UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: February IO, 2016 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Clofentezine. Human-Health Risk Assessment to Support a Section 3 Registration 

Request to Add ew Uses on Avocado and Papaya, and New Uses for Pome Fruit 

Group 11-10, Cherry sub-group l 2- I 2A, Peach sub-group 12-128. and Small Fruit 

Vine Climbing except Fuzzy Kiwifruit Subgroup l 3-07F based on Existing 

Tolerances on Representative Commodities. 

PC Code: 12550 l 

Decision No.: 495217 

Petition No.: NA 

Risk Assessment Type: Single 

Chemical/ Aggregate 

TXR No.: NA 

MRJD No.: NA 

DP Barcode: 0423333 

Registration No.: NA 

Regulatory Action: Section 3 Registration 

Case No.: NA 

CAS No.: 74115-24-5 

40 CFR: 180.572 

FROM: Evisabel 

Bridgett B

Craig. 

obowi

Ph.D., 

ec. Biologist DABT. ~ 

Risk assesso

~ 

r/Toxicologist 

~ · ~ () 

P. Yvonne Barnes, Chemist ~ 

Risk Assessment Branch Vl 

Health Effects Division (7509P) 

THROUGH: Donna Davis, Acting Branch Chief 

Risk Assessment Branch VI 

Health Effects Division (7509P) 

TO: Andy Ertman, Chemical Review Manager 

Barbara Madden, T earn Leader 

Marion Johnson, Branch Chief 

Minor Use and Emergency Response Branch 

Registration Division (7505P) 

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Clofentezine Human-Health Risk Assessment DP No. 423333 

The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with 

estimating the risk to human health from exposure to pesticides. The Registration Division (RD) 

of the Office of Pesticide Programs 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 the existing and proposed new uses of the 

acaricide clofentezine. 

A summary of the findings and an assessment of human health risk resulting from the existing and 

proposed new uses of clofentezine are provided in this document. The risk assessment, hazard 

characterization and endpoint selection were provided by Evisabel Craig (RAB6); the dietary 

exposure assessment and residue chemistry assessment by Yvonne Barnes (RAB6); the 

occupational and residential exposure assessment by B1idgett Bobowiec (RAB6); and the drinking 

water exposure assessment by Rosanna Louie-Juzwiak of the Environmental Fate and Effects 

Division (EFED). 

Page 2 of43 
Clofentezine Human-Health Risk Assessment DP No. 423333

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Table of Contents

1.0 Executive Summary .............................................................................................................. 5

2.0 HED Recommendations ....................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................... 8

2.2.1 Enforcement Analytical Method .................................................................................. 8

2.2.2 Recommended Tolerances............................................................................................ 8

2.2.3 Revisions to Petitioned-For Tolerances....................................................................... 9

2.2.4 International Harmonization........................................................................................ 9

2.3 Label Recommendations................................................................................................. 10

3.0 Introduction......................................................................................................................... 10

3.1 Chemical Identity ............................................................................................................ 10

3.2 Physical/Chemical Characteristics ................................................................................ 10

3.3 Pesticide Use Pattern....................................................................................................... 10

3.4 Anticipated Exposure Pathways.................................................................................... 11

3.5 Consideration of Environmental Justice....................................................................... 12

4.0 Hazard Characterization and Dose-Response Assessment............................................. 12

4.1 Toxicology Studies Available for Analysis.................................................................... 12

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ................................ 13

4.2.1 Dermal Absorption...................................................................................................... 13

4.3 Toxicological Effects ....................................................................................................... 14

4.3.1 Summary of Toxicological Effects.............................................................................. 14

4.4 Safety Factor for Infants and Children (FQPA SF)..................................................... 15

4.4.1 Completeness of the Toxicology Database................................................................. 15

4.4.2 Evidence of Neurotoxicity ........................................................................................... 15

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........... 15

4.4.4 Residual Uncertainty in the Exposure Database ...................................................... 15

4.5 Toxicity Endpoint and Point of Departure Selections ................................................. 15

4.5.1 Dose-Response Assessment......................................................................................... 15

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment........ 16

4.5.3 Cancer Classification and Risk Assessment Recommendation............................... 16

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment.................................................................................................................................. 16

5.0 Dietary Exposure and Risk Assessment........................................................................ 17

5.1 Residues of Concern Summary and Rationale ............................................................. 17

5.2 Food Residue Profile ....................................................................................................... 18

5.3 Water Residue Profile..................................................................................................... 18

5.4 Dietary Risk Assessment................................................................................................. 18

5.4.1 Description of Residue Data Used in Dietary Assessment....................................... 18

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................. 18

5.4.3 Acute Dietary Risk Assessment.................................................................................. 19

5.4.4 Chronic Dietary Risk Assessment.............................................................................. 19

5.4.5 Cancer Dietary Risk Assessment................................................................................ 19

5.4.6 Summary Table............................................................................................................ 19

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................ 19

6.1 Spray Drift....................................................................................................................... 20

6.2 Residential Bystander Post-Application Inhalation Exposure ................................... 20
Clofentezine Human-Health Risk Assessment DP No. 423333

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7.0 Aggregate Exposure/Risk Characterization..................................................................... 20

8.0 Cumulative Exposure/Risk Characterization .................................................................. 20

9.0 Occupational Exposure/Risk Characterization ............................................................... 21

9.1 Occupational Handler Exposure and Risk ................................................................... 21

9.2 Occupational Postapplication Expossure and Risk...................................................... 30

10.0 References............................................................................................................................ 36

Appendix A. Toxicology Profile and Executive Summaries ..................................................... 37

Appendix B. Review of human research..................................................................................... 40

Appendix C. Physical/Chemical Properties................................................................................ 41

Appendix D. Summary of Occupational Exposure Algorithms ................................................ 41

Appendix E. International Residue Limits...............................................................43
Clofentezine Human-Health Risk Assessment DP No. 423333

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1.0 Executive Summary

Clofentezine [3-6-bis(2-chlorphenyl)-1,2,4,5-tetrazine] is an acaricide currently registered for 

occupational foliar applications to almonds, apples, apricots, cherries, Christmas trees plantations 

(except California), grapes (except New York), peaches, pears, persimmons, nectarines, and 

walnuts. In addition to traditional agricultural crops, clofentezine is registered for use on 

commercial ornamentals in greenhouses, saran and shade houses, outdoor containers, and fieldgrown nursery stock. There are no registered or proposed residential uses associated with 

clofentezine at this time. 

This assessment addresses dietary exposure, occupational exposure and risk associated with the 

proposed new uses of clofentezine, as well as the proposed new crop groups. A Section 3 

registration was requested by the Interregional Research Project No. 4 (IR-4), in cooperation with 

the registrant, Makhteshim Agan of North America, Inc. for use of technical clofentezine (EPA 

Reg. No. 74054-1) and the suspension concentrate (SC) formulation APOLLO® SC 

Ovicide/Miticide (EPA Reg. No. 66222-47) containing 42% active ingredient on avocado, and 

papaya, as well as new groups for stone fruit (12-12A and 12-12B), pome fruits (11-10), and small 

fruit vines except fuzzy subgroup (13-07F) based on existing tolerances for the respective 

representative commodities. 

The proposed label recommends that clofentezine be applied only one time per year at first sign of 

mite activity. The maximum single application rate for all crops using ground and handheld 

equipment is 0.25 pound active ingredient per acre (lb ai/A) or 0.005 lb ai/gallon of spray. Aerial 

and chemigation application of clofentezine is prohibited. Clofentezine personal protective 

equipment (PPE) on the proposed labels includes baseline dermal (long sleeved shirt, long pants, 

shoes plus socks) as well chemical resistant gloves (i.e., such as barrier laminate, butyl rubber, 

neoprene rubber, poly-vinyl chloride (PVC), or Viton®).

The toxicology database for clofentezine is complete for risk assessment purposes. In June 2012, 

the HED Hazard and Science Policy Council (HASPOC) waived the requirement for a 

neurotoxicity battery and a route specific inhalation toxicity study. More recently, in June 2013, 

HASPOC waived the requirement for an immunotoxicity study.

Subchronic and chronic studies indicate the liver is the primary target organ for clofentezine with 

secondary effects on the thyroid. Orally-administered clofentezine is rapidly absorbed, 

metabolized, and eliminated. HED had reconsidered the available dermal absorption data for 

clofentezine, and has revised the dermal absorption factor to 10%, consistent with current policy.

The FQPA Safety Factor can be reduced to 1X because there is an adequate toxicity database for 

clofentezine and exposure data are complete or are estimated based on data that reasonably 

account for potential exposures. Two pre-natal developmental toxicity studies were available, one 

in rats and one in rabbits but no evidence (quantitative or qualitative) of increased susceptibility 

was seen in either study. There was no evidence (quantitative or qualitative) of increased 

susceptibility following pre-and/or post-natal exposure in rats for two generations in the 

reproduction study (NOAEL set at the highest dose tested). Also, there was no evidence of 

neurotoxicity in the clofentezine database.
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Clofentezine has been classified as a possible human carcinogen based on male rat thyroid 

follicular cell adenoma and/or carcinoma combined tumor rates. The Q1* value for clofentezine 

using the 3⁄4 inter species scaling factor is 3.76 x 10-2(mg/kg/day)-1. Clofentezine is not considered

a mutagen.

The residue chemistry data base is complete to support the proposed actions that are the subject of 

this memorandum. The nature of the residue in plants is well understood and the residue of 

concern is the parent compound only for both risk assessment and tolerance setting purposes. 

There are no new livestock feedstuffs associated with this petition; therefore a discussion of 

livestock metabolism is not relevant to this action. Adequate residue data, in terms of both number 

of trials and geographic representation, developed by a validated method and supported by storage 

stability data have been provided to support the new uses on avocado and papaya. No new data 

was submitted, or are required to support the new crop groups/subgroups since tolerances are

already established based on all the relevant representative commodities and the use pattern for the 

new crop groups/subgroups is identical to the use patterns for the representative commodities. 

There is an adequate analytical enforcement method available to enforce the proposed tolerances. 

Modelled estimated drinking water concentrations (EDWCs) were generated by the Environmental 

Fate and Effects Division (EFED). Clofentezine chronic and cancer dietary risk assessments were 

conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 3.16 which uses 

2003-2008 food consumption data from the U.S. Department of Agriculture’s National Health and 

Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). 

An acute dietary exposure assessment was not performed as no appropriate endpoints were 

identified from the available clofentezine toxicity studies indicating that clofentezine does not pose 

an acute dietary hazard. Partially refined chronic dietary as well as cancer dietary exposure and 

risk assessments were performed that directly incorporated average field trial residues, percent 

crop treated information, and modelled drinking water estimated residues. The estimated exposure 

to the highest population subgroup (children 1 < 2 years old) resulted in an estimated risk of <1% 

of the chronic population adjusted dose (cPAD). The estimated exposure to the general U.S. 

population resulted in an estimated risk of <1% of the chronic population adjusted dose (cPAD). . 

Applying the Q1* of 3.76 x 10-2 mg/kg/day to the exposure value resulted in a cancer risk estimate 

of 3.8 x 10-7to the general U.S. population.

There are no registered residential uses of clofentezine; therefore, the aggregate assessment 

includes food and water only and, as noted above, is not of concern.

There is potential for occupational exposure associated with handler activities (i.e., mixing, 

loading, and applying) as well as with post-application activities (i.e., re-entering treated areas). 

Based on the proposed use pattern (i.e., one application per season) the duration of exposure for 

the proposed uses is expected to be short-term (ST) 1 to 30 days and intermediate-term (IT) 1 to 6 

months. Long-term exposures greater than 6 months are not anticipated. Combined MOEs at 

baseline PPE (long sleeve shirt, socks, shoes and no respirator) are not of concern (MOEs >100) 

for the proposed crops except for airblast application to avocados and papayas (MOE=97) and 

handheld manual and mechanically pressurized handgun applications (MOEs 80 and 52). Manual 
Clofentezine Human-Health Risk Assessment DP No. 423333

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and mechanically pressurized handgun applications are not of concern with the current proposed 

label PPE of gloves (MOEs are 11,000 and 150 respectively). The addition of double layer dermal 

protection and gloves brings the risk estimate for airblast applications to 110. This PPE is 

currently not on the proposed label. In summary the combined dermal and inhalation MOEs 

ranged from 52 to 1,900 with baseline dermal PPE and no respirator, 88 to 11,000 with the 

addition of gloves, and 110 to 120,000 with double layer dermal protection and gloves. 

