UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 07-JAN-20 15 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLlrrtON PREVENTION 

SUBJECT: Spirodiclofen. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 12487 1 

Decision No.: 494555 

Petition No.: N/A 

Risk Assessment Type: N/ A 

TXRNo.: N/A 

MRID No.: N/A 

DP Barcode: 0422434 

Registration No.: N/A 

Regulatory Action: Registration Review Scoping Document 

Case No.: 7443 

CAS No.: 148477-71 -8 

40 CFR: § 180.608 

/ 

FROM: Kelly Lowe, Environmental Scientist , . ..-,~_,..,_.--

Thomas Bloem, Chern~~~ . 

Monique M. Perron, Sc.D., Toxicologist Jf~ 

Risk Assessment Branch l (RAB 1) 

Health Effects Division (HED, 7509PL_~ 

THROUGH: Charles W. Smith III, Branch Chie~~~~~:f:r--::a--­ George F. Kramer, Ph.D., Senior Chemist 

RABl/HED (7509P) 

TO: Julia Stokes, Chemical Review Manager 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Attached is HED's human health risk assessment scoping document for spirodiclofen to support 

Registration Review. 

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Table of Contents 

Executive Summary ..................................... ................................... : .................... ........................... 3 

1.0 Introduction .... ... ....... .... ........... ........... ........... ............................. ......................... ..................... 4 

2.0 Hazard Characterization/Assessment. ....................................................... .... .... ....................... 4 

3.0 Residue Chemistry ....................................... .... .................................. ........... ... .... .................... 6 

4.0 Dietary Exposure ............................................. ...................... .................... ..... .... ................... .. 7 

5.0 Residential Exposure ..... ................................................ ..... : .. .................................................. 8 

6.0 Aggregate Risk Assessment.. ................... , .. .................................................. ........................... 8 

7.0 Occupational Exposure ................................................. .... ........ ,. ........... ................................... 9 

8.0 Public Health and Pesticide Epidemiology Data ................................................................... 10 

9.0 Tolerance Assessment and International Harmonization .................... ......... ........ .... ............. 10 

10.0 Environmental Justice .................. ........... ........... .................................................................. 10 

11.0 Cumulative ...... ....... ....... ............... ........... ........................................................... .... ......... ..... 10 

12.0 Human Studies ..................... ..................................... ........................................................... 11 

13.0 Risk Assessment Updates and Data Deficiencies ................................................................ 11 

14.0 References .. ........... ....... ........................................................................................................ 12 

Attachment 1: Chemical Identity Tables ........................................ -............................ ................. 14 

Attachment 2: Spirodiclofen Acute, Subchronic, and Chronic Toxicity Profile . ................ ........ 15 

Attachment 3: Summary of Toxicological Doses and Endpoints for Spirodiclofen (from 2009 

Risk Assessment) ......................................................... ................... .............................................. 19 

Attachment 4: Summary of Residues of Concern for Spirodiclofen ........................................... 20 

Attachment 5: Summary of Registered Uses for Spirodiclofen ........... ................. .................. ..... 21 

Attachment 6: Spirodiclofen International Residue Limit Status Sheet. ...................... .......... ..... 22 

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Executive Summary

HED has prepared a scoping document to support Registration Review of the acaricide

spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-

dimethylbutanoate). Spirodiclofen is a tetronic acid acaricide, and acts by interfering with mite 

development. It is active by contact to mite eggs, all nymphal stages, and adult females (adult 

males are not affected).

Spirodiclofen is formulated as a suspension-concentrate (SC) formulation in one end-use product 

[Envidor® 2SC Miticide [2 pounds (lbs) active ingredient (ai)/gallon; EPA Reg. No. 264-831], 

and is currently registered for use on a variety of crops such as citrus, fruit trees, grapes, hops, 

pome fruits, stone fruits, tree nuts, and Christmas tree plantings. 

The most recent human health risk assessments were performed for uses on bushberries and 

tropical fruitsa; however, the petitions for these uses were subsequently withdrawn. The most 

recent human health risk assessment that covers currently registered uses for spirodiclofen was 

performed in 2009, and was for the use of spirodiclofen on tree fruits (Memo, T. Bloem et al., 

06-OCT-2009; D361071).

HED has evaluated the status of the human health assessments for spirodiclofen to determine 

whether sufficient data are available, and whether any updates are needed to support Registration 

Review. HED has considered all available data and human health risk assessments for 

spirodiclofen with respect to its toxicity, exposure, and usage databases, and the most updated 

Agency science policy and risk assessment methodologies to determine the scope of work 

necessary to support Registration Review.

The toxicity database for spirodiclofen is complete as required by the 2007 revised 40 CFR 

Toxicology Data Requirements. No additional toxicological studies are currently required. As 

part of Registration Review, the inhalation endpoint used for spirodiclofen risk assessment will 

be updated to reflect current HED policy.

The residue chemistry database for spirodiclofen is adequate to support current Registration 

Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage 

stability, magnitude of the residue, and processing data are available to support the registered 

uses. Adequate methods are available for enforcement of the currently established tolerances. 

No additional residue chemistry data are required to support the current registrations. 

The dietary-exposure database for spirodiclofen is adequate to support current registration 

requirements. As part of Registration Review, a revised dietary-exposure analysis may be required 

to reflect the most recent dietary-exposure models and potentially revised EDWCs (specifically, 

use of PRZM-GW).

There are no proposed or current registrations for products containing spirodiclofen that allow 

residential use. Therefore, residential handler and post-application exposure assessments will 

not be needed during Registration Review. The need for spray drift and volatilization risk 

assessments for spirodiclofen will be examined during Registration Review.

 

a Memo, J. Tyler et al., 11-NOV-2011, D386201 (Tropical Fruit Risk Assessment); Memo, T. Bloem et al., 28-JUL2010, D371469 (Bushberry Risk Assessment).
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The occupational exposure database is adequate to support the Registration Review process for 

spirodiclofen. The most recent occupational handler and post-application exposure assessments 

are not reflective of maximum application rates or current exposure policies and data, but did not 

identify risks of concern. During Registration Review, updated occupational handler inhalation 

assessments will be conducted to reflect all currently registered uses and maximum application 

rates, using current occupational and residential exposure (ORE) policies and updated inhalation 

toxicological points of departure (PODs). 

