Clofentezine Human Health Risk Assessment DP No. D401611 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: June6, 2013 

SUBJECT: Clofentezine. Preliminary Human Health Risk Assessment for Registration 

Review 

PC Code: 125501 

Decision No.: 464564 

Petition No.: NA 

DP Barcode: D40161 1 

Registration No.: NA 

Regulatory Action: Registration Review 

Risk Assessment Type: Single Case No.: 7602 

Chemical/ Aggregate 

TXR No.: NA 

MRIDNo.: NA 

CAS No.: 7411 5-24-5 

40 CFR: 180.446 

FROM: C

Ri

h

sk 

arles 

Assess

Smi

m

th

e

, 

n

Se

t Br

nior 

anc

Environme

h I 

ntal Scientist/Risk Assessor ~ (l~ 

and 

Sheila Piper, Senior Chemist ~~(?~~ ~ Yung Yang, Ph.D., Senior Toxicologist '71 6 r; U 

Bridgett Bobowiec, Biologist 13~ / 

Shalu Shelat, Industrial en t~/L Risk Assessment Branch VI 

Health Effects Division (7509P) ( /) 

THROUGH: Felecia Fort, Branch Chief .i,Jl.!tNe jf);;;/1 

TO: 

Risk Assessment Branch VI f"' 

Health Effects Division (7509P) 

Wilhelmena Livingston, Chemical Review Manager 

Risk Management and Implementation Branch IV 

Pesticide Re-evaluation Division (7508P) 

Page 1 of 47 
Clofentezine Human Health Risk Assessment DP No. D401611 

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. As part of Registration Review, 

the Pesticide Re-evaluation Division (PRD) of OPP has requested that HED evaluate the 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 registered 

uses of clofentezine. 

HED has evaluated the toxicity and exposure databases for the active ingredient, clofentezine, 

and has conducted a human health risk assessment in support of Registration Review. Based on 

this assessment, HED has determined that there are no potential risk estimates of concern for the 

currently registered uses of clofentezine. 

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

registered uses of clofentezine are provided in this document. The HED team members 

contributing to this risk assessment include Charles Smith (risk assessment), Bridgett Bobowiec 

and Shalu Shelat (occupational and residential assessment), Yung Yang (hazard assessment), and 

Sheila Piper (chemistry and dietary assessment). Ronald Parker of the Environmental Fate and 

Effects Division (EFED) performed the drinking water assessment for clofentezine. 

Page 2 of47 
Clofentezine Human Health Risk Assessment DP No. D401611

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

2.0 Ingredient Profile ....................................................................................................................... 7

2.1 Structure and Nomenclature................................................................................................... 7

2.2 Physical/Chemical Characteristics......................................................................................... 7

2.3 Summary of Existing Uses..................................................................................................... 8

2.4 Anticipated Exposure Pathways............................................................................................. 9

2.5 Consideration of Environmental Justice ................................................................................ 9

3.0 Hazard Characterization and Dose-Response Assessment...................................................... 10

3.1 Toxicology Studies Available for Analysis ......................................................................... 10

3.2 Absorption, Distribution, Metabolism and Elimination (ADME) ....................................... 11

3.3 Toxicological Profile............................................................................................................ 12

3.4 Consideration of Toxicity to Children ................................................................................. 12

3.4.1 Completeness of the Toxicology Database................................................................... 13

3.4.2 Evidence of Neurotoxicity ............................................................................................ 13

3.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ............... 13

3.4.4 Residual Uncertainty in the Exposure Database........................................................... 13

3.5 Toxicity Endpoint and Point of Departure Selections.......................................................... 13

3.5.1 Dose-Response Assessment.......................................................................................... 13

3.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment ............... 14

3.5.3 Cancer Classification and Risk Assessment Recommendations .................................. 14

3.6 Endocrine Disruption ........................................................................................................... 16

4.0 Dietary Exposure and Risk Assessment .................................................................................. 16

4.1 Degradate Residue Profile.................................................................................................... 16

4.1.1 Summary of Environmental Degradation ..................................................................... 16

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

4.1.3 Enforcement Analytical Method................................................................................... 17

4.2 Food Residue Profile............................................................................................................ 18

4.3 Water Residue Profile .......................................................................................................... 18

4.4 Dietary Risk Assessment...................................................................................................... 19

4.4.1 Description of Residue Data Used in Dietary Assessment........................................... 19

4.4.2 Percent Crop Treated Used in Dietary Assessment ...................................................... 20

4.4.3 Acute Dietary Risk Assessment.................................................................................... 20

4.4.4 Chronic Dietary Risk Assessment ................................................................................ 20

4.4.5 Cancer Dietary Risk Assessment.................................................................................. 20

4.4.6 Dietary Risk Assessment Summary Table.................................................................... 20

5.0 Residential (Non-Occupational) Exposure/Risk Characterization .......................................... 21

6.0 Aggregate Exposure/Risk Characterization............................................................................. 22