Clofentezine combined dermal and inhalation cancer risk estimates at baseline for private handlers 

ranged from 1.77E-05 to 4.78E-07 and 1.07E-05 to 8.46E-08 with the addition of chemical 

resistant gloves, 8.08E-06 to 7.67E-8 with double layer dermal protection and gloves for proposed 

uses. Clofentezine combined dermal and inhalation cancer handler risk estimates at baseline for 

commercial handlers ranged from 5.34E-05 to 1.43E-06 baseline dermal and no respirator and 

3.2E-05to 2.54 E-07 with the addition of chemical resistant gloves, and 2.43E-05 to 2.3E-07 with 

double layer dermal protection, gloves, and no respirator. 

The non-cancer post-application exposure estimates do not exceed HED’s level of concern (MOEs 

≥ 100) at day 0 after treatment (DAT) using the highest post-application transfer coefficients for 

the proposed crops (avocado and papaya) and the representative commodities of the new crop 

groups 11-11 and 12-12A and 12-12B. However in considering the proposed new use on crop 

subgroup 13-07F, in light of the revised dermal absorption factor, HED has reevaluated the postapplication exposure and risk associated with the existing registered use on grapes, the 

representative commodity for subgroup 13-07F. There are grape activities, such as tying training, 

hand harvest, hand-leaf pulling and girdling/turning that exceed HED’s level of concern at day 0 

after treatment. Hand harvesting floriculture also exceeds HED’s level of concern until day 3 after 

application. The proposed new uses include a 12 hour reentry interval (REI) consistent with 

previously registered labels. The cancer post-application risk estimates for the proposed crops and 

crop groups/subgroups calculated ranged from 1.34-04 to 6.92E-07 at day 0 after treatment 

(DAT0) and 9.52E10-5 to 4.93E-07 using the average 30 day dose.

There are issues with respect to international harmonization raised by these actions contained in 

this memorandum. While there are no issues with respect to avocado, papaya, and pome fruit, 

establishing the recommended tolerances on stone fruit (12-12A and 12-12B) does raise an issue 

with harmonization relative to the currently established Codex MRLs for stone fruit. Further, 

should the Agency determine that worker risk issues associated with the request to establish a 

subgroup 13-07F tolerance are resolved, there would be issues of harmonization with the currently 

established Codex MRL on grapes, the representative commodity for the subgroup 13-07F. There 

are no issues with respect to Canadian MRLs raised by the establishment of the tolerances in this 

memorandum.

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix B) have 

been determined to require a review of their ethical conduct and all of the studies utilized in this 

assessment have received the appropriate review.

2.0 HED Recommendations
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HED has no objection to the establishment of tolerances for residues of clofentezine in/on avocado 

and papaya, and the new uses on crop group/subgroups 11-10, 12-12A, and 12-12B. 

However, HED has identified worker risks of concern associated with the current registered use on 

grapes, the representative crop for the 13-07F crop subgroup; and therefore cannot recommend in 

favor of establishing that tolerance at this time.

2.1 Data Deficiencies

There are currently no deficiencies in the toxicology, ORE, or residue chemistry databases for 

clofentezine.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An HPLC analytical method for the determination of clofentezine residues in/on fruit was 

submitted with PP# 3F3392 (MRID# 44202401). Briefly, fruit samples are extracted into acetone 

and filtered. An aliquot of the extract is removed and partitioned with hexane. The organic extract 

is rotary evaporated to dryness then reconstituted in hexane for clean up through a silica solid 

phase extraction cartridge. The clofentezine is eluted from the silica, evaporated to dryness, 

adjusted to the final volume and quantified using high performance liquid chromatography with 

UV detection at 268 nm. The limit of quantitation (LOQ) and limit of detection (LOD) were 

determined to be 0.01 ppm and 0.003 ppm, respectively. Although the method was initially 

validated on apples which was the initial registered commodity, it was developed for all fruit. A 

petition method validation (PMV) was successfully completed by the EPA Analytical Chemistry 

Laboratory, and the method was found acceptable. 

While this method was originally developed for fruit matrices, the data collection method used to 

determine residues in avocado employed extraction with the same solvent, acetonitrile, and 

showed acceptable recoveries; therefore HED concludes that this method is suitable as an 

enforcement method for avocado, papaya, as well as all the new commodities associated with the 

proposed crop groups. 

2.2.2 Recommended Tolerances

The tolerance expressions established under 40 CFR §180.446 comply with the HED Interim 

Guidance on Tolerance Expressions (S. Knizner, 05/27/2009); no revisions are necessary. A 

tolerance summary is presented in Table 2.2.2 below.

Table 2.2.2 Tolerance Summary for Clofentezine

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Correct Commodity Definition/Comments

To be established under 40 CFR §180.446 (a) General. (1)

Cherry, subgroup 12-12A 1.0 1.0 Established tolerance for cherry (1.0 ppm) 

should be removed from the 40CFR and 
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Table 2.2.2 Tolerance Summary for Clofentezine

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Correct Commodity Definition/Comments

To be established under 40 CFR §180.446 (a) General. (1)

replaced by this subgroup tolerance.

Fruit, pome, group 11-10 0.5 0.50 Established tolerance for apple and pear (0.5 

ppm) should be removed from 40CFR and 

replaced by this group tolerance.

Peach, subgroup 12-12B 1.0 1.0 Established tolerance for peach should be 

removed from the 40CFR and replaced by this 

group tolerance.

Fruit, small, vine climbing, 

except fuzzy kiwifruit, 

Subgroup 13-07F 

1.0 1.0 Established tolerance for grape (1 ppm) should 

be removed from the 40CFR and replaced by 

this subgroup tolerance.

Avocado 0.3 0.30 N/A

Papaya 0.3 0.30 N/A

2.2.3 Revisions to Petitioned-For Tolerances

No revisions are needed.

2.2.4 International Harmonization

The International Residue Limit (IRL) Status Sheet for clofentezine is attached in Appendix E. 

The tolerance expression in plant commodities is harmonized between the US, Codex and Canada. 

In all three countries, the residue of concern in plants is the parent compound, only.

The recommended tolerance for residues of clofentezine in/on avocado and papaya in the U.S. is 

0.30 ppm. There are no Codex, Canadian, or Mexican MRLs for residues on avocado and papaya.

Therefore, there are no issues with respect to harmonization raised by the new avocado and papaya 

tolerances.

The US is recommending a tolerance of 0.5 ppm for pome fruit. There are MRLs for both Codex 

and Canada at 0.5 ppm for pome fruit. Since the US tolerance matches the Codex and Canadian 

MRLS, there are no international harmonization issues for pome fruit.

The US is recommending a tolerance of 1.0 ppm in stone fruit (12-12A and 12-12B). There are 

Canadian MRLS at 1.0 ppm for stone fruit and a Codex MRL for stone fruit at 0.5 ppm. The 

clofentezine residues in/on representative stone fruit crops, cherry and peach, from the submitted 

US field trial data are greater than 0.5 ppm and setting the tolerances for 12-12A and 12-12B at 0.5 

ppm to harmonize with Codex could result a tolerance exceedance for US growers. Therefore, the

US tolerance is harmonized with the Canadian MRL, but cannot be harmonized with Codex MRL

for stone fruit at this time.

The recommended US tolerance of 1.0 ppm for the crop subgroup fruit, small, vine climbing,

except fuzzy kiwifruit, 13-07F does not harmonize with the Codex MRL of 2.0 ppm. There is no 

Canadian MRL for these commodities. The petitioner proposes to establish the 13-07F subgroup
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tolerance at 1.0 ppm, which would leave the tolerance on grapes at 1.0 ppm, the current US grape 

tolerance level, because several countries including Japan and Korea also maintain an MRL at 1.0 

ppm. Therefore, HED is recommending that the tolerance of 1.0 ppm be established and notes that 

there are issues of international harmonization created by this approach.

2.3 Label Recommendations

No label revisions are needed based on the residue chemistry, occupational or residential exposure

reviews.

3.0 Introduction

3.1 Chemical Identity

Table 3.1: Clofentezine Nomenclature

Chemical Structure

Common Name Clofentezine

IUPAC name 3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine

CAS Name 3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine

CAS Registry Number 74115-24-5

3.2 Physical/Chemical Characteristics

Clofentezine’s vapor pressure (9.75 x 10-10 mm Hg @ 25 °C) and Henry's Law Constant (0.168 

Pa×m3/mol) indicate that the compound is non-volatile under field conditions. Clofentezine has a 

low solubility (34.2 mg/L) in water; however, clofentezine is fairly persistent in the environment. 

Based on the use pattern and environmental fate parameters, there is the potential for clofentezine 

to reach water resources. The octanol/water partition coefficient for clofentezine indicates that it 

may have the potential to accumulate into fatty tissues.

A table of the physicochemical properties of clofentezine can be found in Appendix C. 

3.3 Pesticide Use Pattern

Clofentezine is formulated as a suspension concentrate containing 42% active ingredient or 1.0 lb 

active ingredient per quart (i.e., 4.0 lbs a.i/gallon). Two end-use products are registered: Apollo®

SC Ovicide/Miticide (EPA Reg. No. 66222-47) and Clofentezine SC (EPA Reg. No. 66222-53). 

HED notes that only the Apollo® SC Ovicide/Miticide label includes the agricultural uses of 

clofentezine. Clofentezine is applied at the first sign of mites by ground equipment through 

airblast, groundboom machinery, and handheld equipment once per year. It may not be applied 

aerially or through any type of irrigation system. There are no registered residential uses for 

clofentezine. 
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The Section 3 registration requested by IR-4, in cooperation with the registrant, Makhteshim Agan 

of North America, Inc. proposes the use of Apollo® SC Ovicide/Miticide on avocado, papaya, as 

well as the following crop subgroups expansions: cherry subgroup (12-12A), peach subgroup (12-

12B), pome fruit group (11-10), and small fruit vine climbing except fuzzy subgroup (13-07F). 

The new uses and crop group/subgroups have the same maximum rate (0.25 lb a.i/acre (A) on 

orchard type crops) and the same pre-harvest interval (PHI) as the previously registered crops. 

The PHI for avocado and papaya is 3 days. The PHI for the pome fruit group is 45 days. The PHI 

for the cherries, small fruit, vine climbing except fuzzy kiwi and peaches is 21 days and (10 days 

for peaches in California). The proposed uses and application rates are further described in Table 

3.3.

Table 3.3. Summary of Directions for Proposed Use for Clofentezine 

APOLLO® Suspension Concentrate (SC) - EPA Reg. No. 66222-47 - 4 lbs a.i/gal

Application. 

Equipment Crops

Maximum 

Application Rate PHI (days) Use Directions and Limitations

Airblast, 

Groundboom, 

and Handheld 

Equipment

Avocado

8 oz. product/A

0.25 lb a.i/A

3

Apply at first sign of mite activity.

Do not apply via aerial or 

chemigation. Do not make more 

than one applications of product 

per year. PPE includes baseline 

attire (a long-sleeved shirt and 

long pants, and shoes plus socks) 

and gloves. Do not graze livestock 

in treated areas or harvest the 

cover crop for livestock feed.

Papaya

Fruit, pome, group 11-10 45 

Pears and Asian pear

21 

and

(10 days 

Peaches 

California)

Fruit, small, vine climbing, 

except fuzzy kiwifruit, 

subgroup 13-07F

Cherry, subgroup 12-12A

Peach, subgroup 12-12B

Conclusions:

Adequate use directions have been provided for the new uses on avocado and papaya. The 

petitioner has requested new uses for several crop groups based on the current uses and tolerances 

for the respective representative commodities. The proposed use instructions for the pome fruit 

group 11-10, the cherry subgroup 12-12A, the peach subgroup 12-12B, and the fruit, small, vine 

climbing, except fuzzy kiwifruit, subgroup 13-07F are identical to the use pattern for the currently 

registered representative commodities. 

