg bw/day (NOAEL = 1.38 mg/kg bw/day).  This study provides the lowest NOAEL in the toxicity database for spirodiclofen.  A combined UF of 100 was applied to account for interspecies (10X) and intraspecies (10X) extrapolation.  Thus, the cPAD is estimated as 1.38 divided by 100 or 0.0138 mg/kg bw/day.

Dermal and Inhalation (Short-Term):  The endpoint selected for these exposure scenarios was based on increased adrenal gland weight which coincided with histopathology findings (cytoplasmic vacuoles in the Zona fasciculata of the adrenal glands) at the LOAEL of 8.4 mg/kg bw/day in a subchronic dog study.  Out of three subchronic toxicity studies carried out in dogs, rats, and mice, the LOAEL of 8.4 mg/kg bw/day provides the lowest of POD for effects on the adrenal glands, a hallmark of spirodiclofen toxicity.  A UFD of 3X was applied to account for the use of a LOAEL in the absence of NOAEL (a NOAEL was only observed for males).  In a HIARC 2004 report (HIARC 2004, TXR# 0052618), it was determined that a 3X uncertainty factor would be adequate (for the use of a LOAEL) since the extrapolated NOAEL (8.4/3 = 2.8 mg/kg/day) in the subchronic dog study is comparable to the NOAEL (1.38 or 1.52 mg/kg/day for males or females, respectively) in the chronic dog study.  A 28-day dermal toxicity study performed with spirodiclofen was deemed unacceptable.  However, a 2% dermal-absorption factor estimated from two monkey studies can be used for route-to-route (oral to dermal) extrapolation.  Thus, the equivalent dermal LOAEL is estimated to be 420 mg/kg bw/day.  The same FQPA of 3X would also apply for the use of LOAEL, resulting in a level of concern of 300.  Besides the required acute inhalation toxicity study which resulted in only minimal toxicity (category IV), no other inhalation toxicity study are available for spirodiclofen.  Based on the available toxicity database and the Agency's current practices, the inhalation risk for spirodiclofen is being assessed using the dog chronic toxicity study with a 100% absorption assumption.  A combined UF of 100 was applied to account for interspecies (10X) and intraspecies (10X) extrapolation.  Thus, the level of concern is 100.

The Agency sought expert advice and input on issues related to this route-to-route extrapolation approach (i.e., the use of oral toxicity studies for inhalation risk assessment) from its FIFRA SAP in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhalation risk assessments, including route-to-route extrapolation of toxicity data.  If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for spirodiclofen and/or a re-examination of the inhalation toxicity risk assessment.

Dermal and Inhalation (Intermediate-Term):  This endpoint was based on the same assumptions as the short-term scenario above, except that the chronic dog study with a well established NOAEL was selected.  The effect was based on increased relative adrenal weights in both sexes, increased relative testis weight in males and histopathology findings (cytoplasmic vacuolation) in the adrenal gland of both sexes in a chronic dog study at the LOAEL of 4.7 mg/kg bw/day (NOAEL = 1.38 mg/kg bw/day).  This study provides the lowest NOAEL in the toxicity database for spirodiclofen. A combined UF of 100 was applied to account for interspecies (10X) and intraspecies (10X) extrapolation.  The level of concern is 100.

Cancer:  Spirodiclofen was classified 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.  A Q1* was estimated at 1.49 x 10[-2] (mg/kg bw/day)[-1].