7.0 Cumulative Exposure/Risk Characterization........................................................................... 22

8.0 Occupational Exposure/Risk Characterization ........................................................................ 22

8.1 Occupational Handler Exposure and Risk ........................................................................... 22

8.1.1 Short-/Intermediate-Term Non-Cancer Handler Exposure and Risk............................ 23

8.1.2 Cancer Handler Exposure and Risk .............................................................................. 26

8.2 Occupational Post-Application Exposure and Risk ............................................................. 29

8.2.1 Postapplication Inhalation Exposure............................................................................. 29

8.2.2 Postapplication Dermal Exposure and Risk.................................................................. 29

8.2.2.1 Short-/Intermediate-Term Non-Cancer Postapplication Exposure and Risk................ 29
Clofentezine Human Health Risk Assessment DP No. D401611

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8.2.2.2 Cancer Postapplication Exposure and Risk .................................................................. 30

9.0 References................................................................................................................................ 32

Appendix A. Toxicology Profile and Executive Summaries............................................................. 33

A.1 Toxicology Data Requirements............................................................................................ 33

A.2 Toxicity Profiles................................................................................................................... 34

A.3 Hazard Identification and Endpoint Selection ..................................................................... 36

A.4 Executive Summaries........................................................................................................... 37

Appendix B: Review of Human Research .......................................................................................... 44

Appendix C: Physical and Chemical Properties................................................................................. 45

Appendix D: Percent Crop Treated Memo from BEAD .................................................................... 46
Clofentezine Human Health Risk Assessment DP No. D401611

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1.0 Executive Summary

As part of Registration Review, the Pesticide Re-evaluation Division (PRD) of the Office of 

Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluate the 

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 registered

uses of clofentezine. A summary of the findings and an assessment of human health risk 

resulting from the currently registered uses of clofentezine are provided in this document.

Use Profile: Clofentezine (3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine) is an acaricide that is 

currently registered as a liquid formulation for use on almonds, apples, apricots, cherries, 

Christmas trees, grapes, nectarines, ornamentals (greenhouse and outdoor), peaches, pears, 

persimmons, and walnuts.

Hazard Assessment: The toxicology database for clofentezine is complete as described in 40 

CFR, Part 158. 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 (TXR 

0056333, 6/27/2012). More recently, in June 2013, HASPOC waived the requirement for an 

immunotoxicity study (final report pending).

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 while dermal absorption of clofentezine is low (1%).

The clofentezine Registration Review risk assessment team has recommended that the FQPA 

Safety Factor be reduced to 1X because there is an adequate toxicity database for clofentezine. 

Two pre-natal developmental toxicity studies were available, one in rat and one 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 post 

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

thyroid follicular cell adenoma and/or carcinoma combined tumor rates. The Q

*

1 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 to be a mutagen.

Dietary Exposure (Food and Drinking Water): The residue chemistry data and environmental 

fate data are adequate to assess human exposure. Estimated drinking water concentrations 

(EDWCs) were generated by the Environmental Fate and Effects Division (EFED) using 

computer modeling methods. 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). The groundwater EDWC value was 
Clofentezine Human Health Risk Assessment DP No. D401611

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0.04 ppb. 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).

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

were identified from the available clofentezine toxicity studies for the acute dietary scenario. 

Chronic: A somewhat refined chronic dietary exposure assessment was performed that directly 

incorporated average residues, latest percent crop treated information, and potential drinking 

water 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). 

Cancer: A somewhat refined cancer dietary exposure assessment was performed that directly 

incorporated potential drinking water residues as clofentezine has been classified as a possible 

human carcinogen. Applying the Q1* of 0.0376 (mg/kg/day)-1to the exposure value results in a 

cancer risk estimate of 2.8 x 10-7to the general U.S. population.

Residential Exposure: There are currently no registered residential uses associated with 

clofentezine; therefore, a residential/non-occupational exposure assessment is not required. 

Aggregate Risk: 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, a residential/non-occupational exposure 

assessment is not required. As a result, the clofenetize aggregate risk assessment includes only 

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

no appropriate endpoints were identified from the available clofentezine toxicity studies for the 

acute dietary scenario. 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 2.8 x 10-7.

Occupational Exposure/Risk: Occupational handler exposures to the existing uses of 

clofentezine may occur via the dermal and inhalation route. The short- and intermediate-term 

risk estimates for all occupational handler scenarios do not exceed HED’s level of concern 

(MOEs > 100) at baseline personal protective equipment (PPE). Clofentezine cancer 

occupational handler risk estimates for ranged from 1.8 X 10-6to 7.2 X 10-9and 5.3 X 10-6to 2.2

X 10 -8 for private growers and commercial applicators, respectively.