1.0 Introduction

Spirodiclofen is a tetronic acid acaricide and acts by interfering with mite development. It is 

active by contact to mite eggs, all nymphal stages, and adult females (adult males are not 

affected). Spirodiclofen is formulated as a SC formulation in one end-use product [Envidor®

2SC Miticide (2 lbs ai/gallon; EPA Reg. No. 264-831)], and is currently registered for use on a 

variety of crops such as citrus, fruit trees, grapes, hops, pome fruits, stone fruits, tree nuts, and 

Christmas tree plantings. The most recent risk assessments were performed for uses on 

bushberries and tropical fruitsb; however, the petitions for these uses were subsequently 

withdrawn. The most recent human health risk assessment that covers currently registered uses 

for spirodiclofen was performed in 2009, and was for the use of spirodiclofen on tree fruits

(Memo, T. Bloem et al., 06-OCT-2009; D361071).

2.0 Hazard Characterization/Assessment

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 with both urine and feces as major 

routes of elimination. 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) and was not detected in 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 up to 48 hours post-dose.

Spirodiclofen is classified as having low acute toxicity via the oral (Toxicity Category III), 

dermal (Toxicity Category III), and inhalation (Toxicity Category IV) routes. It is not an eye or 

dermal irritant and is classified as a dermal sensitizer. 

The effects observed following repeated oral exposures to spirodiclofen have been remarkably 

consistent across different studies and species tested. The primary target organs identified are 

the adrenal glands in both sexes and testes in males. Increased cytoplasmic vacuolation of the 

adrenal cortex has been consistently observed across different subchronic and chronic studies 

with spirodiclofen in both sexes of rats, mice, and dogs. The dog was the most sensitive species 

and, at least in rat and dog studies, females appear to be the more sensitive sex. Effects on the 

adrenal glands generally coincided with increased adrenal weight. Other organs with 

 

b Memo, J. Tyler et al., 11-NOV-2011, D386201 (Tropical Fruit Risk Assessment); Memo, T. Bloem et al., 28-JUL2010, D371469 (Bushberry Risk Assessment).
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histopathology findings reported in male dogs included the testes (vacuolation and 

hypertrophy/activation of Leydig cells, tubular degeneration), epididymis (degeneration and/or 

immaturity of germinal epithelium, oligospermia, and aspermia), prostate (immaturity signs), and 

thymus (atrophy). Increased liver weights were also reported in male dogs along with decreases 

in prostate weights. Other effects reported in chronic studies include decreases in cholesterol 

and triglycerides (rats), decreased body weights (rats), increased alkaline phosphatase levels, 

increased vacuolated jejunum enterocytes (rats), and increased incidence of Leydig cell 

hyperplasia (rats and mice).

There was evidence of increased quantitative susceptibility in the rat developmental toxicity 

study, where an increased incidence of slight dilatation of the renal pelvis was observed in 

fetuses at the limit dose (1000 mg/kg/day) in the absence of maternal toxicity. Concern is low 

since the effect was slight, only seen at the limit dose, occurred without statistical significance, 

and did not display a clear dose response. There were no developmental effects seen in the 

rabbit developmental toxicity study while maternal toxicity was evidenced as body weight 

decrements. In the two-generation reproduction toxicity study, offspring effects (body weight 

decrements) occurred in the presence of parental effects. Additional effects observed at higher 

doses included delayed sexual maturation, increased severity of ovarian luteal cell 

vacuolation/degeneration, decreased testicular spermatid and epididymal sperm counts, and 

atrophy of the testes, epididymides, prostate, and seminal vesicles.

Spirodiclofen is not considered to be a neurotoxic compound based on acute, subchronic, and 

developmental neurotoxicity studies. 

In a dermal toxicity study, spirodiclofen did not exhibit toxicity up to the limit dose (1000 

mg/kg/day). A dermal absorption factor of 2% was previously estimated based on the results of 

two dermal absorption studies in monkeys.

In a recently submitted immunotoxicity study in mice (MRID 49072601), there was no evidence 

of immunotoxicity up the highest dose tested (1216 mg/kg/day). 

The 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 adenocarcinoma in female rats, and liver tumors in mice. There 

is no evidence of genotoxicity from spirodiclofen.

The toxicology database for spirodiclofen is complete except for a subchronic inhalation study 

that is required in accordance with the current 40 CFR Part 158 Toxicology Data Requirements; 

however the Hazard and Science Policy Council (HASPOC) concluded based on a weight-ofevidence approach that the study is not required at this time (K. Rury; 03-MAR-2014; TXR 

#0056904). Therefore, the database is considered complete to support existing registrations and 

Registration Review.

The endpoints from the most recent human health risk assessment for spirodiclofen (Memo, T. 

Bloem et al., 06-OCT-2009; D361071) can be found in Attachment 3. Since the last risk 

assessment, the study classification of the 28-day dermal toxicity study has been updated from 

unacceptable to acceptable/non-guideline (Memo, M. Perron; 07-OCT-2014; D423215). As a 

result, a quantitative dermal assessment is no longer required for spirodiclofen assessments since

no effects were seen in the dermal toxicity study up to the limit dose, and although increased 

quantitative susceptibility was seen in the rat developmental toxicity study, the developmental 
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effect was slight and only seen at the limit dose. An endpoint for a long-term inhalation scenario 

also would not be needed because long-term exposures are not expected based on the use pattern 

for spirodiclofen. Consequently, selection of one endpoint to assess short- and intermediate-term 

inhalation scenarios would be appropriate.

Conclusions: The toxicity database for spirodiclofen is complete as required by the 2007 revised 

40 CFR Toxicology Data Requirements. No additional toxicological studies are currently 

required. As part of Registration Review, the inhalation endpoint used for spirodiclofen risk 

assessment will be updated to reflect current HED policy. This change is not expected to 

significantly alter the risk conclusions for spirodiclofen, but will significantly simplify the 

assessment.

3.0 Residue Chemistry

Spirodiclofen (Envidor 2SC Miticide; EPA Reg. No. 264-831) is currently registered for foliar 

applications to the following food/feed crops: avocado, black sapote, canistel, grape, hops, mamey 

sapote, mango, papaya, pistachio, sapodilla, star apple, citrus fruit group 10, pome fruit group 11, 

stone fruit group 12, and tree nut group 14. The following paragraphs are a summary of the 

residue chemistry database. 

