Spirodiclofen Human-Health Risk Assessment DP#386201

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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); 
Spirodiclofen Human-Health Risk Assessment DP#386201

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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). 
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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
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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®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. 
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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-observedadverse-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-adverseeffect-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.
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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. 
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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 (newuse 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 10-6for commercial 

applicators and at or below 1.3 x 10-6for 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). 
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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 10-7to 1.7 x 10-6for 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 -
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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®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)

PHI1

(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.
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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®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/cm3

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 10-7Pa (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 

O

O

Cl

Cl

O

O H3C

H3C

H3C
Spirodiclofen Human-Health Risk Assessment DP#386201

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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 wholebody 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 dermalabsorption 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 
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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 
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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 twogeneration 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 wellestablished 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 
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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 Longterm (>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 Longterm (>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. 
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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-JUN2005; 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 Fruit1

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-JUN2009; 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-OHenol. 

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. 
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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-Sep2009). 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 
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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 
Spirodiclofen Human-Health Risk Assessment DP#386201

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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]dec3-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]dec3-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 -
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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) %cPAD1

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®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.
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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-
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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 usepatterns 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.
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Table 8.1.1. Occupational Handler Dermal and Inhalation Exposures and Risk Estimates.

Dermal and

Inhalation Unit 

Exposures

(μg/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 MOEs4 Intermediate-term 

MOEs4

Mixer/Loader – Airblast Application

Dermal

Baseline5: 220

Inhalation

Baseline6: 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/ 

gloves2: 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 
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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 shortterm 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 cm2/hr); hand harvesting (1,400 cm2/hr); and thinning fruit (3,600

cm2/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

(cm2/hr)

DFR 

(ug/cm2)

2

Days After 

Treatment

Daily Dose3

(mg/kg/ay) MOE4

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/cm2) x TC (cm2/hr) x 0.001 mg/μg 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 10-6for 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 
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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 Dose1

(mg/kg/day)

Inhalation 

Dose1

(mg/kg/day)

Combined 

ADD2

(mg/kg/day)

LADD3

(mg/kg/day)

Cancer

Risk4

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-075

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 10-7to 

1.7 x 10-6.
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Table 8.3.2.1. Cancer Exposure/Risk Estimates for Spirodiclofen Post-application Workers.

Crop DAT1 DFR2

(ug/cm2)

Transfer Coefficient

(cm2/hr)

Daily Dose3 

(mg/kg/day) LADD4 Cancer Risk5

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 (μg/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
Spirodiclofen Human-Health Risk Assessment DP#386201

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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)
Spirodiclofen Human-Health Risk Assessment DP#386201

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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]decane2-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

O

O

Cl

Cl

O

O H3C

H3C

H3C

Cl

Cl

O

O

O

OH

Cl

Cl

O

O

OH

OH

Cl

Cl

HO

OH

O

Cl O O

O

Cl

Cl

O

HO

Cl

Cl

O

O

OH

Cl

Cl

OH

O

OH O

O
Spirodiclofen Human-Health Risk Assessment DP#386201

Page 28 of 32

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).
Spirodiclofen Human-Health Risk Assessment DP#386201

Page 29 of 32

Subchronic, Chronic, and Other Toxicity for Spirodiclofen.

Guideline No./ 

Study Type/

MRID Nos.

Doses/Classification Results

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 

F1females, and increased severity of adrenal cortical 

vacuolation in F0 and F1females.

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 μg/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 

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.
Spirodiclofen Human-Health Risk Assessment DP#386201

Page 30 of 32

Subchronic, Chronic, and Other Toxicity for Spirodiclofen.

Guideline No./ 

Study Type/

MRID Nos.

Doses/Classification Results

Aberration 

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.
Spirodiclofen Human-Health Risk Assessment DP#386201

Page 31 of 32

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 
Spirodiclofen Human-Health Risk Assessment DP#386201

Page 32 of 32

(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

.