Occupational postapplication exposures to the existing uses of clofentezine may occur via the 

dermal route. The short- and intermediate-term risk estimates for all activities do not exceed 

HED’s level of concern (MOEs > 100) using predicted Day 0 residue values from the DFR 

study. The postapplication cancer risk estimates for all activities ranged from 1.31 X 10 -6to 

9.38 X 10-8.
Clofentezine Human Health Risk Assessment DP No. D401611

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The restricted entry intervals (REI) listed on the existing clofentezine labels are based on the 

acute toxicity of the technical material. 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 post-application risk estimates were not a concern on day 0 (12 

hours following application) for all post-application activities. Under WPS for agricultural 

pesticides, active ingredients classified as Acute III or IV for acute dermal, eye irritation and 

primary skin irrigation are assigned a 12-hour REI. Therefore, the REI of 12 hours on current 

clofentezine labels is adequate to protect agricultural workers from post-application exposures to 

clofentezine.

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 

(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 Ingredient Profile

Clofentezine is an acaricide currently registered for use on a number of commodities.

2.1 Structure and Nomenclature

Table 2.1: 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

2.2 Physical/Chemical Characteristics

The physical and chemical properties, as well as a summary of relevant environmental fate 

parameters are detailed in Appendix C. Clofentezine’s vapor pressure (9.75 x 10-10 mm Hg @

25.0°C) and Henry's Law Constant (3.9 x 10-10, atm-m

3mole-1

) 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. 
Clofentezine Human Health Risk Assessment DP No. D401611

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2.3 Summary of Existing Uses

Clofentezine is formulated into a suspension concentrate containing 42.0 % active ingredient and 

contain 1.0 lb active ingredient per quart (i.e., 4.0 lb a.i./gallon). The product has the trade 

names; APOLLO®SC Ovicide/Miticide (EPA Reg. No. 66222-47) and Clofentezine SC (EPA 

03-05-2012). Currently registered use sites include the following; almonds, apples, apricots, 

cherries, Christmas tree (except California) and Christmas tree plantations, grapes (except New 

York), nectarines, pears, peaches, persimmons, and walnuts. The rates of application range from 

0.125 - 0.25 lb a.i. /acre on apples, grapes (except New York), pears, and Christmas trees and 

Christmas tree plantations (except California). Application rates range from 0.0625 - 0.25 lb ai/ 

acre for almonds, apricots, cherries, peaches, nectarines, persimmons and walnuts. The preharvest interval or PHI ranges from 14 to 45 days for the majority of the crops except for 

persimmons which has a PHI of 140 days.

In addition to traditional agricultural crops, the Clofentezine SC label permits commercial 

application to ornamentals in greenhouses, saran and shade houses, outdoor containers and fieldgrown nursery stock. The rate of application 2 fl. ounces per 100 gallons, or 0.0625 lbs a.i./acre 

when used in high volume sprays using hand-held equipment. For low volume applications apply 

0.125 to 0.25 lbs of ai/ acre. 

Clofentezine is applied primarily by airblast and groundboom machinery. It may not be applied 

aerially or through any type of irrigation system. The label recommends that clofentezine be 

applied only one time per year. The label lists a 12 hour restricted-entry interval or REI. The 

label also indicates personal protection equipment requirement or PPE to include a long-sleeved 

shirt and long pants, chemical resistant gloves, such as barrier laminate, butyl rubber, neoprene 

rubber, poly-vinyl chloride (PVC), or Viton®and shoes plus socks. The uses and application 

rates are further described in Table 2.3.

Table 2.3: Summary of Directions for Currently Registered Uses of Clofentezine

Commodity

Product: 

EPA Reg. 

No.

Application 

Equipment

Max Single 

Application 

Rate

(lb ai/A)

Max # 

Applications

Per Season

Max Seasonal 

Application 

Rate

(lb ai/A)

PHI1

(days)

Use Directions 

and Limitations

Almonds

66222-47

66222-65

Ground 0.25 lb ai/A 1 0.25 lb ai/A

30 days (14 

days in 

California) Apply at first 

sign of mite 

activity. Do not 

apply by 

irrigation or air. 

Do not apply 100 

feet within body 

of water. Do not 

graze livestock in 

treated area.

Apples 45 days

Apricots 21 days

Cherries 21 days

Christmas Trees 

(except CA)

NA

Grapes (except NY) 21 days (10 

days CA Nectarines

Peaches 21 days (10 

days CA)

Pears 21 days

Persimmons 140 days

Walnuts 30 days
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Table 2.3: Summary of Directions for Currently Registered Uses of Clofentezine

Commodity

Product: 

EPA Reg. 

No.

Application 

Equipment

Max Single 

Application 

Rate

(lb ai/A)

Max # 

Applications

Per Season

Max Seasonal 

Application 

Rate

(lb ai/A)

PHI1

(days)

Use Directions 

and Limitations

Ornamentals 

(greenhouses, 

saran/shade, outdoor 

containers, field-grown)

66222-53 NA

2.4 Anticipated Exposure Pathways

Humans may be exposed to clofentezine in their diet resulting from residues present in foods 

treated with clofentezine. Further, given the environmental fate parameters of clofentezine and 

the registered agricultural uses, the potential exists for clofentezine to reach water resources 

resulting in potential residues in drinking water. There are currently no residential uses of 

clofentezine, so exposure in residential and non-occupational settings is not likely. There is a 

potential for occupational handler and post-application exposures.