Application Scenarios for Food/Feed Crops: Envidor 2SC Miticide (EPA Reg. No. 264-831; 2 lb 

ai/gallon) is the only currently registered spirodiclofen end-use product. The current label permits 

foliar applications to the registered crops at rates of 0.31-0.53 lb ai/acre/season and indicates that 

thorough coverage of plant parts is required for pest control (pre-harvest interval (PHI) = 2-14 

days). The current labeled instructions are as reviewed/recommended by HED. 

Nature/Magnitude of the Residue - Crops: Based on the results of (1) the citrus, grape, and apple 

metabolism studies (Memo, M Clock-Rust et al., 22-JUN-2005, D285047), (2) the apple, grape, 

and orange processing studies (Memo, T. Bloem, 22-JUN-2005, D341847; Memo, T. Bloem, 24-

JUN-2009, D359773; and Memo, T. Bloem, 20-JUN-2011, D390192), and (3) conclusions relating 

to the residues in hops (Memo, M. Sahafeyan, 3-JAN-2008, D346710), HED concluded that the 

residues of concern in the currently-registered crops are either parent or parent + BAJ2510 (see 

Attachment 4). HED notes that BAJ2510 is only a residue of concern in the processed 

commodities of grape, citrus fruit, stone fruit, berry (CG 13), and tropical fruit. No additional crop 

metabolism data are required to support the registered crops. 

Adequate field trial data have been submitted to support the current registrations with the currently 

established tolerances, excluding almond hull, as recommended by HED; the almond hull 

tolerance should be adjusted from 20.0 ppm to 20 ppm. No additional magnitude of the residue 

data or supporting data are required to support the registered uses. 

Nature/Magnitude of the Residue - Poultry: The petitioner has not submitted information 

concerning the nature/magnitude of the residue in poultry, and these data are not required as none 

of the registered crops are significant poultry feed commodities (Table 1: Feedstuff (June-2008)). 

Nature/Magnitude of the Residue - Ruminants: Based on adequate goat metabolism and cattle 

feeding studies, HED concluded that the residues of concern in ruminants, for purposes of 

tolerance enforcement and risk assessment, are spirodiclofen and BAJ 2510 (see Attachment 4; 

Memo, M Clock-Rust et al., 22-JUN-2005, D285047). No additional ruminant metabolism data 

are required to support the registered uses. 
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The currently established cattle, goat, horse, sheep, and milk tolerances, excluding the meat 

byproduct tolerances, are as recommended by HED, and are based on an adequate cattle feeding 

study and the cattle maximum theoretical dietary burden (MTDB); the meat byproduct tolerance 

should be adjusted from 0.1 ppm to 0.10 ppm. No additional magnitude of the residue data are 

required to support the registered uses. Tolerances in/on hog are not required as none of the 

registered crops are significant hog feed commodities (Table 1: Feedstuff (June-2008)). 

Analytical Enforcement Methods: HED determined that the Bayer analytical method 109351 is 

appropriate for enforcement of the currently established tolerances. This method has been 

forwarded to the Food and Drug Administration (FDA) for inclusion in the Pesticide Analytical 

Manual (PAM; Memo, T. Bloem, 23-SEP-2009, D368434). 

Conclusions: The residue chemistry database for spirodiclofen is adequate to support current 

Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational 

crops), storage stability, magnitude of the residue, and processing data are available to support 

the registered uses. Adequate methods are available for enforcement of the currently established 

tolerances. No additional residue chemistry data are required to support the current registrations. 

HED notes that the currently established almond hull tolerance should be altered from 20.0 ppm 

to 20 ppm and the currently established meat byproduct (cattle, goat, horse, sheep) tolerance 

should be altered from 0.1 ppm to 0.10 ppm. 

4.0 Dietary Exposure

The most recent dietary-exposure analysis was conducted in 2009 and used the Dietary Exposure 

Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 2.03) which 

incorporated consumption data from United States Department of Agriculture (USDA) 

Continuing Survey of Food Intake by Individuals (CSFII; 1994-1996 and 1998; D363344, T. 

Bloem, 23-SEP-2009).

An acute dietary risk assessment was not conducted as an endpoint attributable to a single dose 

was not identified. The chronic and cancer analyses were refined using field trial data, 

experimentally determined processing factors, percent crop treated estimates, and new use 

percent crop treated estimates (hop, pome fruit, stone fruit, grape, and citrus). The resulting 

chronic risk estimates (food and water) were ≤3.3% the cPAD and are not of concern to HED 

(infants <1 year 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 (40%; assumes 100% transfer of residues from 

hops to beer; spirodiclofen Log KOW = 5.83), water (19%; 87% of the basin cropped and 100% 

crop treated), and orange (17%; default processing factors were assumed). It is noted that the 

petitioner has subsequently submitted an adequate orange processing study, which will allow for 

refinement of the orange residue estimates (D285249, T. Bloem, 18-APR-2005; D390192, T. 

Bloem, 20-JUN-2011).

HED notes that the 2009 chronic and cancer dietary assessments did not incorporate ground 

water estimated drinking water concentrations (EDWCs) modeled using the Pesticide Root Zone 

Model for GroundWater (PRZM-GW). The impacts of using this model to estimate ground 

water concentrations of spirodiclofen will need to be considered during Registration Review. 
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Conclusions: The dietary-exposure database is adequate to support current registration 

requirements. As part of Registration Review, a revised dietary exposure analysis may be required 

to reflect the most recent dietary-exposure models and potentially revised EDWCs (specifically, 

use of PRZM-GW).

5.0 Residential Exposure

There are no registered or proposed spirodiclofen products that allow residential use; therefore, a 

quantitative residential exposure assessment was not conducted.

Spray Drift and Volatilization: Residential bystander exposures resulting from off-site transport 

(e.g., spray drift or volatilization) may occur as a result of applications of spirodiclofen. The 

potential for spray drift will be quantitatively evaluated for each pesticide during the Registration 

Review process that ensures that all uses for that pesticide will be considered concurrently. The 

approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk 

Assessment (SOPs) – Residential Exposure Assessment Standard Operating Procedures Addenda 

1: Consideration of Spray Drift. This document outlines the quantification of indirect nonoccupational exposure to drift. In terms of volatilization, the agency has developed a 

Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analyses are required for specific chemicals.