The submitted labels are adequate to evaluate the residue chemistry data relative to the petitioned 

for tolerances. 

3.4 Anticipated Exposure Pathways

Humans may be exposed to clofentezine in food and drinking water, since clofentezine may be 

applied directly to growing crops and applications may result in clofentezine reaching surface and 

ground water sources of drinking water. In an occupational setting, applicators may be exposed 

while handling the pesticide prior to application, as well as during application and upon re-entry 

into the field after application. There are currently no residential uses of clofentezine, so exposure 

in residential and non-occupational settings is not likely. This risk assessment considers all of the 

exposure pathways based on the proposed new uses of clofentezine, but also considers the existing 

registered uses.
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3.5 Consideration of 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://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to wellestablished 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 

National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA; 2003-2008) 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 and ethnic 

group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post 

application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The studies available for consideration of clofentezine toxicity provide a comprehensive and 

complete database for risk assessment purposes. In June 2012, the HASPOC waived the 

requirement for a neurotoxicity battery (TXR 0056333, 6/27/2012). The HASPOC concluded that 

based on a weight of evidence (WOE) approach considering all the available hazard and exposure 

information for clofentezine, that the acute/subchronic oral neurotoxicity studies in the rat are not 

required at this time. This approach considered all the available hazard and exposure information 

for clofentezine, including: (1) the lack of neurotoxicity in the available toxicity studies for 

clofentezine; (2) the known target organs of clofentezine are the liver and thyroid; (3) the most 

sensitive endpoint (hepatotoxicity) is currently used to assess exposure risk and is considered 

protective of any potential neurotoxicity; and (4) neurotoxicity is not the most sensitive endpoint 

of clofentezine toxicity. 

Use of an oral NOAEL for inhalation risk assessment was also discussed at the June 2012 

HASPOC meeting. The HASPOC concluded that based on a WOE approach, that a subchronic 

inhalation toxicity study for clofentezine is not required at this time. This approach considered all 

of the available hazard and exposure information for clofentezine, including: (1) the 

physical/chemical properties and toxicological profile of clofentezine which indicates the thyroid 

and the liver to be target organs; (2) the use of an oral point of departure (POD) for assessing 

inhalation exposure that results in MOEs greater than 2,100 for risk via the inhalation route from 

occupational exposure; and (3) clofentezine’s low acute inhalation toxicity. 
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More recently, in June 2013, HASPOC waived the requirement for an immunotoxicity study (TXR 

0056690, 06/07/2013). The HASPOC concluded that based on a WOE approach, that an 

immunotoxicity study for clofentezine is not required at this time. This approach considered all of 

the available hazard and exposure information for clofentezine, including: (1) the toxicology 

database for clofentezine does not reveal any evidence of treatment-related effects on the immune 

system; (2) the known target organs of clofentezine are the liver and thyroid; (3) the most sensitive 

endpoint (hepatotoxicity) is currently used to assess exposure risk and is considered protective of 

any potential immunotoxicity; and (4) immunotoxicity is not the most sensitive endpoint of 

clofentezine toxicity. 

The available toxicity studies for clofentezine are listed in Table A. 1 in Appendix A. The data 

from the following studies were used to evaluate the hazard potential of clofentezine (see 

Appendix A: Tables A.2 and A.3): 

 Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, 

and dermal sensitization)

 Subchronic oral toxicity studies (rat and dog) 

 Developmental (rat and rabbit) and reproductive toxicity (rat) studies 

 Chronic oral toxicity studies (rat and dog)

 Carcinogenicity studies [rat (chronic combined) and mouse]

 Metabolism studies (rat)

 Mutagenicity battery

 Dermal penetration

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Orally-administered clofentezine is rapidly absorbed, metabolized, and eliminated. In a 

metabolism study (MRID 4092001), male and female rats given clofentezine technical at 1000 

mg/kg manifested peak plasma levels of between 14 and 16 ppm at 6-8 hours post dosing which 

then declined to 3 ppm at 24 hours post dosing. Plasma half-life was approximately 3.5 hours. 

Whole body autoradiography of rats given a 10 mg/kg dose indicated poor gastrointestinal 

absorption with 60-70% of the given dose excreted in the feces during the first 24 hours and about 

20% excreted in the urine. The major metabolites were 3-(2'-methyl-thio-3' hydroxy phenyl)-6-(2'-

chloro-phenyl)-1,2,4,5-tetrazine and 3-,4-, and 5-hydroxyclofentezine. Both liver and kidney had 

the highest tissue concentration after 72 hours.

4.2.1 Dermal Absorption

Two dermal absorption studies have been submitted for clofentezine. In the first study (MRID 

00159102; Campbell et al., 1986), clofentezine was applied at doses of 36, 338, and 1,380 μg/cm2 

for 10 hours. Following 10 hours of exposure, 0.61, 0.13, and 0.08% of the dose was absorbed, 

respectively (amount in urine, feces, and carcass). High amounts of radioactivity were identified 

remaining at the skin site (>30%) and on the dressing (~40-60%) in all dose groups. 

A second dermal study (MRID 49705401; Challis, et al., 1989) was conducted utilizing a more 

thorough washing procedure and analysis up to 120 hours post-exposure to determine if continued 
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absorption occurred after washing. In this study, clofentezine was applied at doses of 0.38, 3.8, 

and 38 μg/cm2for 10 hours. The total absorbed dose at 24 hours after exposure was 1.44%, 4.66, 

and 8.66% with 2.63, 1.79, and 1.67% remaining on the skin site after washing, respectively. At 

120 hours, the total absorbed dose was 1.44, 3.81, and 9.69% with less than 0.1% remaining on the 

skin site in all groups. 

In the two available studies, the percentage of chemical absorbed increased with decreasing 

amount applied indicating saturation of the dermal absorption process or “dermal loading” in the 

higher application groups. This is also supported by the increased amount of chemical absorbed 

over time at the low doses in both studies as well as decreased amounts remaining at the skin site 

at the extended time periods. In the second study at 24 hours, the amount of chemical absorbed in 

the 38 μg/cm2group was nearly double (1.44% vs. 0.61 %) the amount at 10 hours in the 36 

μg/cm2 group in the first study (low dose). Additionally, the lowest dose tested in the second study 

(0.38 μg/cm2), which appeared to have minimal to no dermal loading, showed continued 

absorption from 24 to 120 hours (7.45 to 9.69%, respectively) and a non-detectable amount of 

chemical remaining at the skin site. Although the previous risk assessment used a DAF of 1% 

based on the first study (1986), the methodology employed in this study does not conform to 

current policy. Therefore, based on the available data, the dermal absorption of clofentezine is 

considered to be 10% (rounded from 9.69% obtained from the 1989 study) for this risk assessment. 

This value was chosen as it represents a dose which did not appear to have significant dermal 

loading and takes into account the continued absorption over time demonstrated when evaluating 

the data across both studies. 

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

Subchronic and chronic studies indicate the liver is the primary target organ for clofentezine with 

secondary effects on the thyroid. Body weight and body weight gain were decreased whereas liver 

weights were increased and hepatocellular enlargement was reported along with other observations

(increases in plasma cholesterol and triglyceride levels). The induction of the liver enzyme,

UDPGT and the subsequent increase in the metabolism and the excretion of the thyroid hormone 

T4 reduced the availability of T4 required for the general metabolism and the maintenance of

homeostasis. The decreased levels of plasma T4 resulted in the stimulation of the thyroid by the

pituitary gland to raise the plasma T4 levels. Thyroid changes in the form of colloid depletion,

thyroid follicular cell hypertrophy and hyperplasia were observed as a means to regain the 

homeostasis.

Two pre-natal developmental toxicity studies were available, on in rat and on in rabbit. No 

evidence (quantitative or qualitative) of increased susceptibility was seen in either study 

(developmental NOAELs were set at or above the limit dose for both studies). There was no 

evidence (quantitative or qualitative) of increased susceptibility seen following pre-and/or postnatal exposure in rats for two generations in the reproduction study (NOAEL set at the highest 

dose tested). 

Clofentezine does cause thyroid tumors in male rats after long-term high exposure resulting in 

progressive effects on the thyroid that leads to hyperplasia and eventual tumor formation. No 

mechanism or mode of action has been submitted to the Agency at this time for clofentezine. As a 
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result, clofentezine has been classified as a possible human carcinogen based on male rat thyroid 

follicular cell adenoma and/or carcinoma combined tumor rates (Memo, A. Kocialski, 1998; 

TXR013002). Clofentezine is not considered to be a mutagen.

Clofentezine has low acute toxicity by the oral, dermal and inhalation routes of exposure 

(Categories III and IV). It is a mild eye irritant, a weak dermal sensitizer, and is not considered to 

be a skin irritant.

4.4 Safety Factor for Infants and Children (FQPA SF)

The risk assessment team has concluded that the FQPA SF should be reduced to 1x because there 

is an adequate toxicity database for clofentezine and exposure data are complete or are estimated 

based on data that reasonably account for potential exposures. There was no evidence of 

qualitative or quantitative susceptibility in developmental and reproduction studies and there was 

no evidence of neurotoxicity in the submitted studies. The dietary assessment is based on reliable 

data and does not underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The toxicity database is considered complete. With the exception of the guideline studies which 

have been waived by the HASPOC, all required guideline studies have been submitted including 

the developmental toxicity studies in rats and rabbits, and the two-generation reproduction study in 

rats.. 

4.4.2 Evidence of Neurotoxicity

As discussed in Section 4.1, neither an acute nor a subchronic neurotoxicity study has been 

conducted for clofentezine. However, there is no evidence of neurotoxicity following subchronic 

or chronic dosing in multiple species in the clofentezine database and clofentezine is not 

structurally related to known neurotoxic compounds. As a result, the HASPOC waived the 

requirement for a neurotoxicity battery (TXR 0056333, 6/27/2012).

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility of offspring following pre- or postnatal exposure 

to clofentezine in rats or rabbits.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to exposure. Conservative, upper-bound 

assumptions were used to determine exposure through dietary sources (food and drinking water), 

such that these exposures have not been underestimated. There are currently no residential uses 

and no outstanding exposure data requirements for clofentezine.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Acute Dietary Endpoint: No acute population adjusted dose (PAD) was selected for the general 

U.S. population (including females 13-49 years of age) or any population subgroups. No 
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appropriate toxicological endpoint attributable to a single exposure was identified in the available 

toxicology studies including the rat and the rabbit developmental studies.

Chronic Dietary Endpoint: Quantification of chronic dietary risks was performed using a one year 

feeding study in dogs with a NOAEL of 1.25 mg/kg/day based on liver changes and elevated 

serum cholesterol, triglycerides, and alkaline phosphatase (LOAEL = 25.0 mg/kg/day). An 

Uncertainty Factor (UF) of 100 was applied to account for interspecies extrapolation (10X) and

intraspecies variability (10X), and FQPA (1x). The chronic population adjusted dose (cPAD) was 

calculated to be 0.013 mg/kg/day.

Short- and Intermediate-Term Dermal Endpoint: No route specific dermal study is available for 

clofentezine. Quantification of dermal risks was performed using a 90-day rat feeding study with a 

NOAEL of 2 mg/kg/day based on increased cholesterol, increased liver weights, thyroid colloid 

depletion and thyroid follicular cell hypertrophy (LOAEL = 20 mg/kg/day). Since an oral dose 

was selected, a dermal absorption factor of 10% should be used in estimating dermal risks (see 

Section 3.2.1). An UF of 100 is applied which includes interspecies extrapolation (10X) and 

intraspecies variability (10X).