2.5 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://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the U.S. Department of 

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

(NHANES/WWEIA) 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 

postapplication 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.

2.6 Enforcement Analytical Method

An adequate method is available for clofentezine, Method J-95R-02, which utilizes high pressure

liquid chromatography (HPLC). The limit of quantitation (LOQ) and limit of detection (LOD) 

were determined to be 0.01 ppm and 0.003 ppm, respectively. HED concluded that the method 

was suitable for enforcement purposes. The method was forwarded to FDA for inclusion in 
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PAM-II. Pesticide analytical method (PAM)-I multiresidue methods are not acceptable for 

tolerance enforcement.

3.0 Hazard Characterization and Dose-Response Assessment

3.1 Toxicology Studies Available for Analysis

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

complete database based on the revised 40 CFR Part 158 Toxicology Data Requirements. 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. 

More recently, in June 2013, HASPOC waived the requirement for an immunotoxicity study 

(final report pending). 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 [2 rat and dog) 

Developmental (rat and rabbit) and reproductive toxicity (rat) studies 
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Chronic oral toxicity studies (rat and dog)

Carcinogenicity studies [rat (chronic combined) and mouse]

Metabolism studies (rat)

Mutagenicity battery

Dermal penetration

3.2 Absorption, Distribution, Metabolism and Elimination (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.

3.2.1 Dermal Absorption

In a dermal absorption study (MRID 159102; Campbell et al., 1986), radiolabeled 14Cclofentezine of 50 SC formulation was applied to the skin of male rats at dose levels of 0.18, 

1.69, or 6.92 mg/cm2(equivalent to 4.8, 44 or 180 mg/kg, respectively) for a 10 hour exposure. 

Following 10 hours post-application, the amount of radioactivity found on the gauze ranged from 

43% to 59% of the applied dose at three dose levels tested. At 10 hours post-application, 

approximately 8% to 47% of the applied doses were found in the skin wash fraction and 10% to 

32% of the applied dose remained on the treated skin. Based on the amount of combined 

clofentezine found in the urine, feces, GI tract and carcass, the percent absorption at 10 hours

ranged from 0.61%, 0.08%, and 0.09% at the 4.8, 44, and 180 mg/kg dose levels tested, 

respectively. Since only 50% of the applied dose was available for dermal absorption, the 

corrected dermal absorption rates were estimated to be 1.22%, 0.16%, and 0.18% at the 4.8, 44, 

or 180 mg/kg dose levels tested, respectively.

There was a significant dose distribution of the material in the dosed/washed skin which was 

considered potentially absorbable. However, only a very small portion of the material that 

entered the skin during the 10 hour exposure period actually continued through it into the 

systemic compartment most likely due to the low water solubility of clofentezine (2.5 ug/L) and 

possibly would be lost during exfoliation of the stratum corneum. Water solubility is necessary 

for a chemical to leave the lipid based stratum corneum and enter the water based viable 

epidermis on its passage into the systemic compartment (Memorandum dated April 2, 1999,

Zendzian, R.). This conclusion was supported by another dermal absorption study (Challis, et 

al., 1989). In this study, male rats were administered radiolabeled clofentezine at doses of 0.38, 

3.8, and 38 μg/cm2. After 10 hours, the treated skin was washed rigorously with soap and water, 

and animals were sacrificed at 24 or 120 hours following administration of the test material. 

Total absorbed doses were 12.64%, 6.45%, and 2.98% at 24 hours and 11.09%, 4.03% and

1.60% at 120 hours at the 0.38, 3.8, and 38 μg/cm

2

dose levels tested, respectively. The amount 
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of the administered dose recovered in the skin at the application site was less than 3% in all dose 

groups due to a rigorous washing regime (gentle scrubbing with a toothbrush). It is to be noted 

that the applied doses in the Challis study were 1000 fold (μg/cm2vs mg/cm2) lower than the 

Campbell study which would result in higher percent dermal absorption value. Nevertheless, the 

total absorbed doses were lower in the 120 hours than the 24 hours measurements in all dose 

levels suggesting that the amount of continuous absorption from the skin residue is negligible. 

Therefore, based on all of the available data, HED selected a dermal absorption rate of 1% for 

use in clofentezine dermal risk assessment. 

3.3 Toxicological Profile

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 decreases 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 post 

natal 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 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.

3.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The clofentezine Registration Review risk assessment team has recommended that the FQPA 

Safety Factor 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 
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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.