Conclusions: There are no proposed or current registrations for products containing 

spirodiclofen that allow residential use. Therefore, residential handler and post-application 

exposure assessments will not be needed during Registration Review. The need for spray drift 

and volatilization risk assessment for spirodiclofen will be examined during Registration 

Review.

6.0 Aggregate Risk Assessment

The most recent aggregate risk assessment for currently registered uses of spirodiclofen was 

performed in conjunction with the 2009 HED human health risk assessment (Memo, T. Bloem et 

al., 6-OCT-2009; D361071). The Agency conducts aggregate exposure assessments by 

summing dietary (food and water) and residential exposures (residential or other nonoccupational exposures). Since there are no registered/proposed uses of spirodiclofen that result 

in residential exposure, the chronic and cancer aggregate risk assessments are equal to the 

chronic and cancer dietary estimates (food and water only), respectively. Short-, intermediate-, 

and long-term aggregate-risk assessments were not performed because there are no registered or 

proposed uses of spirodiclofen that result in residential exposures. 

Conclusions: A new aggregate risk assessment may be required to reflect potentially revised

EDWCs. 
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7.0 Occupational Exposure

Spirodiclofen is registered for use on a variety of crops such as citrus, fruit trees, grapes, hops, 

pome fruits, stone fruits, tree nuts, and Christmas tree plantings. Attachment 4 provides a 

summary of the occupational use pattern. One end-use product, a SC formulation, is registered 

that allows for application rates ranging from 0.28-0.53 lb ai/A depending on the crop and 

applications can be made using aerial (for only certain crops) and airblast equipment. 

Based on the registered use patterns, there is a potential for dermal and inhalation exposure to 

spirodiclofen in occupational scenarios from handling spirodiclofen products during the 

application process (i.e., mixer/loaders, applicators, and mixer/loader/applicators). In addition, 

there is a potential for post-application worker exposure from entering into areas previously 

treated with spirodiclofen. HED notes that based on the updated classification of the 28-day 

dermal study (Memo, M. Perron; 07-OCT-2014; D423215), a quantitative dermal assessment 

will no longer be required for spirodiclofen.

Occupational Handlers: In the 2009 risk assessment for spirodiclofen, an occupational handler 

assessment was conducted for aerial and airblast applications at an application rate of 0.31 lb 

ai/A. There were no non-cancer risk estimates of concern (i.e., all combined MOEs ≥ 300) 

provided the PPE recommended on the label (i.e., gloves) was worn. Cancer risk estimates were 

at or below 5.6 x 10-5for commercial applicators, and at or below 1.9 x 10-5for private farmers 

at baseline or with required personal-protection equipment (PPE) (gloves). 

The 2009 risk assessment does not reflect the most up-to-date exposure data or inputs for 

occupational handlers, nor do they reflect the maximum application rates registered for this 

chemical. Although a quantitative dermal assessment is no longer required for spirodiclofen, 

during Registration Review, updated occupational handler inhalation assessments may be 

conducted to reflect the maximum application rates registered for spirodiclofen using current 

ORE policies and updated toxicological inhalation PODs.

Occupational Post Application: A dislodgeable foliar residue (DFR) study is available for 

spirodiclofen. The study was submitted by Bayer Corporation, and examined the dissipation of 

residues on citrus and apple trees following application of spirodiclofen (ENVIDOR® 2SC 

Miticide). The study was reviewed by HED, and deemed acceptable for use in occupational 

post-application risk assessments (Memo, M. Dow, 29-JUN-2004, D285247, MRID 456973-13). 

These data have been used in previous assessments to assess some (but not all) of the registered 

crops for spirodiclofen. 

In the 2009 risk assessment for spirodiclofen, an occupational post-application assessment was 

conducted at an application rate of 0.31 lb ai/A, and represents activities with transfer 

coefficients as high as 3,000 cm2/hr (for thinning fruit). Short-term risk estimates were not of 

concern (i.e., MOEs ≥300) on the day of treatment (i.e., Day 0) for all post-application exposure 

activities. In addition, the estimated post-application cancer risk estimates are below or equal to 

1 x 10-6. 

The most recent occupational post-application exposure assessment is not reflective of current 

exposure policies and data, nor does it cover the highest application rate for some crops and the 

highest post-application activities. However, since a quantitative dermal assessment is no longer 

required for spirodiclofen, an updated occupational dermal post-application assessment is not 

required during Registration Review.
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Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for spirodiclofen at this time. 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.

Conclusions: The occupational exposure database is adequate to support the Registration 

Review process for spirodiclofen. The most recent occupational handler and post-application 

exposure assessments are not reflective of current exposure policies and data, but did not identify 

risks of concern. During Registration Review, updated occupational handler inhalation 

assessments may be conducted to reflect all currently registered uses and maximum application 

rates, current ORE policies and/or updated toxicological inhalation PODs. 

8.0 Public Health and Pesticide Epidemiology Data

The Agency has reviewed the available incident data for spirodiclofen (Memo, S. Recore and E. 

Evans, D422435, 23-OCT-2014) and concludes that based on the low frequency and low severity

of cases involving spirodiclofen reported in both the Incident Data System (IDS) and Sentinel 

Event Notification System for Occupational Risk (SENSOR)-Pesticides, there does not appear to 

be a concern at this time that would warrant further investigation. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment.

9.0 Tolerance Assessment and International Harmonization

U.S. tolerances and Canadian, Mexican, and Codex maximum residue limits (MRLs) are 

summarized in Attachment 5. The U.S., Canadian, and Codex residue definitions are identical 

except for the Codex definition for livestock, which does not include the BAJ 2510 metabolite. 

U.S. tolerance values are harmonized with the Canadian and/or Codex MRLs in many instances 

but not all. Decisions concerning harmonization of the U.S. tolerance values with either the 

Canadian and/or Codex MRLs will be made as part of Registration Review. 

10.0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

most recent spirodiclofen human-health risk assessment, in accordance with U.S. Executive 

Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and 

Low-Income Populationsc.” The OPP typically considers the highest potential exposures from 

the legal use of a pesticide when conducting human health risk assessments, including, but not 

limited to, people who obtain drinking water from sources near agricultural areas, the variability 

of diets within the U.S., and people who may be exposed when harvesting crops. Should these 

highest exposures indicate potential risks of concern, OPP further refines the risk assessments to 

ensure that the risk estimates are based on the best available information.