Short- and Intermediate-term Inhalation Endpoints: No route specific inhalation study is available 

for clofentezine. Quantification of inhalation risks was performed using a 90-day rat feeding study

with a NOAEL of 2 mg/kg/day based on increased cholesterol, increased liver weights, thyroid 

colloid depletion and thyroid follicular cell hypertrophy (LOAEL = 20 mg/kg/day). Since an oral 

study was selected, absorption via inhalation is presumed to be equivalent to oral absorption. An

UF of 100 is applied which includes interspecies extrapolation (10X) and intraspecies variability 

(10X).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For clofentezine, dermal and inhalation exposures can be combined since the same oral study was 

used to select endpoints and doses for dermal and inhalation risk assessment. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Clofentezine can cause thyroid tumors in male rats after long-term high exposure resulting in 

progressive effects on the thyroid that leads to hyperplasia and eventual tumor formation. No 

mechanism or mode of action has been submitted to the Agency for clofentezine at this time. As a 

result, clofentezine has been classified as a possible human carcinogen based on male rat thyroid 

follicular cell adenoma and/or carcinoma combined tumor rates (Memo, A. Kocialski, 1998; 

TXR013002). The Q1

*

value for use in clofentezine risk assessment using the 3⁄4 inter species 

scaling factor is 3.76 x 10-2(mg/kg/day)-1. Clofentezine is not considered to be a mutagen.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment
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Table 4.5.4.1: Toxicological Doses and Endpoint for Use in Clofentezine Dietary and Non-Occupational Human Health 

Risk Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, Level of Concern 

for Risk Assessment

Study and Toxicological 

Effects

Acute Dietary

(All populations) No appropriate endpoint was identified including developmental toxicity studies in rats and rabbits.

Chronic Dietary (all 

populations) 

NOAEL = 

1.25 

mg/kg/day

UFA = 10X 

UFH = 10X 

FQPA SF = 1X

Total UF = 100X

Chronic RfD 

= 0.013 mg/kg/day

cPAD = Chronic RfD

 FQPA SF

= 0.013 mg/kg/day

1-year chronic dog studyLOAEL = 25 mg/kg based on 

increased liver weights, 

hepatocellular enlargement, and 

increased serum cholesterol, 

triglycerides and alkaline 

phosphatase levels.

Cancer (oral, 

dermal, inhalation)

Classification: possible human carcinogen (classification of C), Q* using the 3⁄4 interspecies scaling factor 

is 3.76 x 10-2(mg/kg/day)-1

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect 

level, PAD = population adjusted dose (a = acute, c = chronic), RfD = reference dose, LOC = level of concern, NA = Not Applicable. UFA= 

extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among members of the human population (intraspecies).

Table 4.5.4.2: Toxicological Doses and Endpoint for Use in Clofentezine Occupational Human Health Risk Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, Level of Concern 

for Risk Assessment

Study and Toxicological 

Effects

Dermal 

Short- Term (1- 30 

days) 

Intermediate – Term

(1-6 months)

Oral

NOAEL = 

2.0 

mg/kg/day

UFA = 10X 

UFH = 10X 

Total UF = 100X

Dermal Absorption = 

10%

Occupational LOC for MOE = 

100

13-week rat studyLOAEL= 20 mg/kg/day based 

on increased cholesterol, 

increased liver weights, thyroid 

colloid depletion and thyroid 

follicular cell hypertrophy.

Inhalation 

Short- Term (1- 30 

days) 

Intermediate – Term

(1-6 months)

Oral

NOAEL = 

2.0 

mg/kg/day

UFA = 10X 

UFH = 10X 

Total UF = 100X

Occupational LOC for MOE = 

100

13-week rat studyLOAEL= 20 mg/kg/day based 

on increased cholesterol, 

increased liver weights, thyroid 

colloid depletion and thyroid 

follicular cell hypertrophy.

Cancer (oral, 

dermal, inhalation)

Classification: possible human carcinogen (classification of C), Q* using the 3⁄4 interspecies scaling factor 

is 3.76 x 10-2(mg/kg/day)-1

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect 

level, PAD = population adjusted dose (a = acute, c = chronic), RfD = reference dose, LOC = level of concern, NA = Not Applicable. UFA= 

extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among members of the human population (intraspecies).

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

No new metabolism data was submitted or required to support this petition. The nature of the 

residue has been adequately delineated in plants. In plant crops, the residue of concern is the 

parent, clofentezine (A. Smith, 04/26/1988; RCB Nos. 3190 and 3191). Table 5.1 provides a 

summary.

Table 5.1. Summary of Clofentezine residues to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Clofentezine Clofentezine

Water Clofentezine Clofentezine
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5.2 Food Residue Profile

Clofentizine is typically applied to growing crops as a foliar application. Given 

information in the metabolism studies that suggest that clofentezine is unlikely to be absorbed by 

the roots of plants and does not translocate throughout the plant, it is likely that clofentezine 

residues will be primarily the parent compound and will be found as surface residues on fruits and 

leaves. Clofentezine is not likely to concentrate in processed commodities. Clofentezine is solid at 

room temperature with a vapor pressure such that losses through volatilization/sublimation are 

expected to be minimal, it is considered non-volatile. 

5.3 Water Residue Profile

The drinking water assessment for clofentezine conducted in 2012 is appropriate to support new 

uses on papaya and avocado, based on communication with EFED (D423336, R. Louie-Juzwiak, 

May 27, 2015). The residues of concern for clofentezine in drinking water is the parent compound, 

clofentezine only. Tier II Estimated Drinking Water Concentrations (EDWCs) were generated to 

support clofentezine use on almonds, apples, Christmas trees, nectarines, containerized plants, 

peaches, pears, pecans, persimmons and walnuts. The surface water EDWCs are based on the 

USEPA Pesticide Root Zone Model (PRZM) and Exposure Analysis Modeling System (EXAMS) 

using the EXPRESS shell, Version 1.03.02. The highest surface water EDWCs values are 7.59 ppb 

(1-in-10 year acute) and 0.062 ppb (1-in-10 year annual average). These concentration values were

produced by the EFED North Carolina apple scenario and corrected for the required 100 buffer. 

The SCI-GROW groundwater concentration is 0.041 ppb. Table 5.3 provides EDWCs for 

clofentezine. 

Table 5.3. Maximum Estimated Surface Water and Groundwater Concentrations for Clofentezine

Drinking Water Source Model Use rate

(lbs a.i/A/season)

Acute

(ppb)

Chronic

(ppb)

Parent only

Surface water FIRST

0.26

7.59 1 0.062 2

Groundwater SCI-GROW -- 0.041

Note: Bolded value was used for the chronic dietary assessment.

1 Represents North Carolina apple scenario

2 Represents California grape scenario

5.4 Dietary Risk Assessment

Clofentezine chronic and cancer dietary exposure and risk assessments were conducted using the 

DEEM-FCID, Version 3.16, which incorporates 2003-2008 consumption data from USDA’s 

NHANES/WWEIA. 

5.4.1 Description of Residue Data Used in Dietary Assessment

Average crop field trial residues were used for all commodities in the dietary assessment. 

Livestock calculated secondary residues were also included in these assessments.

5.4.2 Percent Crop Treated Used in Dietary Assessment
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The Biological and Economics Analysis Division (BEAD, 12/09/14) provided updated estimated 

% CT information for several commodities. The average percent crop treated estimates were used 

in the chronic and cancer dietary risk assessments for the following crops that are currently 

registered for clofentezine: almonds: 5%; apples: 2.5%; apricots: 2.5%; cherries: 5%; grapes: 1%; 

nectarines: 5%; peaches 5%; pears 5%; and walnuts: 5%.

5.4.3 Acute Dietary Risk Assessment

An acute dietary exposure assessment was not performed as no appropriate endpoints were 

identified from the available clofentezine toxicity studies which indicates that clofentezine does 

not pose an acute dietary risk. 

5.4.4 Chronic Dietary Risk Assessment

A partially refined chronic dietary exposure assessment was performed that directly incorporated

average field trial residues, percent crop treated, and modelled drinking water estimated residues. 

The estimated exposure to the highest population subgroup (children 1 < 2 years old) resulted in an 

estimated risk of <1% of the chronic population adjusted dose (cPAD). The estimated exposure to 

the general U.S. population resulted in an estimated risk of <1% of the chronic population adjusted 

dose (cPAD). 

5.4.5 Cancer Dietary Risk Assessment

A partially refined cancer dietary exposure assessment was performed that directly incorporated 

average field trial residues, percent crop treated, and modelled drinking water estimated residues as 

clofentezine has been classified as a possible human carcinogen. Applying the Q1* of 3.76 x 10-2

mg/kg/day to the exposure value results in a cancer risk estimate of 3.8 x 10-7to the general U.S. 

population.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Clofentezine1

Population Subgroup cPAD (mg/kg/day)

Chronic Dietary Cancer

Dietary Exposure 

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

Risk

Q* = 3.76 x 10-2

General U.S. Population

0.013

0.000010 <1 0.000010 3.8 x 10-7

All Infants (< 1 year old) 0.000029 <1

N/A N/A

Children 1-2 years old 0.000039 <1

Children 3-5 years old 0.000024 <1

Children 6-12 years old 0.000013 <1

Youth 13-19 years old 0.000006 <1

Adults 20-49 years old 0.000008 <1

Adults 50 -99 years old 0.000008 <1

Females 13-49 years old 0.000008 <1

1 Population with the greatest exposure is in bold. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered or proposed residential uses and/or commercial uses at residential sites of 

clofentezine at this time. Therefore, a residential exposure assessment is not required.
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6.1 Non-Occupational Spray Drift Exposure

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., airblast) employed for 

clofentezine. The agency has been working with the Spray Drift Task Force (a task force 

composed of various registrants which was developed as a result of a Data Call-In issued by EPA), 

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). 1 The agency has also developed a policy on how to appropriately consider spray 

drift as a potential source of exposure in risk assessments for pesticides. The potential for spray 

drift will be quantitatively evaluated for each pesticide during the Registration Review process 

which 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. 

6.2 Non-Occupational Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

nearby pesticide applications. The agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific 

Advisory Panel (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 has evaluated 

the SAP report and 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 analysis is required for 

clofentezine.

7.0 Aggregate Exposure/Risk Characterization

Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and 

any non-occupational (residential) uses. There are currently no registered residential uses 

associated with clofentezine; therefore, the clofentezine aggregate risk assessment includes only 

dietary exposure (food and water). An acute dietary exposure assessment was not performed as 

clofentezine does not pose an acute dietary risk. The chronic dietary exposure estimates from food 

and drinking water do not exceed HED’s level of concern. The cancer dietary exposure estimates 

from food and drinking water result in a cancer risk estimate of 3.8 x 10-7. Sections 5.4.4 and 5.4.5

discuss the chronic and cancer dietary (food and water) exposure assessments.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 

 

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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clofentezine and any other substances. For the purposes of this assessment, therefore, EPA has not 

assumed that clofentezine has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism of 

toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

The proposed uses for clofentezine are on possible commercial agricultural crops; therefore, there 

is potential for occupational handler and post-application exposure. 

9.1 Occupational Handler Exposure and Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(i.e., amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques that 

can potentially be used, occupational handler exposure is expected from the proposed uses. The 

quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

1. Mixing/loading liquid concentrates to support airblast applications,

2. Mixing/loading liquid concentrates to support groundboom applications,

3. Applying sprays with airblast equipment,

4. Applying sprays with groundboom equipment, 

5. Mixing/loading/applying liquid concentrates to support mechanically and manuallypressurized handgun applications, and

6. Mixing/loading/applying liquid concentrates to support backpack sprayer applications.

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include 

PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) 

database, or other registrant-submitted occupational exposure studies. Some of these data are 

proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The 

standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table2”, which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the Agency 

website3. 

 

2 Available: http://www2.epa.gov/sites/production/files/2015-09/documents/handler-exposure-table-2015.pdf

3 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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9.1.1 Short-/Intermediate-Term Non-Cancer Handler Exposure and Risk

Handler exposure is expected to be short- or intermediate-term in duration based on information 

provided on the proposed labels. The short- and intermediate-term toxicological endpoints are the 

same for the respective routes of exposure; therefore, the estimates of risk for short-term duration 

exposures are protective of those for intermediate-term durations. Long-term exposures are not 

expected; therefore, a long-term assessment was not conducted. 

Short- and intermediate-term occupational handler exposure and risks were estimated using 1) unit 

exposures taken from the “Occupational Pesticide Handler Unit Exposure Surrogate Reference 

Table”; 2) the maximum clofentezine label application rates; and 3) amount handled/area treated 

values take from ExpoSAC SOP No. 9.1, “Standard Values for Daily Acres Treated in 

Agriculture”.