3.4.1 Completeness of the Toxicology Database

The toxicology database for clofentezine is complete as described in 40 CFR, Part 158. In June 

2012, HASPOC waived the requirement for a neurotoxicity battery and a route specific 

inhalation toxicity study (TXR 0056333, 6/27/2012). More recently, in June 2013, HASPOC 

waived the requirement for an immunotoxicity study (final report pending).

3.4.2 Evidence of Neurotoxicity

As discussed in Section 3.1, 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).

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

There are no residual uncertainties for pre-and or post natal susceptibility for clofentezine. No 

evidence of increased quantitative or qualitative susceptibility was observed in the 

developmental toxicity studies in rats and rabbits or in a 2-generation reproduction study in rats.

3.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary 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 fro clofentezine.

3.5 Toxicity Endpoint and Point of Departure Selections

3.5.1 Dose-Response Assessment

The details for selecting toxicity endpoints and points of departure (PODs) are presented in 

Appendix A2. Based on the existing use pattern for clofentezine, the expected exposure profile 

will be for dietary, occupational dermal, and occupational inhalation exposures. 

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

U.S. population (including infants and children) or any population subgroups. No appropriate 

toxicological endpoint attributable to a single exposure was identified in the available toxicology 

studies including the rat and the rabbit developmental studies.
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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). 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 = 20mg/kg/day). Since an oral 

dose was selected, a dermal absorption factor of 1% should be used in estimating dermal risks 

(see Section 3.2.1). An MOE of 100 is required 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 = 

20mg/kg/day). Since an oral study was selected, absorption via inhalation is presumed to be 

equivalent to oral absorption. An MOE of 100 is required which includes interspecies

extrapolation (10X) and intraspecies variability (10X).

3.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational exposures to a pesticide, the risk assessment must address 

exposures from two major sources: dermal and inhalation exposures, and determine whether the 

individual exposures can be combined if they have the same toxicological effects. 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. 

3.5.3 Cancer Classification and Risk Assessment Recommendations

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.
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3.5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 3.5.4.1: Toxicological Doses and Endpoint for Use in Clofentezine Dietary and NonOccupational 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 3.5.4.2: 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)

NOAEL = 2.0 

mg/kg/day

UFA = 10X 

UFH = 10X 

Total UF = 100X

Dermal Absorption = 1%

Occupational LOC = 

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)

NOAEL = 2.0 

mg/kg/day

UFA = 10X 

UFH = 10X 

Total UF = 100X

Occupational LOC = 

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).
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3.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of registration review, EPA will review these data and select the most 

sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. 

However, as required by FFDCA section 408(p), paclobutrazol is subject to the endocrine 

screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. In November 

of 2010, issued test orders/data call-ins for the second group of 134 chemicals, which contains 51

pesticide active ingredients. Clofentezine is among the group of 51 pesticide active ingredients 

on the second list to be screened under the EDSP. Accordingly, as part of registration review, 

EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening 

assays for clofentezine. For further information on the status of the EDSP, the policies and 

procedures, the list of chemicals, future lists, the test guidelines and the Tier 1 screening battery, 

please visit our website: http://www.epa.gov/endo/.

4.0 Dietary Exposure and Risk Assessment

4.1 Degradate Residue Profile

4.1.1 Summary of Environmental Degradation

Abiotic hydrolysis, direct photolysis in water (clear shallow water), and microbial-mediated 

degradation are major routes of transformation for clofentezine in the environment. Although 
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clofentezine under laboratory conditions appears to be more persistent in aerobic soil (t1/2 = 4 

weeks in clay, 6 weeks in loamy sand and 8 weeks in clay loam), abiotic hydrolysis and/or direct 

photolysis are likely to control the degradation of clofentezine in the environment. However, 

extensive mineralization (i.e., CO2 formation, up to 56% in aerobic soil after one year) was 

found in the aerobic soil metabolism studies. Clofentezine has a low solubility (34.2 mg/L) in 

water; however, clofentezine is fairly persistent in the environment. Clofentezine has low 

potential to volatilize from soil or water because of low vapor pressure and Henrys Constant.

The major degradates of clofentezine are 2-chlorobenzonitrile (direct aqueous photolysis), 2-

chlorobenzoic acid (2-chlorobenzylidine)hydrazide (abiotic hydrolysis), 2-chlorobenzoic 

hydrazone, 2-chlorobenzonitrile, and 2-chlorobenzaldehyde. Except for CO2, only trace amounts 

of other degradates were identified in aerobic soils. None of these degradation products are 

considered residues of concern for drinking water in the human health risk assessment

4.1.2 Residues of Concern Summary and Rationale

The nature of the residue has been adequately delineated in target crops and livestock for 

clofentezine. In fruit crops, the residue of concern is the parent, clofentezine per se (A. Smith, 

4/26/1988; RCB Nos. 3190 and 3191). In livestock, the residues of concern are the combined 

residues of clofentezine and the 3-(2-chloro-4- hydroxyphenyl)-6-(2-chlorophenyl)-1,2,4,5-

tetrazine metabolite (M. Bradley, 8/03/1989; DEB Nos. 5367 and 5371).