11.0 Cumulative

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 

 

c http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf
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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/.

12.0 Human Studies

Past spirodiclofen risk assessments rely 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 

Agricultural Handler Exposure Task Force (AHETF) Database, and the Agricultural Reentry 

Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies.

13.0 Risk Assessment Updates and Data Deficiencies

No data deficiencies were identified for spirodiclofen. EPA notes the following risk assessment 

updates will need to be completed during Registration Review:

o Toxicology: 

o The inhalation endpoint used for spirodiclofen risk assessment will be updated to 

reflect current HED policy.

o Residue Chemistry/Dietary Exposure: 

o The almond hull tolerance should be adjusted from 20.0 ppm to 20 ppm and the 

meat byproduct tolerances (cattle goat, horse, and sheep) should be adjusted from 

0.1 ppm to 0.10 ppm. 

o A revised dietary-exposure analysis may be required to reflect the most recent 

dietary-exposure models and potential revised EDWCs (specifically, use of 

PRZM-GW)

o Occupational/Residential Exposure: 

o Updated occupational handler inhalation assessments may be conducted to reflect 

all currently registered uses and maximum application rates, current ORE policies 

and/or updated inhalation toxicological PODs.

o The need for spray drift and volatilization risk assessments for spirodiclofen will 

be examined during Registration Review.
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14.0 References

Memoranda Relevant to Registration Review.

Author Barcode Date Title

Mary Clock-Rust

et al.

D285047 June 22, 2005 Spirodiclofen. Human Health Risk Assessment for Use on Citrus

Fruit, Grape, Pome Fruit, Stone Fruit, and Tree Nut Crops.

Mary Clock-Rust

et al.

D339672 April 1, 2008 Human-Health Risk Assessment for Spirodiclofen for Use on Hops.

Thomas Bloem

et al.

D361071 October 6, 2009 Spirodiclofen. Human-Health Risk Assessment Associated with the 

Section 3 Registration for Application to Avocado, Black Sapote, 

Canistel, Mamey Sapote, Mango, Papaya, Sapodilla, and Star 

Apple.

Thomas Bloem

et al.

D371469 July 28, 2010 Spirodiclofen. Human-Health Risk Assessment Associated with the 

Section 3 Registration for Application to the Bushberry Subgroup 

13-07B.

Jennifer-R Tyler

et al.

D386201 November 11, 

2011

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.

Thomas Bloem D406962 November 20, 

2012

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone Fruit, 

and Tree Nut Crops. Amended Human-Health Risk Assessment.

Mark I. Dow D285247 June 29, 2004 Review of "Determination of Dislodgeable Foliar Residue in Citrus 

and Apple Treated with Envidor 2SC Miticide.

Mark I. Dow D307979 September 16, 

2004

SPIRODICLOFEN - Exposure/Risk Assessment for the Proposed 

Use of Spirodiclofen on Citrus, Grape, Pome Fruit, Stone Fruit and 

Tree Nuts.

Mark I. Dow D315793 April 20, 2005 AMENDMENT TO: SPIRODICLOFEN - Exposure/Risk 

Assessment for the Proposed Use of Spirodiclofen on Citrus, 

Grape, Pome Fruit, Stone Fruit, and Tree Nuts (DP Code 307979, 

Dated 16 September 2004).

Mark I. Dow D337174 April 2, 2007 SPIRODICLOFEN - Review of "Occupational Exposure & Risk 

Assessment for Mixer/Loader-Applicators and Reentry Workers 

During Use of ENVIDOR on Christmas Trees."

Mark I. Dow D346747 December 12, 

2007

SPIRODICLOFEN - Occupational Exposure/Risk Assessment for 

the Use of Spirodiclofen on Hops.

Mark I. Dow D358809 January 7, 2009 SPIRODICLOFEN - Exposure/Risk Assessment for the Uses of 

Spirodiclofen on Grapes and Christmas Trees.

Lata 

Venkateshwara

D363346 September 23, 

2009

Spirodiclofen: Occupational and Residential Exposure/Risk 

Assessment for the Tropical Fruit Subgroup

Lata 

Venkateshwara

D371645 August 5, 2010 Spirodiclofen: Occupational and Residential Exposure/Risk 

Assessment for the Bushberry Subgroup

Lata 

Venkateshwara

D387337 November 10, 

2011

Spirodiclofen: Occupational and Residential Exposure/Risk 

Assessment for 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

T. Bloem D285249 18-Apr-2005

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Summary of Analytical 

Chemistry and Residue Data.

T. Bloem D324834 2-Feb-2006

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Review of Amendment Dated 6-

December-2005 Submitted in Response to Residue 

Chemistry Deficiencies Identified in D285249 (T. Bloem, 

18-Apr-2005).

T. Bloem D341847 25-Oct-2007

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Review of Amendment Dated 6-

December-2005 Submitted in Response to Residue 

Chemistry Deficiencies Identified in D324834 (T. Bloem, 2-

Feb-2006).

M. Sahafeyen D346760 9-Jan-2008 Spirodiclofen. Petition for Registration for Use on Hops. 

Summary of Analytical Chemistry and Residue Data. 
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Memoranda Relevant to Registration Review.

Author Barcode Date Title

T. Bloem D359773 24-Jun-2009

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Review of Amendment Dated 12-

November-2008 Submitted in Response to Residue 

Chemistry Deficiencies Identified in D341847 (T. Bloem, 

25-Oct-2007).

T. Bloem D363343 23-Sep-2009

Spirodiclofen in/on Avocado, Black Sapote, Canistel, 

Mamey Sapote, Mango, Papaya, Sapodilla, and Star Apple. 

Summary of Analytical Chemistry and Residue Data.

T. Bloem D368434 23-Sep-2009 Enforcement Methods Forwarded to FDA.

T. Bloem D371643 28-Jul-2010 Spirodiclofen in/on the Bushberry Subgroup 13-07B. 

Summary of Analytical Chemistry and Residue Data.