Combined ST and IT occupational handler dermal and inhalation MOEs ranged from 52 to 1,900 

with baseline dermal PPE and no respirator, 88 to 11,000 with the addition of gloves, and 110 to 

120,000 with double layer dermal protection and gloves. All occupational handler scenarios 

resulted in inhalation MOEs far greater than the LOC of 100 with no respirator. Airblast 

application to avocado and papaya as well as the exiting registered orchard crops have a combined 

risk estimates that exceeds HED’s level of concern at baseline dermal plus gloves and no respirator 

mitigation. See the following tables 9.1.1 and 9.1.2 for occupational noncancer handler risk 

estimates.
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Table 9.1.1 Short/Intermediate Term Occupational Handler Dermal and Inhalation Noncancer Exposure and Risk Estimates for Clofentezine with 10% Dermal Absorption1

Exposure Scenario

Crop / Target Category

Appli

catio

n 

Rate

Amount 

Handled3

Dermal Dose (mg/kg/day)4 Dermal MOE5

Inhalation 

Dose (mg/kgday)6

Inhalati

on 

MOE7

Formulation Application 

Equipment

SL/No 

G

SL/G DL/G SL/N

o G SL/G DL/G No-R No-R

Mixer/Loader

L/SC/EC

Airblast Nursery (ornamentals, vegetables, trees, container)

0.25

A

20 A 0.00138 0.0002 0.0002 1400 8500 11000 0.00001 140000

Orchard/Vineyard 40 A 0.00275 0.0005 0.0004 730 4300 5500 0.00003 73000

Groundboom

Nursery (ornamentals, vegetables, trees, container 

stock), Greenhouse (ornamentals, roses, cut flowers, 

container, vegetables)

60 A 0.00413 0.0007 0.0006 480 2800 3700 0.00004 49000

Orchard/Vineyard 40 A 0.00275 0.0005 0.0004 730 4300 5500 0.00003 73000

Field crop, typical 80 A 0.0055 0.0009 0.0007 360 2100 2700 0.00006 36000

Applicator

Spray

(all starting 

formulation

s)

Airblast Nursery (ornamentals, vegetables, trees, container)

0.25

A

20 A 0.0111 0.0099 0.0093 180 200 220 0.0003 6800

Orchard/Vineyard 40 A 0.0221 0.0199 0.0185 90 100 110 0.00053 3400

Groundboom

Nursery (ornamentals, vegetables, trees, container 

stock), Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables)

60 A 0.0015 0.0003 0.0002 1400 6600 8500 0.00006 31000

Orchard/Vineyard 40 A 0.001 0.0002 0.0002 2000 10000 13000 0.00004 47000

Field crop, typical 80 A 0.002 0.0004 0.0003 1000 5000 6300 0.00009 24000

Mixer/Loader/Applicator

L/SC/EC

Backpack

Greenhouse (ornamentals, roses, cut flowers, 

container, vegetables) 

0.005 

lb 

ai/gal

lon

40 

0.0033 0.0028 0.0016 610 710 1300 0.00035 5700

Nursery (ornamentals, vegetables, trees, container) 

And Christmas Tree Farms, 0.0146 0.0076 0.0042 140 260 470 0.00017 12000

Manuallypressurized 

Handwand

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables), and nursery 

(ornamentals, vegetables, trees, container stock)

40 A 0.025 0.0001 0.0001 80 19000 22000 0.00008 27000

Mechanically

-pressurized 

Handgun

Orchard/Vineyard, Nursery (ornamentals, vegetables, 

trees, container) And Christmas Tree Farms, and Field 

crop, typical

1000 A 0.0379 0.0129 0.0085 53 160 240 0.00054 3700

Mechanically

-pressurized 

Handgun

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables) 1000 0.0219 0.0156 0.01 91 130 200 0.0075 270

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2015).

2. Based on registered or proposed label (EPA Reg. No. 66222-47). Formulated clofentezine products are liquid concentrates, soluble concentrates, or emulsifiable concentrates (L/SC/EC)

3. Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (mg/lb ai) * Application Rate * Area treated or Amount handled * Absorption Factor (10%))  Body Weight (80 kg).

5 Dermal MOE = Dermal NOAEL (2 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/A) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).

7. Inhalation MOE = Inhalation NOAEL (2 mg/kg/day) ÷ Inhalation Dose (mg/kg/day)
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 24 of 43

Table 9.1.2 Short/Intermediate Term Combined Occupational Handler Noncancer Exposure and Risk Estimates for Clofentezine with 10 % Dermal Absorption1

Exposure Scenario

Crop / Target Category

Applica

tion 

Rate

Amount Handled / 

Area Treated3

Combined Dose (mg/kg-day) Combined MOE4

Formulation Application 

Equipment

SL/No G 

+ No-R

SL/G + 

No-R

DL/G + 

No-R

SL/No G 

+ No-R

SL/G + 

No-R

DL/G + 

No-R

Mixer/Loader

L/SC/EC

Airblast

Nursery (ornamentals, vegetables, trees, 

container)

0.25

A

20 A 0.00139 0.00025 0.000197 1400 8000 10000

Orchard/Vineyard 40 A 0.00278 0.0005 0.000391 720 4100 5100

Groundboom

Nursery (ornamentals, vegetables, trees, 

container stock) and Greenhouse (ornamentals, 

roses, cut flowers, container stock, vegetables)

60 A 0.00417 0.00075 0.000587 480 2600 3400

Orchard/Vineyard 40 A 0.00278 0.0005 0.000391 720 4100 5100

Field crop, typical 80 A 0.00555 0.001 0.000783 360 2000 2500

Applicator

Spray

(all starting 

formulations)

Airblast

Nursery (ornamentals, vegetables, trees, 

container stock) 0.25 20 A 0.0114 0.0102 0.00955 180 190 210

Orchard/Vineyard 0.25 40 A 0.0227 0.0205 0.0191 88 97 110

Groundboom

Nursery (ornamentals, vegetables, trees, 

container stock) and Greenhouse (ornamentals, 

roses, cut flowers, container stock, vegetables)

0.25 60 A 0.00154 0.00037 0.0003 1300 5400 6700

Orchard/Vineyard 0.25 40 A 0.00103 0.00024 0.000201 1900 8200 10000

Field crop, typical 0.25 80 A 0.00205 0.00049 0.0004 960 4100 5000

Mixer/Loader/Applicator

L/SC/EC

Backpack Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables)

0.005

lb ai/ 

gallons

40 gallons 0.00365 0.00315 0.00191 550 630 1100

Backpack Nursery (ornamentals, vegetables, trees, 

container stock) and Christmas Trees 40 gallons 0.0148 0.0078 0.0044 140 250 450

Manuallypressurized 

Handwand

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables) and Nursery 

(ornamentals, vegetables, trees, container stock)

40 gallons 0.0251 0.00018 0.000166 80 11000 12000

Mechanically

-pressurized 

Handgun

Orchard/Vineyard and Nursery (ornamentals, 

vegetables, trees, container stock) and Field 

crop, typical

1000 gallons 0.0384 0.0134 0.00904 52 150 230

Mechanically

-pressurized 

Handgun

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables) 1000 gallons 0.0294 0.0231 0.0175 68 88 110

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”(September, 2015); Level of mitigation: Baseline, PPE, and Eng. Controls. SL/No G (Single layer dermal protection consisting of 

long sleeve shirt, long pants, and socks and shoes) no gloves; SL/G (single layer dermal protection) plus the addition of gloves, No-R (no respirator). DL/G (double layer dermal protection with gloves)

2. Based on registered or proposed label (EPA Reg. No. 66222-47). Formulated clofentezine products are liquid concentrates, soluble concentrates, or emulsifiable concentrates (L/SC/EC)

3. Exposure Science Advisory Council Policy #9.1.

4 Combined MOE = 1/ ((1/Dermal MOE) + (1/Inhalation MOE)) 

5. Orchard crops include the registered crops almonds, apricots, cherries, Christmas trees, grapes, peaches, pears, persimmons, nectarines, walnuts. Nursery includes commercial ornamentals grown in greenhouse, outdoor 

saran and shade houses, and field grown nursery stock.
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 25 of 43

9.1.2 Cancer Handler Exposure and Risk

Cancer risk estimates were calculated using a linear low-dose extrapolation approach in which a 

Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q1* that has 

been calculated for clofentezine based on dose response data in the appropriate toxicology study 

(Q1* = 3.76 x 10-2(mg/kg/day)-1). Absorbed average daily dose (ADD) levels were used as the 

basis for calculating the LADD values. Dermal and inhalation ADD values were first added 

together to obtain combined ADD values. LADD values were then calculated and compared to 

the Q1* to obtain cancer risk estimates. 

The risk estimates were calculated using the maximum rate of 0.25 lb ai/A as a typical rates were 

not available for the avocado and papaya. Crops subgroups were also presented with the 

maximum rate of 0.25 lb ai/A. Cancer risk estimates are presented for private and commercial 

handlers with dermal baseline PPE as well as dermal baseline plus gloves PPE. Inhalation 

cancer risk estimates are presented with no respirator. Clofentezine combined dermal and 

inhalation cancer risk estimates at baseline for private handlers ranged from 6.43E-07 to 1.16E05 and 1.15E-07 to 9.48E-06 with the addition of chemical resistant gloves for proposed uses. 

Clofentezine combined dermal and inhalation cancer risk estimates at baseline for private 

handlers ranged from 1.77E-05 to 4.78E-07 and 1.07E-05 to 8.46E-08 with the addition of 

chemical resistant gloves, 8.08E-06 to 7.67E-8 with double layer dermal protection and gloves 

for proposed uses. Clofentezine combined dermal and inhalation cancer handler risk estimates at 

baseline for commercial handlers ranged from 5.34E-05 to 1.43E-06 baseline dermal and no 

respirator and 3.2E-05to 2.54 E-07 with the addition of chemical resistant gloves, and 2.43E-05 

to 2.3E-07 with double layer dermal protection, gloves, and no respirator. See table 9.1.2 and 

9.1.3 for further description of handler occupational cancer risk estimates. 
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 26 of 43

Table 9.1.2 Occupational Private/Farmer Handler Cancer Exposure and Risk Estimates for Proposed Use of Clofentezine Registered Uses with 10% Dermal Absorption1

Exposure Scenario

Crop / Target Category

Dermal Dose 

(mg/kg/day)

Inhalation 

Dose 

(mg/kgday)

Lifetime Average Private/Farmer

Lifetime Average 

Combined Dose 

(mg/kg-day)2

Private/Farmer 

Handler Cancer Risk Dermal Dose 3

(mg/kg/day)

Inhalation 

Dose 

(mg/kgday)

Formulat

ion

Application 

Equipment

SL

/N

o 

G

S

L/

G

DL

/G No-R

SL

/N

o 

G

SL

/G

DL

/G No-R

SL/N

o G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

SL/N

o G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

Mixer/Loader

L/SC/EC Groundboom

Nursery (ornamentals, vegetables, trees, container 

stock) and Greenhouse (ornamentals, roses, cut 

flowers, container stock, vegetables)

0.0

04

1

0.

00

07

0.0

00

6

4.11E-05

5.0

8E

-05

8.6

7E

-06

6.7

1E

-06

5.05E-07 5.13E

-05

9.17

E-06

7.22

E-06

1.93E

-06

3.45

E-07

2.71

E-07

Orchard/Vineyard

0.0

02

8

0.

00

05

0.0

00

4

2.74E-05

3.3

8E

-05

5.7

8E

-06

4.4

7E

-06

3.37E-07 3.42E

-05

6.11

E-06

4.81

E-06

1.29E

-06

2.3E

-07

1.81

E-07

Field crop, typical

0.0

05

5

0.

00

09

0.0

00

7

5.48E-05

6.7

6E

-05

1.1

6E

-05

8.9

5E

-06

6.74E-07 6.82E

-05

1.22

E-05

9.63

E-06

2.56E

-06

4.59

E-07

3.62

E-07

Applicator

Spray

(all 

starting 

formulati

ons)

Groundboom

Nursery (ornamentals, vegetables, trees, container 

stock) and Greenhouse (ornamentals, roses, cut 

flowers, container stock, vegetables)

0.0

01

5

0.