Table 4.1.2: Summary of Metabolites and Degradates 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

Livestock Ruminant

Clofentezine and 3-(2-chloro-4-

hydroxyphenyl)-6-(2-chlorophenyl)-

1,2,4,5-tetrazine metabolite

Clofentezine and 3-(2-chloro-4-

hydroxyphenyl)-6-(2-chlorophenyl)-

1,2,4,5-tetrazine metabolite

Drinking Water Clofentezine Not Applicable

4.1.3 Enforcement Analytical Method

A high-performance liquid chromatography (HPLC) analytical method for the determination of 

clofentezine residues in/on apples was previously submitted and considered acceptable. The 

limit of quantitation (LOQ) and limit of detection (LOD) were reported as 0.01 ppm and 0.003

ppm, respectively. HED concluded that the method was suitable for enforcement purposes. 

Multiresidue methods in FDA’s analytical method (PAM-I) were found to be inadequate for 

enforcement (due to poor recoveries).
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4.2 Food Residue Profile

Crop Field Trials

Adequate crop field trial data are available for clofentezine in/on almonds, peaches, nectarines, 

persimmons, and grapes following application of a SC formulation containing 0.25 lb ai/A. 

The established tolerances range from 0.02 ppm in walnuts to 5.0 ppm in almond hulls (40 CFR 

§180.446).

Meat, Milk, Poultry, and Eggs

The residue data from the cattle feeding study are adequate to satisfy data requirements (H. 

Fonouni 12/15/88; DEB Nos 4600-4601). Currently established tolerances for residues of

clofentezine and its 3-(2-chloro-4- hydroxyphenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine 

metabolite ranged from 0.01 ppm in milk to 0.4 ppm in liver, Poultry residue data is not required 

for clofentezine as there are not poultry feed items registered at this time.

Processed Food and Feed

Processing studies for the currently registered clofentezine uses are adequate. Clofentezine 

processing studies are available for apples and grapes. The apple juice processing factor was 

also translated to pear juice. Default processing factors were used for all other registered 

processed commodities.

Storage Stability

Storage stability studies for the currently registered clofentezine uses are adequate. The 

available data show that clofentezine residues are stable in apples for up to 381 days (M. 

Bradley; 8/17/1994; PP#:6F3392/6H5500), in peaches for up to 2 years (R. Griffin; 5/22/1990; 

PP#:9F3699), and in almonds for one year (M. Bradley; 8/15/1990; PP#:9F3793).

Rotational Crops

Studies examining confined and field accumulation of clofentezine in rotational crops are not 

required as none of the currently registered commodities are rotated.

4.3 Water Residue Profile

There are no monitoring data currently available for clofentezine or its residues of concern in 

drinking water. Estimated drinking water concentrations (EDWCs) were generated by the 

Environmental Fate and Effects Division (EFED) using computer modeling methods. Tier II 

EDWCs were generated to support clofentezine use on almonds, apples, Christmas trees, 

nectarines, containerized plants, peaches, pears, persimmons, pecans, and walnuts (R. Parker; 

D404287; 08/03/2012). The surface water EDWCs are based on the USEPA Pesticide Root 

Zone Model (PRZM) and Exposure Analysis Modeling System (EXAMS) using the EXPRESS 

shell. Estimated groundwater EDWCs were calculated using the screening model SCI-GROW 

(Screening Concentrations in Ground Water, version 2.3, 07/29/03). 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). 

The SCI-GROW groundwater concentration is 0.04 ppb. Table 4.3 provides the EDWCs for 

clofentezine.
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Table 4.3: Maximum Estimated Surface Water and Groundwater Concentrations for 

Clofentezine

Drinking Water Source Model Use rate

(lbs ai/A/season)

Acute

(ppb)

Chronic

(ppb)

Parent only

Surface water FIRST

0.26

7.59 10.062 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

4.4 Dietary Risk Assessment

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

Exposure Evaluation Model DEEM-FCIDTM, Version 3.16 which uses food consumption data 

from the USDA’s NHANES/WWEIA from 2003-2008.

4.4.1 Description of Residue Data Used in Dietary Assessment

The dietary risk assessment includes anticipated residues (ARs) based on field trial data that 

were previously calculated for apple, almond, nectarine, peach, pear, cherry, and apricot (Memo, 

J. Rowell, 2/17/99; D252865). HED concludes that incorporation of the previously calculated 

ARs is acceptable.

This memorandum also presented ARs for milk and meat, liver, kidney, meat byproducts of 

cattle horse, goat, and sheep. These ruminant ARs were calculated using the % diet figures from 

Table 1 of OPPTS 860.1000. HED has since refined these percent diet figures (Revised Table 1, 

6/30/2008), however, since incorporation of the figures in the refined Table 1 would lead to a 

lower dietary burden than that calculated in the 1999 memorandum, HED concludes that 

incorporation of the previously calculated ruminant ARs is acceptable. 