T. Bloem D390192 20-Jun-2011

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Review of Amendment Dated 5-

May-2011 Submitted in Response to Residue Chemistry 

Deficiencies Identified in D359773 (T. Bloem, 24-Jun2009).

T. Bloem D387339 10-Oct-2011

Spirodiclofen 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. Summary of Analytical Chemistry and Residue 

Data.

T. Bloem D387338 15-Oct-2011

Spirodiclofen. Dietary Risk Assessment in Support of the 

Requested use 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.

T. Bloem D396737 15-Dec-2011 Spirodiclofen. Bushberry Subgroup 13-07B; changes to the 

HED-Recommended Tolerance.

T. Bloem D400006 5-Jun-2012

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Review of Amendment Dated 17-

January-2012 Submitted in Response to Residue Chemistry 

Deficiencies Identified in D390192 (T. Bloem, 20-Jun2011).

T. Bloem D411178 22-May-2013

Spirodiclofen in/on Citrus Fruit, Grape, Pome Fruit, Stone 

Fruit, and Tree Nut Crops. Review of Amendment Dated 14-

January-2013 Submitted in Response to Residue Chemistry 

Deficiencies Identified in D40006 (T. Bloem, 5-Jun-2012).

Attachments: 

Attachment 1: Chemical Identity Tables.

Attachment 2: Spirodiclofen Acute, Subchronic, and Chronic Toxicity Profile.

Attachment 3: Summary of Toxicological Doses and Endpoints for Spirodiclofen.

Attachment 4: Summary of Residues of Concern for Spirodiclofen.

Attachment 5: Summary of Registered Uses for Spirodiclofen.

Attachment 6: Spirodiclofen International Residue Limit Status Sheet.

cc: K. Lowe (RAB1)

RDI: RAB1 (11/19/14)

K. Lowe:S10948:PY-S:(703)347-8989:7509P:RAB1
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Attachment 1: Chemical Identity Tables.

Table A.1.1. Spirodiclofen 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® 2SC Miticide; EPA Reg. No. 264-831)

Table A.1.2. 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 10-7 Pa (2.25 x 10-9 mm Hg)

Dissociation constant, pKa

Not determinable due to the instability in 

aqueous solutions at >pH 4

Log(KOW) at pH 4 and 20oC 5.83

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

>350 nm

O

O

Cl

Cl

O

O H3C

H3C

H3C
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Attachment 2: Spirodiclofen Acute, Subchronic, and Chronic Toxicity Profile.

Table A.2.1. 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 –

Table A.2.2. Subchronic, Chronic, and Other Toxicity for Spirodiclofen.

Guideline No./ Study 

Type

MRID Nos. (year)

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 = 234

mg/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

Acceptable/Non-guideline

NOAEL = 1000 mg/kg/day (HDT).

LOAEL = not established.

870.3700a

Prenatal 

Developmental 

- Rat 

45696906 (2000)

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

Acceptable/Guideline

Maternal: 

NOAEL =1000 mg/kg/day (HDT).

LOAEL = not established.

Developmental: 

NOAEL = 300 mg/kg/day.

LOAEL = 1000 mg/kg/day based on an increased 

incidence of slight dilatation of the renal pelvis.
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Table A.2.2. Subchronic, Chronic, and Other Toxicity for Spirodiclofen.

Guideline No./ Study 

Type

MRID Nos. (year)

Doses/Classification Results

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).

LOAEL = not established.

870.3800

Reproduction and 

Fertility Effects

- Rat

45696802,45696709 (2000)

(0,70,350,1750 ppm)

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

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

Acceptable/guideline

Parental/system:

For males: NOAEL = 5.2-6.4 mg/kg/day, LOAEL = 26.2-

30.2 mg/kg/day based on decreased body weight in F0

males; decreased absolute and relative liver weight in F0

males; decreased cholesterol and triglycerides in F1 males; 

and increased severity of adrenal cortical vacuolation in F1

males. For females: NOAEL = 5.5-7.0 mg/kg/day, 

LOAEL = 27.6-34.4 mg/kg/day based on decreased 

unesterified fatty acids in F1 females, and increased 

severity of adrenal cortical vacuolation in F0 and F1

females.

Reproductive:

For males: NOAEL = 26.2-30.2 mg/kg/day, LOAEL = 

134.8-177.6 mg/kg/day based on delayed sexual 

maturation; decreased testicular spermatid and epididymal 

sperm counts (oligospermia); and atrophy of the testes, 

epididymides, prostate and seminal vesicles. For females: 

NOAEL = 27.6-34.4 mg/kg/day, LOAEL = 139.2-192.7 

mg/kg/day based on increased severity of ovarian luteal 

cell vacuolation/degeneration.

Offspring:

NOAEL = 5.2-6.4 (M)/5.5-7.0 (F) mg/kg/day, LOAEL = 

26.2-30.2 (M)/ 27.6-34.4(F) mg/kg/day based on 

decreased body weight and body-weight gain in F1 male 

and female pups. 

870.4100b

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.

870.4300

Combined Chronic/ 

Carcinogenicity 

-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

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 
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Table A.2.2. Subchronic, Chronic, and Other Toxicity for Spirodiclofen.

Guideline No./ Study 

Type

MRID Nos. (year)

Doses/Classification Results

Acceptable/guideline 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.

870.5100

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 

Aberration 

45696615 (1996)

Acceptable/guideline

Negative, tested in Chinese hamster lung (V79) cells at 

concentrations 5-80 ug/mL or 0.75-12 ug/mL -S9 or 10-

160 ug/mL +S9.

870.5395

In vivo Mouse Bone 

Morrow 

Micronucleus

45696701 (1996)

Acceptable/guideline

Negative, tested at a dose 800 mg/kg (MTD). Clinical 

signs and cytotoxicity were seen at 800 mg/kg.

870.6200

Acute Neurotoxicity

- Rat

45696725 (2000)

0, 200, 500 ,2000 mg/kg

Acceptable/guideline

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

870.6200

Subchronic 

Neurotoxicity

- Rat 

45696726 (2001)

(0,100,1000,12500 ppm)

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

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

Acceptable/guideline

NOAEL = 70.3(M)/87.3(F) mg/kg/day. LOAEL = 

1088.8(M)/ 1306.5(F) mg/kg/day based on decreased 

body weights, food consumption, and increased urine 

staining in both sexes and decreased motor and locomotor 

activity (week 4) in females only.