00

03

0.0

00

2

6.38E-05

1.8

2E

-05

3.7

2E

-06

2.9

E067.84E-07 1.89E

-05

4.51

E-06

3.69

E-06

7.11E

-07

1.7E

-07

1.39

E-07

Orchard/Vineyard 0.0

01

0.

00

02

0.0

00

2

4.25E-05

1.2

1E

-05

2.4

7E

-06

1.9

4E

-06

5.22E-07 1.27E

-05

0.00

0003

2.47

E-06

4.78E

-07

1.13

E-07

9.29

E-08

Field crop, typical 0.0

02

0.

00

04

0.0

00

3

0.0001

2.4

1E

-05

4.9

5E

-06

3.8

7E

-06

1.04E-06 2.52E

-05

0.00

0006

4.92

E-06

9.48E

-07

2.26

E-07

1.85

E-07

Mixer/Loader/Applicator

L/SC/EC

Backpack

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables) 

0.0

03

0.

00

28

0.0

01

6

0.0004

4.0

6E

-05

3.4

4E

-05

1.9

2E

-05

4.3E-06 4.49E

-05

3.87

E-05

2.35

E-05

1.69E

-06

1.46

E-06

8.84

E-07

Nursery (ornamentals, vegetables, trees, container 

stock) and Christmas Tree farm

0.0

14

6

0.

00

76

0.0

04

2

0.0002

0.0

00

18

0.0

00

1

0.0

00

05

0.000002 0.000

182

0.00

0096

0.00

0054

6.84E

-06

3.61

E-06

2.03

E-06

Manuallypressurized 

Handwand

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables) and Nursery 

(ornamentals, vegetables, trees, container stock)

0.0

25

0.

00

01

9.1

3E

-05

0.0001

0.0

00

3

1.3

3E

-06

1.1

2E

-06

9.22E-07 0.000

309

2.25

E-06

2.04

E-06

1.16E

-05

8.46

E-08

7.67

E-08

Mechanicall

ypressurized 

Handgun

Orchard/Vineyard and Nursery (ornamentals, 

vegetables, trees, container stock) and Christmas 

Tree Farm and Field crop, typical

0.0

37

9

0.

01

3

0.0

08

5

0.00054

0.0

00

5

0.0

00

16

0.0

00

10

4

0.000007 0.000

472

0.00

0165

0.00

0111

1.77E

-05

6.20

E-06

4.17

E-06
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 27 of 43

Table 9.1.2 Occupational Private/Farmer Handler Cancer Exposure and Risk Estimates for Proposed Use of Clofentezine Registered Uses with 10% Dermal Absorption1

Exposure Scenario

Crop / Target Category

Dermal Dose 

(mg/kg/day)

Inhalation 

Dose 

(mg/kgday)

Lifetime Average Private/Farmer

Lifetime Average 

Combined Dose 

(mg/kg-day)2

Private/Farmer 

Handler Cancer Risk Dermal Dose 3

(mg/kg/day)

Inhalation 

Dose 

(mg/kgday)

Formulat

ion

Application 

Equipment

SL

/N

o 

G

S

L/

G

DL

/G No-R

SL

/N

o 

G

SL

/G

DL

/G No-R

SL/N

o G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

SL/N

o G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

Greenhouse (ornamentals, roses, cut flowers, 

container stock, vegetables)

0.0

21

9

0.

01

6

0.0

1

0.0075

0.0

00

3

0.0

00

2

0.0

00

12

3

9.22E-05 0.000

361

0.00

0284

0.00

0215

1.36E

-05

1.07

E-05

8.08

E-06

1 Private growers are assessed assuming 10 days of exposure per year. The term “private grower” means that the grower or one of the workers would apply the pesticides to land owned or operated by the 

grower. 

2 Total LADD = Total Absorbed Dose [Dermal Dose + Inhalation Dose] * Days per year of exposure X years per lifetime of exposure / (365 days/year x Lifetime expectancy.

3 Cancer risk estimates = LADD * Q1

*

, where Q1

* = 3.76 X 10 -2

(mg/kg/day)-1.

4 Crops are assessed at the maximum rate of 0.25 lb ai/A or 0.005 lbs ai/gallon. Typical rates not provided. Formulated clofentezine products are liquid concentrates, soluble concentrates, or emulsifiable 

concentrates (L/SC/EC).

5 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2015); Level of mitigation: SL/No G (Single layer dermal protection consisting of long sleeve shirt, 

long pants, and socks and shoes) no gloves; SL/G (single layer dermal protection) plus the addition of gloves, DL/G (Double layer dermal protection plus the addition of gloves), No-R (no respirator),
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 28 of 43

Table 9.1.3 Short/Intermediate Term Occupational Commercial Handler Cancer Exposure and Risk Estimates Clofentezine with 10 % Dermal Absorption1

Exposure Scenario

Crop / Target Category

Dermal Dose 

(mg/kg/day)

Inhalatio

n Dose 

(mg/kgday

Lifetime Average 

Dermal Dose 

(mg/kg/day)

Lifetim

e 

Averag

e 

Inhalati

on 

Dose 

(mg/kgday)

Contract/Commercial 

Handler

Lifetime Average 

Combined Dose 

(mg/kg-day)2

Contract/Commercia

l Handler 

Cancer Risk (mg/kgday)2

Formula

tion

Application 

Equipment

SL/No 

G

SL/G DL/

G

No-R

SL/N

o G SL/G DL/G

No-R

SL/No 

G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

SL/N

o G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

Mixer/Loader

L/SC/E

C

Groundboo

m

Nursery (ornamentals, vegetables, trees, 

container stock) and Greenhouse 

(ornamentals, roses, cut flowers, 

container stock, vegetables)

0.0041 0.0007 0.00

055 4.11E-05 0.00015

0.000

03

2.01

E05

1.52E060.0001

5

2.75

E05

2.16

E-05

5.79E

-06

1.03

E06

8.12

E-07

Orchard/Vineyard 0.0028 0.0005 0.00

036 2.74E-05 0.00010

1.73

E-05

1.34

E05

1.01E060.0001

0

1.83

E05

1.44

E-05

3.87E

-06

6.88

E07

5.41

E-07

Field crop, typical 0.0055 0.001 0.00

073 5.48E-05 0.00020

3.47

E-05

2.68

E05

2.02E060.0002

1

3.67

E05

2.89

E-05

7.71E

-06

1.38

E06

1.09

E-06

Applicator 

Spray

(all 

starting 

formulat

ions)

Groundboo

m

Nursery (ornamentals, vegetables, trees, 

container stock) AND Greenhouse 

(ornamentals, roses, cut flowers, 

container stock, vegetables)

0.0015 0.0003 0.00

024 6.38E-05 5.46E-05

1.12

E-05

8.7

E06

2.35E065.68E05

1.35

E05

1.11

E-05

2.14E

-06

5.08

E07

4.17

E-07

Orchard/Vineyard 0.001 0.0002 0.00

016 4.25E-05 3.63E-05

7.41

E-06

5.83

E06

1.57E060.0000

4

0.00

001

7.41

E-06

1.43E

-06

3.38

E07

2.79

E-07

Field crop, typical 0.002 0.0004 0.00

032 0.00009 7.23E-05

1.49

E-05

1.16

E05

3.13E067.56E050.00

002

1.48

E-05

2.84E

-06

6.77

E07

5.56

E-07

Mixer/Loader/Applicator 

L/SC/E

C

Backpack

Greenhouse (ornamentals, roses, cut 

flowers, container stock, vegetables) 0.0033 0.0028 0.00156 0.00035 0.00012

0.000

10

5.75

E05

1.29E050.0001

4

0.00

012

7.04

E-05

5.08E

-06

4.36

E06

2.65

E-06

Nursery (ornamentals, vegetables, trees, 

container stock) and Christmas Tree farm 0.0146 0.0077 0.00423 0.0002 0.00054

0.000

28

0.00

016 0.00001 0.00055

0.00

029

0.00

016

2.05

E-05

1.08

E05

6.09

E-06
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 29 of 43

Table 9.1.3 Short/Intermediate Term Occupational Commercial Handler Cancer Exposure and Risk Estimates Clofentezine with 10 % Dermal Absorption1

Exposure Scenario

Crop / Target Category

Dermal Dose 

(mg/kg/day)

Inhalatio

n Dose 

(mg/kgday

Lifetime Average 

Dermal Dose 

(mg/kg/day)

Lifetim

e 

Averag

e 

Inhalati

on 

Dose 

(mg/kgday)

Contract/Commercial 

Handler

Lifetime Average 

Combined Dose 

(mg/kg-day)2

Contract/Commercia

l Handler 

Cancer Risk (mg/kgday)2

Formula

tion

Application 

Equipment

SL/No 

G

SL/G DL/

G

No-R

SL/N

o G SL/G DL/G

No-R

SL/No 

G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

SL/N

o G + 

No-R

SL/

G + 

NoR

DL/

G + 

NoR

Manuallypressurized 

Handwand

Greenhouse (ornamentals, roses, cut 

flowers, container stock, vegetables) and 

Nursery (ornamentals, vegetables, trees, 

container stock)

0.025 0.0001

9.13

E050.00008 0.000

92

3.98

E-06

3.37

E06

2.77E060.0009

3

6.75

E06

6.12

E-06

3.48

E-05

2.54

E07

2.3E

-07

Mechanicall

ypressurized 

Handgun

Orchard/Vineyard and Nursery 

(ornamentals, vegetables, trees, container 

stock) and Christmas Tree farm, Field 

crop, typical

0.0081 0.0024 0.00

181 0.00024 0.0003

0.000

09

6.68

E050.00001 0.0003

1

9.88

E05

7.56

E-05

1.16

E-05

3.71

E06

2.84

E-06

Greenhouse (ornamentals, roses, cut 

flowers, container stock, vegetables) 0.0379 0.0129 0.0085 0.0005 0.0014

0.000

48

0.00

031 0.00002 0.00142

0.00

049

0.00

033

5.34

E-05

1.86

E05

1.25

E-05

1 Commercial growers are assessed assuming 30 days of exposure per year. 

2 Total LADD = Total Absorbed Dose [Dermal Dose + Inhalation Dose] * Days per year of exposure X years per lifetime of exposure / (365 days/year x Lifetime expectancy.

3 Cancer risk estimates = LADD * Q1

*

, where Q1

* = 3.76 X 10 -2

(mg/kg/day)-1.

4 Crops are assessed at the maximum rate of 0.25 lb ai/A or 0.005 lbs ai/gallon. Typical rates not provided. 

5 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2015).
Clofentezine Human-Health Risk Assessment DP No. 423333

Page 30 of 43

9.2 Occupational Post-Application Exposure and Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

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 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(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 has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-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 analysis is 

required for clofentezine.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

9.2.2. Occupational Post-application Dermal Exposure/Risk Estimates

A quantitative dermal post-application exposure assessment was conducted and noncancer and 

cancer risk estimates were calculated. HED classifies exposures from 1 to 30 days as short-term 

and exposures 30 days to six months as intermediate-term. For clofentezine, based on the 

proposed use, ST and IT exposure are anticipated. 

Occupational Post-application Non-Cancer Dermal Risk Estimates
Clofentezine Human-Health Risk Assessment DP No. 423333

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Short- and intermediate-term non-cancer dermal post application exposure and risks were 

estimated using 1) standard default values for dermal transfer coefficients from the Science 

Advisory Council for Exposure Policy Number 3.2: Agricultural Transfer Coefficients, June 3, 

2011; 2) the maximum clofentezine label application rates; 3) a dislodgeable foliar residue 

(DFR) study on apples (MRID 43898901) grown in Washington State (DFR = 0.515 ug/cm2 on 

day of application) that was used as a surrogate for all registered crops; and 4) the assumption 

that an average occupational workday is 8 hours long.

The non-cancer post-application exposure estimates do not exceed HED’s level of concern 

(MOEs ≥ 100) at day 0 after treatment (DAT) using the highest post-application transfer 

coefficients for the proposed crops, avocado and papaya. However there are existing grape 

activities included in the crop group 13-07F that do exceed HED’s level of concern at day 0 after 

treatment. These post-application activities include, tying training, hand harvest, hand-leaf 

pulling and girdling/turning. See table 9.2.2.1 for a summary of occupational post-application 

risk estimates for clofentezine.
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Table 9.2.2.1 Short-Term Occupational Post-application Dermal Non-Cancer Exposure and Risk Estimates for Proposed Clofentezine Uses Using the 

Highest Transfer Coefficients and Existing 

Crop/Site

Policy Crop 

Group 

Category

Activities

Transfer 

Coefficient 

(cm2/hr.)