Default processing factors were assumed for all existing crop uses with the exception of apple 

and pear juice (0.105 processing factor), raisins (0.3 processing factor), and grape juice (0.09 

processing factor). The residue file created using the DEEMTM software for these dietary 

exposure analyses reflects these processing factors.
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4.4.2 Percent Crop Treated Used in Dietary Assessment

The Biological and Economics Analysis Division (BEAD) provided updated estimated % CT 

information for several commodities (J. Alsadek; 02/17/2012). For the chronic and cancer 

assessment, the average weighted %CT values were included for the following crops that are 

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

grapes: 1%; nectarines: 5%; peaches 5%; pears 5%; and walnuts: 5%. See Appendix D.

4.4.3 Acute Dietary Risk Assessment

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

identified from the available clofentezine toxicity studies for the acute dietary scenario. 

4.4.4 Chronic Dietary Risk Assessment

A somewhat refined chronic dietary exposure assessment was performed that directly 

incorporated potential drinking water 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). 

4.4.5 Cancer Dietary Risk Assessment

A somewhat refined cancer dietary exposure assessment was performed that directly 

incorporated potential drinking water residues as clofentezine has been classified as a possible 

human carcinogen. Applying the Q1* of 0.0376 (mg/kg/day)-1to the exposure value results in a 

cancer risk estimate of 2.8 x 10-7to the general U.S. population.

4.4.6 Dietary Risk Assessment Summary Table

Table 4.4.6: Summary of Dietary Exposure and Risk Estimates for Clofentezine

Population Subgroup

Chronic Dietary Cancer

Dietary Exposure 

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

General U.S. Population 0.000008 <1 0.000008 2.8 x 10-7

All Infants (< 1 year old) 0.000026 <1

Children 1-2 years old 0.000035 <1

Children 3-5 years old 0.000022 <1

Children 6-12 years old 0.000012 <1

Youth 13-19 years old 0.000005 <1

Adults 20-49 years old 0.000005 <1

Adults 50+ years old 0.000006 <1

Females 13-49 years old 0.000005 <1
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5.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are currently no registered residential uses associated with clofentezine; therefore, a 

residential/non-occupational exposure assessment is not required. 

5.1 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for clofentezine. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information1). On a 

chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift with specific products 

with significant risks associated with drift.

5.2 Inhalation Postapplication Exposure

Based on the Agency's current practices, a quantitative residential postapplication inhalation 

exposure assessment was not performed for clofentezine at this time primarily because 

clofentezine’s vapor pressure (9.75 x 10-10 mm Hg @ 25.0°C) and Henry's Law Constant (3.9 x 

10-10, atm-m

3mole-1

) indicate that the compound is non-volatile under field conditions. 

However, volatilization of pesticides may be a potential source of postapplication 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 is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for clofentezine.

 

1

Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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6.0 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, a residential/non-occupational exposure assessment is not 

required. As a result, the clofentezine aggregate risk assessment includes only dietary exposure 

(food and water). An acute dietary exposure assessment was not performed as no appropriate 

endpoints were identified from the available clofentezine toxicity studies for the acute dietary 

scenario. 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 2.8 x 10-7. Sections 4.4.4 and 4.4.5 discuss the chronic and 

dietary (food and water) exposure assessments.

7.0 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 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/.

8.0 Occupational Exposure/Risk Characterization

Clofentezine is currently registered for use as a foliar spray on a number of fruit and tree nut 

crops as well for use on Christmas trees (see Table 2.3). Based on the existing use pattern for 

clofentezine, there is potential for both occupational handler and occupational post-application 

exposure to occur.

8.1 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 

(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 currently registered use patterns and types of equipment and techniques that can 

potentially be used, occupational handler exposure is expected for clofentezine. The quantitative 

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

scenarios: 
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1) Mixing/loading liquids for airblast and groundboom;

2) Applying sprays via airblast and groundboom equipment;

3) Mixing/loading/applying liquids via mechanically-pressurized handgun;

4) Mixing/loading/applying liquids via manually pressurized handwand; and

5) Mixing/loading/applying liquids via backpack sprayer for greenhouses, shade houses, and 

nursery stock.

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

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

data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the 

Agricultural Handler Exposure Task Force (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 occupational 

handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

8.1.1 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”.

Table 8.1.1 presents the estimated dermal, inhalation, and combined non-cancer occupational 

handler risk estimates for the currently registered uses of clofentezine at baseline personal 

protective equipment (PPE). The short- and intermediate-term combined risk estimates for all

occupational handler scenarios do not exceed HED’s level of concern (MOEs > 100). HED 

notes that current clofentezine labels require PPE consisting of a long-sleeved shirt, long pants, 

shoes plus socks, and pair of chemical-resistant gloves for all applicators and other handlers. 