870.6300

Developmental 

Neurotoxicity

46324901 (2004)

(0, 70, 350, or 1500 ppm)

0/0, 6.5/14.0, 32.1/69.7, or 135.9/273.8 

mg/kg/day (gestation/lactation)

The study classification is reserved for the 

guideline requirement pending receipt of 

additional morphometric measurements for 

the low- and mid-dose groups.

Maternal NOAEL = 135.9/273.8 mg/kg/day.

LOAEL = Not established.

Offspring NOAEL = Not established.

LOAEL = 6.5/14.0 mg/kg/day based on effects in memory 

phase of the water maze test in PND 60 females.

870.6300

Developmental 

Neurotoxicity

47166501 (2007)

(0, 70, 350, or 1500 ppm)

0/0, 5.4/13.0, 28.6/65.7, and 119.2/262.1 

mg/kg/day (gestation/lactation)

Maternal NOAEL = 119.2/262.1 mg/kg/day.

LOAEL= Not established.

Offspring NOAEL = 119.2/262.1 mg/kg/day.

LOAEL = Not established.

870.7485

Metabolism and 

pharmacokinetics

45696509 (2000)

Acceptable/Non-guideline

Dosed radioactivity was readily absorbed and excreted, 

with 53.1-58.2% of the dose being recovered in the urine 

by 24 hours post-dose. Concentrations of radioactivity 

were highest in the small intestines at 1-hour post-dose, 

followed by liver and renal cortex. Concentrations in all 

other tissues (except fat and dental root) were below the 

concentration in blood. By 4 hours post-dose, the 
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Table A.2.2. Subchronic, Chronic, and Other Toxicity for Spirodiclofen.

Guideline No./ Study 

Type

MRID Nos. (year)

Doses/Classification Results

concentrations declined in the small intestines but 

increased in all other tissues. Radioactivity in the small 

intestines continued to decline at 8 hours post-dose, while 

radioactivity peaked in the bladder and liver (5.460-6.463 

μg equiv./g). Radioactivity also continued to remain high 

in fat, renal cortex, and dental root. Concentrations in 

most tissues had declined by 6- to 10-fold by 24 hours 

post-dose. By the 48-hour interval, concentrations were 

<LOD in all tissues except liver and renal cortex. 

870.7485

Metabolism and 

pharmacokinetics

45696511 (2000)

2 or 100 mg/kg single dose or 14-day 

repeated dose of 2 mg/kg

Acceptable/Guideline

Absorption was rapid with Tmax values of 3-4 hours at 

low dose and 8 hours for the high dose. Urine and feces 

were both major routes of elimination. Tissue burdens 

were negligible. Approximately 11% of the administered 

dose appeared in the bile as biotransformation products. 

Female rats tended to exhibit greater absorption and 

urinary excretion than males. Metabolism was extensive 

with parent compound only detected in small qunatitities 

in feces.

870.7485

Metabolism and 

pharmacokinetics

45696512 (2000)

15-week dietary pretreatment of 50 or 2500 

ppm followed by single dose of 2 mg/kg

Acceptable/Non-guideline

Urine was a major route of excretion (56-75% of 

administered dose after 48 hours). Elimination via the 

feces accounted for 22-31% over the same period. No 

indication of bioaccumulation. Parent was extensively 

metabolized with no parent compound detected in the 

urine. In feces, parent accounted for 0.38-13.5% of the 

administered dose. The dietary pretreatment did not affect 

metabolism and disposition in the animal. 

870.7600

Dermal penetration -

Monkey

45697311 (2002)

6.46 μg/cm2

Acceptable/Non-guideline

Total absorbed dose (determined as sum of radioactivity 

in excreta, cage debris, cage wash/wipes, chair wipe, and 

urine pan wash/wipe) was 2.12±0.94% of administered 

dose.

870.7600

Dermal penetration -

Monkey

45697312 (2002)

51.6 μCi

Acceptable/Non-guideline

Total absorbed dose (determined as sum of radioactivity 

in excreta, cage debris, cage wash/wipes, chair wipe, and 

urine pan wash/wipe) was 1.77% of administered dose.

870.7800

Immunotoxicity

49072601 (2013)

(0, 500, 1500, 5500 ppm)

0, 108, 334, 1216 mg/kg/day

Acceptable/guideline

NOAEL = 1216 mg/kg/day.

LOAEL = not established.
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Attachment 3: Summary of Toxicological Doses and Endpoints for Spirodiclofen (from 

2009 Risk Assessment).

Table A.3.1. Summary of Toxicology Endpoints for Spirodiclofen in Dietary, Non-Occupational, and Occupational Risk 

Assessment.

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. Assessment not necessary.

Chronic Dietary

(All populations)

NOAEL = 1.38 mg/kg/day

UF = 100

cRfD = 0.014 mg/kg/day

FQPA SF = 1X

cPAD = cRfD ÷ FQPA SF 

= 0.014 mg/kg/day

Chronic Oral Toxicity Study in Dogs; LOAEL= 4.7 mg/kg/day 

based on increased relative adrenal weights in both sexes, 

increased relative testis weight in males and histopathology 

findings in the adrenal gland of both sexes.

Short-term Incidental 

Oral, Dermal and 

Inhalation

(1-30 Days)

LOAEL = 8.4 mg/kg/day

dermal-absorption rate= 2%

FQPA SF = 3X

Residential/Occupational 

LOC for MOE <300

Subchronic Oral Toxicity Study in Dogs; LOAEL= 8.4 

mg/kg/day based on increased adrenal gland weight (two out 

of four animals) which corroborated with histopathology 

findings (cytoplasmic vacuoles in the Zona fasciculata of the 

adrenal glands) in females; a NOAEL for females was not 

established. 

Intermediate-term 

Incidental Oral, 

Dermal, and 

Inhalation

(1-6 Months)

NOAEL = 1.38 mg/kg/day

dermal-absorption rate = 2%

FQPA SF = 1X

Residential/Occupational 

LOC for MOE <100

Chronic Oral Toxicity Study in Dogs; See above under 

Chronic Dietary.

Long-term Dermal 

and Inhalation (>6 

Months)

NOAEL = 1.38 mg/kg/day

dermal-absorption rate = 2%

FQPA SF = 1X

Residential/Occupational 

LOC for MOE <100

Chronic Oral Toxicity Study in Dogs; See above under 

Chronic Dietary.