DFR1

Dermal Dose 

(mg/kg/day)2 MOE3

0 DAT4 7 DAT 30 DAT 0 DAT 7 DAT 30 DAT

Avocado 99 Hand-Harvesting 1,400

0.5 ug/cm2

0.007 0.006 0.003 290 340 590 Papaya

Floriculture NA 4,800 0.0239 0.02 0.011 84 99 170

Cherry (12-12A)

Peach (12-12B) Thinning Fruit 3,600 0.018 0.015 0.009 110 130 230

Pome Fruits (11-10)

Grape, Wine 

And 

Grape, 

Juice (13-07F)

Tying/Training, HandHarvesting, Hand-Leaf 

Pulling

10,100 0.051 0.043 0.025 40 47 82

Grape, Table

And 

Grape Raisin

Girdling/ Turning 19,300 0.097 0.082 0.047 21 25 43

Tying/Training, HandHarvesting, Hand-Leaf 

Pulling

5,500 0.028 0.023 0.013 73 86 1506

1. DFR = MRID (43898901) Brady, S.; Kelly, I. (1991) Dissipation of Clofentezine Foliar Dislodgeable Residues Following Application of Apollo SC to Apples Grown in Washington State, 1989: Lab 

Project Number: R152.03.89: 1322-89-101-05-02B-01: 38292,38293. Unpublished study prepared by Northwest Agricultural Research, Inc.; Landis International, Inc.; and Analytical Bio-Chemistry 

Labs, Inc. 65 p MRID (43898901) Brady, S.; Kelly, I. (1991) Dissipation of Clofentezine Foliar Dislodgeable Residues Following Application of Apollo SC to Apples Grown in Washington State, 1989.

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (10%)]  BW (80 kg).

3 MOE = POD (2.0 mg/kg/day) / Daily Dermal Dose. 

4. Day after treatment (DAT)

5 .Bolded number are risk estimates that exceed concern

6 DAT14 table and raisin grapes has a post-application MOE of 100.
Clofentezine Human-Health Risk Assessment DP No. 423333

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Occupational Post-application Cancer Dermal Risk Estimates

Cancer dermal post application exposure and risks were estimated using 1) standard default

values for dermal transfer coefficients from the Science Advisory Council for Exposure Policy 

Number 3.2: Agricultural Transfer Coefficients, June 3, 2011; 2) typical application rates 

supplied in a Biological and Economic Analysis Division (BEAD) memo (Doucoure, 2011); 3) a 

dislodgeable foliar residue (DFR) study on apples (MRID 43898901) grown in Washington State 

(DFR = 0.51 ug/cm2 on day of application) that was used as a surrogate for all registered crops; 

4) the assumption that an average occupational workday is 8 hours long; 5) the assumption that 

exposure to a post-application scenario occurs 30 days a year at day 0 residues; 6) a standard 

value for years per lifetime of exposure (35 years over a lifetime); and 7) a standard value for 

lifetime expectancy of 78 years taken from the Exposure Factors Handbook 2011 Edition Table 

18-1 (U.S. EPA, 2011).

The cancer post-application risk estimates with the highest transfer coefficients for the proposed 

crops and crop groups calculated ranged from 9.71E-06 to 1.0E-04 at day 0 after treatment 

(DAT) and 6.92E-06 to 1.0E-04 using the average 30 day dose. The existing grape postapplication activity of girdling/turning is the highest cancer number. See table 9.2.2.2 for cancer 

post-application risk estimates.
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Table 9.2.2.2. Occupational Post-Application Cancer Exposure and Risk Estimates for Proposed Clofentezine Uses Using the Highest Transfer 

Coefficients.

Crop/Site Policy Crop 

Group Category Activities

Transfer 

Coefficient 

(cm2/hr.)

DFR1

Dermal LADD (mg/kg/day)1 Cancer Risk Estimate2

0 DAT4 30 Day 

Average 0 DAT 30 DayAverage

Avocado 99 Hand-Harvesting 1,400

0.5 

μg/cm2

2.58E-04 1.84E-04 9.71E-06 6.92E-06 Papaya

Floriculture NA 4,800 0.000883 0.000629777 3.32E-05 2.37E-05

Stone Fruit (12-12) Thinning Fruit 3,600 6.64E-04 4.73E-04 2.50E-05 1.78E-05

Pome Fruits (11-10)

Grape, Wine 

And 

Grape, 

Juice

(13-07F)

Tying/Training, HandHarvesting, Hand-Leaf 

Pulling

10,100 0.0019 0.0013 7E-05 5E-05

Grape, Table

And 

Grape Raisin

Girdling/ Turning 19,300 0.0036 0.0025 1E-04 1E-04

Tying/Training, HandHarvesting, Hand-Leaf 

Pulling

5,500 0.0010 0.0007 4E-05 3E-05

1 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

2 Daily Dose (mg/kg/day)= DFR (μg/cm2) x 0.001 mg/ug x Tc (cm2/hr) x DA (10%) x ET (8 hr/day)/80 kg

3 Cancer risk estimate = Dermal LADD (0 DAT or 30 day average doses mg/kg/day) × Q1

*

, where Q1

* = 3.76 X 10-2

(mg/kg/day)-1.
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Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of clofentezine. 

Clofentezine is classified as Toxicity Category III via the dermal route and Toxicity Category IV 

for skin irritation potential. It is a weak skin sensitizer. Short- and intermediate-term postapplication risk estimates were not a concern on day 0 (12 hours following application) for all 

post-application activities for the proposed crop groups avocado and papaya. Under 40 CFR 

156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary 

skin irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection 

Statement interim REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to clofentezine from application to avocado and papaya, however there 

were risk estimates of concern for crop group 13-07F and floriculture crops, therefore HED is 

recommending the REI be revised on the label to address those concerns
Clofentezine Human-Health Risk Assessment DP No. 423333

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10.0 References

BEAD memo:

 Doucoure, 2011. Clofentezine Usage Data to Support HED’s Lifetime Average Daily 

Dose Calculations

Drinking Water Memo: 

 Louie-Juzwiak, R. 2015. Clofentezine - Drinking Water Assessment for Proposed New 

Use on Avocado, Papaya, and Crop Group Expansions for Pome fruit (11-10), Cherry 

Subgroup (12-12A), Peach Subgroup (12-12B), and Small Fruit, Vine Climbing (except 

Fuzzy Kiwi) (Subgroup 13-07F). D423336.

Dietary Memo: 

 Barnes, Y. Clofentezine. Chronic and Cancer Dietary (Food and Drinking Water) 

Exposure Assessments in Support of Establishment of Permanent Tolerances and Section 

3 Registration for New Use on Avocado and Papaya and Crop Group/Subgroup 

Expansions for Pome Fruit, Group 11-10; Cherry Subgroup 12-12A; Peach Subgroup 12-

12B and Fruit, small, vine climbing, except fuzzy kiwi, Subgroup 13-07F. DP number: 

D429749, 11/10/2015.

HASPOC Memos: 

 Rury, K. (2012). Clofentezine: Summary of Hazard and Science Policy Council 

(HASPOC) Meetings: Recommendations on the need for the inhalation, and acute and 

subchronic neurotoxicity studies. June 27, 2012, TXR No. 0056333. 

 Habiba, U. (2013). Clofentezine: Summary of Hazard and Science Policy Council 

(HASPOC) Meetings: Recommendations on the need for an immunotoxicity study. June 

07, 2013. TXR# 0056690.

ORE Memo:

 Bobowiec, B., Occupational and Residential Exposure Assessment for the Proposed Uses 

on Avocado, Papaya, and expansion of crop subgroups; Cherry (12-12A), Peach (12-

12B), Pome Fruits (11-10), and Small Fruit Vines (13-07F). DP number: D429731, 

10/16/2015.

Previous Risk Assessment: 

 Smith, C. (2013). Clofentezine. Preliminary Human Health Risk Assessment for 

Registration Review. PC Code: 125501; DP Number: D401611, June 06, 2013.

Registration Review Scoping Document:

 Reaves, E. and C. Smith. (2007). Clofentezine: Registration Review Scoping Document 

for Human Health Assessments; PC Code: 125501; DP Number: D336110. January 31, 

2007. 

Residue Chemistry:

 Barnes, Y. Clofentezine: Petition for the Establishment of Permanent Tolerances and 

Registration for New Use on Avocado and Papaya and Crop Group/Subgroup Expansions 

for Pome Fruit, Group 11-10; Cherry Subgroup 12-12A; Peach Subgroup 12-12B and 
Clofentezine Human-Health Risk Assessment DP# 423333

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Fruit, small, vine climbing, except fuzzy kiwifruit, Subgroup 13-07F, Summary of 

Analytical Chemistry and Residue Data. DP number: D 429732, 11/10/2015

Attachments 

Appendix A. Toxicology Profile and Executive Summaries

Appendix B. Review of Human Research

Appendix C. Physical/Chemical Properties

Appendix D. Summary of Occupational Algorithms

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for clofentezine are in Table A.1. Use of the new guideline numbers does not 

imply that the new (1998) guideline protocols were used.

TABLE A.1: Toxicology Data Requirements for Clofentezine

Test Technical

Required Conducted

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (non-rodent)

870.3200 21/28-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

CR1

yes

yes

no

no

waived

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (non-rodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (non-rodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation (bacterial)

870.5300 Mutagenicity—Gene Mutation (mammalian)

870.5375 Mutagenicity—Structural Chromosomal Aberrations

870.5395 Mutagenicity—Other Genotoxic Effects 

870.5500 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

no

no

yes2

yes2

no

no

no

waived

waived

no
Clofentezine Human-Health Risk Assessment DP# 423333

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TABLE A.1: Toxicology Data Requirements for Clofentezine

Test Technical

Required Conducted

870.7485 General Metabolism

870.7600 Dermal Penetration 

870.7800 Immunotoxicity

yes

no

yes3

yes

yes

waived

1

In June 2012, the HASPOC waived the conditional requirement for an inhalation study (TXR 0056333, 6/27/2012).

2

In June 2012, the HASPOC waived the requirement for a neurotoxicity battery (TXR 0056333, 6/27/2012).

3

In June 2013, the HASPOC waived the requirement for an immunotoxicity study (TXR#0056690, 06/07/2013).

A.2 Toxicity Profiles

Table A . 2 . 1: Acute Toxicity of Clofentezine

Guideline No. Study Type MRIDs # Results Toxicity

Category

870.1100 Acute Oral- Rats 00159071 LD50 >3230 mg/kg III

870.1200 Acute Dermal- Rats 00105902 LD50 >1332 mg/kg III (Suppl)1

870.1300 Acute Inhalation- Rats 00138753* LC50 >11.35 mg/L (6hr.) IV

870.2400 Primary Eye Irritation- Rabbits 00105907* mild irritant IV

870.2500 Primary Skin Irritation- Rabbits 00159073 not a skin irritant IV

870.2600 Dermal Sensitization- Guinea pigs 00159074 weak sensitizer NA

*80% formulation [80 WP]

1 All animals had intact skin and sufficiently high doses to clearly establish a toxicity category classification were not used.

TABLE A.2.2: Subchronic, Chronic and Other Toxicity Profile for Clofentezine

Guideline No/ 

Study type

MRID No. (year)/ 

Classification /Doses Results

870.3100

Subchronic-FeedingMouse

none incorporated into the two year mouse oncogenicity study

870.3100

Subchronic 28 day 

Feeding in

Male Rats

40975503 (1989)

Acceptable/non-guideline

0, 10, 400, 3000, or 30000 

ppm

M: 0, 1, 40, 300 or

3000 mg/kg/day (> Limit

Dose)

NOAEL (systemic) = 1.0 mg/kg/day [10 ppm]

LOAEL (systemic) = 40.0 mg/kg/day [400 ppm], based on increased 

enzyme activity (uridine diphosphate glucuronyltransferase; UDPGT), and

thyroid activity (hypertrophy, hyperplasia, and mitotic activity of follicular

cells, colloid depletion and an increase in thyroid weight).

870.3100

Subchronic 13 WeekFeeding-Rat

00105911 (1981)

00159079

40467905

Acceptable/guideline

0, 40, 400, or 4000 ppm 

M & F: 0, 2, 20, or 200 

mg/kg/day

NOAEL (systemic) = 2.0 mg/kg/day [40 PPM]

LOAEL (systemic) = 20.0 mg/kg/day [400 PPM], based on increased 

cholesterol levels, liver-to-body weight ratios, liver weights, and 

centrilobular hepatocellular enlargement.
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870.3150

Subchronic 13 WeekFeeding Dog

00105912 (1981)

00126844

Acceptable/guideline

0, 3200, 8000, or 20000 ppm 

M & F: 0, 80, 200 or 500 

mg/kg/day

NOAEL was not established. LOAEL (systemic) < 80.0 mg/kg/day

[<3200 ppm], based on increased liver weights in both sexes and

electrocardiographic changes in females.

870.3200

21-Day Dermal

Toxicity-Rat

None No study available

870.3465

90-Day Inhalation 

Toxicity None No study available

870.3700a

Developmental

Toxicity-Rat

00114270 (1982)

00159095

Acceptable/guideline

0, 320, 1280, or 3200 

mg/kg/day

Maternal NOAEL = 1280 mg/kg/day (above the Limit Dose) LOAEL = 

3200 mg/kg/day, based on differential staining and

slight enlargement of the centrilobular hepatocytes.

Developmental NOAEL >3200 mg/kg/day (above the

Limit Dose)

LOAEL >3200 mg/kg/day

870.3700b

Developmental

Toxicity-Rabbit

00130761 (1983)

Acceptable/guideline

0, 250, 1000, or 3000 

mg/kg/day

Maternal NOAEL = 1000 mg/kg/day (Limit Dose)

LOAEL = 3000 mg/kg/day, based on decreased body

weight and food consumption

Developmental NOAEL= 1000 mg/kg/day (Limit

Dose)

LOAEL = 3000 mg/kg/day, based on decreased mean fetal weight.

870.3800

Reproductive

Toxicity-Rat

00147884 (1984)

00159070

Acceptable/guideline

0, 4, 40, or 400 ppm

M & F: 0, 0.2, 2.0 or 20.0 

mg/kg/day

Parental/Systemic NOAEL =20.0 mg/kg/day

LOAEL > 20.0 mg/kg/day

Reproductive NOAEL = 20.0 mg/kg/day

LOAEL > 20.0 mg/kg/day

Offspring NOAEL= 20.0 mg/kg/day

LOAEL > 20.0 mg/kg/day

870.4100a

Chronic

toxicity/Carcinogenici

ty-Rat

00147883 (1985)

00159081

40289801

Acceptable/guideline

0, 10, 40, or 400 ppm M:

0, 0.43, 1.72 or 17.3 

mg/kg/day

F: 0, 0.55, 2.18, or 22.1 

mg/kg/day

NOAEL (systemic) = 1.72 mg/kg/day [40 ppm]

LOAEL (systemic) = 17.3 mg/kg/day [400 ppm], based on increased

liver weights and liver-to-body weight ratios and increased thyroxin levels;

and centrilobular hepatocellular hypertrophy and vacuolation, focal cystic

degeneration of hepatoacytes, and diffuse distribution of fat deposits in 

liver (M).

870.4100b Evidence of carcinogenicity in male rats [thyroid tumors]

Chronic Feeding- One

Year Dog

00149491(1983)

Acceptable/guideline

0, 50,1000 or 20000 ppm M

& F: 0, 1.25, 25, or 500 

mg/kg/day

NOAEL (systemic) = 1.25 mg/kg/day [50 ppm]

LOAEL (systemic) = 25.0 mg/kg/day [1000 ppm], based on increased

liver weights, hepatocellular enlargement, and increased serum

cholesterol, triglycerides, and alkaline phosphatase levels.
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870.4200b

CarcinogenicityMouse

00147885 (1985)

00159094

40302001

Acceptable/guideline

0, 50, 500, or 5000 ppm 

M: 0, 5.0, 50.7 or 543.0 

mg/kg/day

F: 0, 5.3, 56.9, or 557.1 

mg/kg/day

NOAEL (systemic) = 50.70 mg/kg/day [500 ppm]

LOAEL (systemic) = 543.0 mg/kg/day [5000 ppm], based on decreased

body weights and body weight gains, increased incidence of eosinophilic

areas in hepatocytes of males; in females increased incidence of

basophilic and/or eosinophilic foci or areas of hepatocyte alterations,

mortality with amyloidosis as a contributing factor for increased mortality.

No evidence of carcinogenicity

Yeast cell

Saccharomyces

cerevisiae gene

conversion/mitotic 

recombination

00130765 (1983) Non-mutagenic and negative for mitotic recombination

Gene Mutation -

Salmonella

00105909 (1980)

Doses: 3.3 to 33 μg/plate

Non-mutagenic (±) activation.

Mouse Lymphoma 00159096 (1982)

40958301

Acceptable/guideline

Doses: 0, 15, 30, 70, 100, or

128 μg/ml -S9 or 0, 2, 10,

30, 80, 100, or 128 μg/ml

+S9.

Non-mutagenic (±) activation.

Micronucleus Assay

Mice

00114269(1982)

Doses: 0, 800, 1600, or 3200 

mg/kg

Non-mutagenic

Dominant Lethal Rat 00130764 (1983)

0, 4, 40, or 400pm

Non-mutagenic

870.7485

Metabolism-Rat

40942001(1985)

00159099

00159132

00105925

Acceptable/guideline

Male and female rats given clofentezine technical at 1000 mg/kg 

manifested peak plasma levels of between 14 and 16 ppm at 6-8 hours post

dosing which then declined to 3 ppm at 24 hours post dosing. Plasma halflife was approximately 3.5 hours. Whole body autoradiography of rats

given a 10 mg/kg dose indicated poor gastrointestinal absorption with 60-

70% of the given dose excreted in the feces during the first 24 hours and

about 20% excreted in the urine. Major metabolites were 3-(2'-methyl-thio3' hydroxy phenyl)-

6-(2'-chloro-phenyl)-1,2,4,5-tetrazine and 3-,4-, and 5-

hydroxyclofentezine. Both liver and kidney had the highest tissue 

concentration after 72 hours.

870.7600

Dermal penetration 49705401 (1989)

Acceptable/non-guideline 

1.0, 0.1, and 0.01 mg/rat 

(equivalent to 38.5, 3.85, 

and 0.385 μg/cm2skin)

Dermal absorption was estimated as 1.4%, 4.7%, and 10.0% 24 

hours after a 10-hour application in rats treated with 1.0, 0.1, and 

0.01 mg/rat, respectively. Similar results were obtained 120 hours 

after a 10-hour treatment; being 1.5%, 3.9%, and 10.6% in rats 

treated with 1.0, 0.1, and 0.01 mg/rat, respectively.

Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force 

(ORETF) Database, the Agricultural Handler Exposure Task Force (AHETF), and the 
Clofentezine Human-Health Risk Assessment DP# 423333

Page 41 of 43

Agricultural Reentry Task Force (ARTF) have been determined to require a review of their 

ethical conduct, have received that review, and have been determined to be ethically conducted.

Appendix C. Physical/Chemical Properties

Appendix Table C.1: Clofentezine Physical and Chemical Properties

Parameter Value

Molecular Weight 303.1 g/mol

Water solubility (20°C) 2.9 x 10-2 mg/L

Vapor pressure (25°C) 9.75 x 10-10 mmHg

Henry’s Law Constant (25°C) 3.9 x 10-10, atm-m3mole-1

Octanol/water partition coefficient (25°C) log Kow = 3.1

Appendix D. Summary of Occupational Exposure Algorithms

D.1 Occupational Non-Cancer Algorithms

Daily Exposure: Daily handler exposures are estimated for each applicable handler task with 

the application rate, the amount of acres treated or gallons applied in a day, and the applicable 

unit exposure using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) * Application Rate (lbs ai/A) * Daily 

Amount Handled (A/day) * Conversion Factor (mg/1,000 μg)

Where: 

Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation absorption,

Unit Exposure = Unit exposure value (μg ai/day),

Application Rate = Normalized application rate based on a logical unit treatment (lb ai/A), and 

Daily Amount Handled = Normalized application area based on a logical unit treatment such as acres (A/day). 

Daily Dose: Daily dose (inhalation) was calculated by normalizing the daily inhalation exposure 

value by body weight. 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day)/Body Weight (kg)

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide 

active ingredient/kg body weight/day),

Daily Exposure = Amount (mg ai/day) amount inhaled that is available for inhalation absorption, and

Body Weight = Body weight determined to represent the population of interest in a risk assessment.

Margin of Exposure (MOE): The daily inhalation dose received by occupational handlers was 

compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers for 

each exposure route. All MOE values were calculated for inhalation exposure using the 

following formula:

MOE = NOAEL (mg/kg/day)/Average Daily Dose (mg/kg/day)
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Where:

MOE = Margin of exposure value used by HED to represent risk or how close a chemical exposure is to being a 

concern (unitless),

ADD = Average daily dose (ADD) is absorbed dose received from exposure to pesticide, and

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred in the study.

D.2 Occupational Cancer Algorithms

After the development of the ADD values, the next step required to calculate carcinogenic risk 

estimates is to amortize these values over the anticipated lifetime, which results in the LADD. 

LADD values are calculated using the following equation:

LADD = ADD * 

Days per Year of Exposure

365 Days per Year * 

Years per Lifetime of Exposure

Lifetime Expectancy

where:

LADD = absorbed dose over a lifetime (mg ai/kg/day),

ADD = average daily dose absorbed in a given scenario (mg 

ai/kg/day),

Days per Year of Exposure = annual frequency of an application by an individual 

(days/year),

Years per Lifetime of Exposure = amount of a lifetime that an individual would be 

expected to use pesticides (years), and

Lifetime Expectancy = average life expectancy of an individual (years).

Cancer risk estimate calculations are completed by comparing the LADD values calculated 

above to the Q1* for the chemical. Cancer risk estimates are calculated using the following 

equation:

Total Cancer Risk Estimate = (Dermal LADD + Inhalation LADD) * Q1*

where:

Cancer Risk Estimate = probability of incidence of cancer cases over a lifetime (unitless),

Dermal LADD = absorbed dose from dermal exposure over a lifetime (mg ai/kg/day),

Inhalation LADD = absorbed dose from inhalation exposure over a lifetime (mg 

ai/kg/day), and

Q1* = quantitative dose response factor used for linear, low-dose response 

cancer risk estimate calculations (mg/kg/day)

-1
Clofentezine Human-Health Risk Assessment DP# 423333

Page 43 of 43

Appendix E. International Residue Limits Table

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.446: Clofentezine

Plant: Clofentezine

Livestock: Clofentezine and 3-(2-chloro-4-

hydroxyphenyl)-6-(2-chlorophenyl)-1,2,4,5-

tetrazine metabolite

Plant: Clofentezine

Livestock and dairy: 3,6-

bis(2-chlorophenyl)-

1,2,4,5-tetrazine, 

including the metabolite 

3-(2-chloro-4-

hydroxyphenyl)-6-(2-

chlorophenyl)-1,2,4,5-

tetrazine

Plant commodities: 

clofentezine 

Animal commodities:

sum of clofentezine, 

and all metabolites 

containing the 2-

chlorobenzoyl 

moiety, expressed as 

clofentezine 

The residue is fat 

soluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Avocado 0.3

Papaya 0.3

Fruit pome group 11-10 0.5 0.5 apple, pear 0.5 

Cherry, subgroup 12-12A 1.0 0.5 stone fruits

Peach, subgroup 12-12B 1.0 1 nectarine, peach

Fruit, small, vine climbing, except 

fuzzy kiwifruit, Subgroup 13-07F 1.0

2.0 grapes, 

dried grapes = 

(currants, raisins and 

sultanas)

Completed by: M. Negussie, 05/11/2015

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those 

proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.