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. RfD = reference dose. LOC = level of concern. MOE = margin of exposure = NOAEL ÷ exposure. 
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Attachment 4: Summary of Residues of Concern for Spirodiclofen. 

Table A.4.1: 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.
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Attachment 5: Summary of Registered Uses for Spirodiclofen.

Table A.5.1. Summary of Registered Uses for Spirodiclofen

Use site/Crop Application 

Equipment

Maximum 

Application 

Rate (lb ai/A)

Max rate per 

crop season 

(lb ai/A)

Max # 

apps/crop 

season

PHI 

(days) REI

Citrus

Oranges, Grapefruit, Lemons, 

Limes, Calamondin, Citrus 

(citron), Chironja, Tangelos, 

Tangor, Kumquat, Mandarin, 

Tangerines, Pummelo, Satsuma 

Mandarin

Airblast 0.33 0.33 1 7

12 hours

Grapes Airblast 0.53 0.53 1 14

Hops Airblast 0.386 0.386 1 14

Pome 

Fruits

Apples, Crabapples, Loquat, 

Mayhaw, Pears, Oriental Pear, 

Quince

Airblast 0.28 0.28 1 7

Stone 

Fruits

Apricots, Cherries (sweet and 

tart), Nectarines, Peach, Plum, 

Prunes

Airblast 0.28 0.28 1 7

Tree 

fruits

Avocado, Black Sapote, 

Canistel, Mamey Sapote, 

Mangos, Papayas, Sapodilla, 

Star Apple 

Aerial 

(avocado 

only), 

Airblast

0.31 0.31 1 2

Tree 

Nuts

Almonds, Beechnut, Brazil Nut, 

Butternut, Cashews, Chestnuts, 

Chinquapin, Filberts, Hickory 

Nuts, Macadamia Nuts, Pecans, 

Pistachio Nuts, Walnut (black 

and English)

Airblast 0.53 0.53 1 7

Christmas Tree Plantings Aerial and 

Airblast 0.386 0.386 1 NA
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Attachment 6: Spirodiclofen International Residue Limit Status Sheet.

Table A.6.1. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition

US Canada Mexico1 Codex

40 CFR §180.608

Plants: (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 

Livestock: (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 

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

Plants: spirodiclofen

Livestock: spirodiclofen including the 

metabolite 1-oxaspiro[4.5]dec-3-en-2-

one, 3-(2,4-dichlorophenyl)-4-

hydroxy-(9CI)

--

spirodiclofen (the residue is 

fat soluble)

Tolerance/Maximum Residue Limit (ppm)

Commodity1 US Canada Mexico1 Codex2

Almond, hulls 20 -- -- 15

Apple, wet pomace 2.4 -- -- 4 apple pomace, dry

Avocado 1.0 1 -- --

Black sapote 1.0 1 -- --

Canistel 1.0 1 -- --

Citrus, juice 0.60 0.6 -- --

Citrus, oil 35 20 -- --

Fruit, citrus, group 10 0.50

0.5 calamondin, citrus citron, citrus 

hybrids, grapefruits, kumquats, 

lemons, limes, oranges, pummelos, 

Satsuma mandarins, tangerines

-- 0.4

Fruit, pome, group 11 0.80

0.8 apples, Asian pears, azaroles, 

Chinese quinces, crabapples, Japanese 

quinces, loquats, mayhaws, medlars, 

pears, quinces

-- 0.8

Fruit, stone, group 12 1.0

1 apricots, fresh prune plums, 

nectarines, peaches, plumcots, plums, 

sweet cherries, tart cherries

-- 2

Grape 2.0 2 -- 0.2

Grape, raisin 6.0 4 raisins --

0.3 dried grapes (=currants, 

raisins, and sultanas)

Hop, dried cones 30 40 -- 40 hops, dry

Mamey sapote 1.0 1 -- --

Mango 1.0 1 -- --

Nut, tree, group 14 0.10

0.1 almond nuts, beechnuts, black 

walnuts, Brazil nuts, butternuts, 

cashew nuts, chestnuts, chinquapin 

nuts, English walnuts, hazelnuts 

(filbert), hickory nuts, macadamia nuts, 

pecan nuts

-- 0.05

Papaya 1.0 1 -- 0.03 (*)

Pistachio 0.10 0.1 -- 0.05 tree nuts

Sapodilla 1.0 1 -- --

Star apple 1.0 1 -- --

Cattle, fat 0.02 0.02 -- --
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Table A.6.1. Summary of US and International Tolerances and Maximum Residue Limits 

Cattle, meat byproducts 0.10 0.1 --

0.05 (*) edible offal 

(mammalian)

Cattle, meat 0.02 0.02 --

0.01 (*) (fat) meat (from 

mammals other than marine 

ammmals)

Goat, fat 0.02 0.02 -- --

Goat, meat byproducts 0.10 0.1 --

0.05 (*) edible offal 

(mammalian)

Goat, meat 0.02 0.02 --

0.01 (*) (fat) meat (from 

mammals other than marine 

ammmals)

Horse, fat 0.02 0.02 -- --

Horse, meat byproducts 0.10 0.1 --

0.05 (*) edible offal 

(mammalian)

Horse, meat 0.02 0.02 --

0.01 (*) (fat) meat (from 

mammals other than marine 

ammmals)

Milk 0.01 0.01 -- 0.004 (*)

Milk, fat 0.03 0.03 -- --

Sheep, fat 0.02 0.02 -- --

Sheep, meat byproducts 0.10 0.1 --

0.05 (*) edible offal 

(mammalian)

Sheep, meat 0.02 0.02 --

0.01 (*) (fat) meat (from 

mammals other than marine 

mammals)

MRLs with no U.S. equivalent

Coffee beans -- -- -- 0.03 (*)

Cucumber -- -- -- 0.07

Currants, Black, Red, White -- -- -- 1

Gherkin -- -- -- 0.07

Peppers, sweet (including pimento 

or pimiento) -- -- -- 0.2

Strawberry -- -- -- 2

Tomato -- -- -- 0.5

Grape juice -- 2.4 -- --

Completed: M. Negussie; 08/27/14

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed 

postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the 

sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.