MOEs would only be higher (i.e., less risky) with the addition of waterproof chemical resistant 

gloves required on the current labels.
Clofentezine Human Health Risk Assessment DP No. D401611

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Table 8.1.1: Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Clofentezine (with baseline protection)

Exposure Scenario Crop or Target Application 

Rate 1

Area Treated 

or Amount 

Handled 

Daily2

Baseline Unit 

Exposure

(mg/lb ai)3

Baseline Dose

(mg/kg/day)4

Baseline Short- and 

Intermediate-term 

MOEs5

Combined Short 

and Intermediateterm MOEs Dermal Inhalation Dermal Inhalation Dermal Inhalation 

Mixer/Loader

Mixing/Loading liquids 

for groundboom and 

airblast applications 

(AHETF)

Airblast: Nursery (ornamentals, 

vegetables, trees, container stock)

0.25 lbs 

ai/A

20 A

0.22 0.00022

0.00014 0.000014 14000 140000 13000

Airblast: Almonds, Apples, Apricots, 

Cherries

Christmas Trees (except CA), Grapes 

(except NY), Nectarines, Peaches, 

Pears, Persimmons, Walnuts 

Groundboom: field-grown ornamentals

40 A 0.00028 0.000027 7300 73000 6600

Groundboom: greenhouse and nursery 

ornamentals 60 A 0.00041 0.00004 4800 49000 4400

Applicator

Applying Sprays 

Ground via 

Groundboom (AHETF)

Field-grown ornamentals 0.25 lbs 

ai/A

40 A

0.0786 0.00034

0.000098 0.000043 20000 47000 14000

Greenhouse and nursery ornamentals 60 A 0.00015 0.00006 14000 31000 9600

Applying Sprays via 

Open Cab Airblast 

(AHETF)

Nursery (ornamentals, vegetables, 

trees, container stock)

0.25 lbs 

ai/A

20 A

1.77 0.00471

0.0011 0.00029 1800 6800 1400

Almonds, Apples, Apricots, Cherries, 

Christmas Trees (except California), 

Grapes (except New York), 

Nectarines, Peaches, Pears, 

Persimmons, and Walnuts

40 A 0.0022 0.00059 900 3400 710

Mixer/Loader/Applicator

Mixing/Loading/Apply

ing Liquids with 

Backpack Sprayer 

broadcast (AHETF)

Greenhouse and nursery (ornamentals, 

vegetables, trees, container stock), 

Almonds, Apples, Apricots, Cherries

Christmas Trees (except CA), Grapes 

(except NY), Nectarines, Peaches, 

Pears, Persimmons, Walnuts

0.005 lbs 

ai/gal 40 gals 13.2 0.14 0.00033 0.00035 6100 5700 2900

Mixing/Loading/ 

Applying Liquids with 

Manually-pressurized 

Handwand (PHED)

Greenhouse and nursery (ornamentals, 

vegetables, trees, container stock), 

Almonds, Apples, Apricots, Cherries

Christmas Trees (except CA), Grapes 

(except NY), Nectarines, Peaches, 

Pears, Persimmons, Walnuts

0.005 lb 

ai/gal 40 gals 100 0.03 0.0025 0.000075 800 27000 780
Clofentezine Human Health Risk Assessment DP No. D401611

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Table 8.1.1: Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Clofentezine (with baseline protection)

Exposure Scenario Crop or Target Application 

Rate 1

Area Treated 

or Amount 

Handled 

Daily2

Baseline Unit 

Exposure

(mg/lb ai)3

Baseline Dose

(mg/kg/day)4

Baseline Short- and 

Intermediate-term 

MOEs5

Combined Short 

and Intermediateterm MOEs Dermal Inhalation Dermal Inhalation Dermal Inhalation 

Mechanicallypressurized Handgun

(PHED)

Almonds, Apples, Apricots, Cherries

Christmas Trees (except CA), Grapes 

(except NY), Nectarines, Peaches, 

Pears, Persimmons, Walnuts

0.005 lb 

ai/gal

1000 gals 1.3 0.0039 0.0008 0.0002 2500 8200 1900

Greenhouse and nursery (ornamentals, 

vegetables, trees, container stock)

0.005 lb 

ai/gal 1000 gals 3.5 0.12 0.00219 0.0075 910 270 210

1. Application Rate = Maximum rate listed from labels.

2. Taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1. Revised September 25, 2001.

3. Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 26, 2011). 

4. Dose (mg/kg/day) = Unit Exposure (mg/lb ai) * Application Rate * Area treated or Amount handled Body Weight (80 kg). 

5. MOE = Margin of Exposure = NOAEL Dose. MOEs ≥ 100 are not of concern.
Clofentezine Human Health Risk Assessment DP No. D401611

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8.1.2 Cancer Handler Exposure and Risk

Cancer occupational handler exposure and risks were estimated using 1) unit exposures taken 

from the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; 2) typical 

application rates supplied in a Biological and Economic Analysis Division (BEAD) memo

(Doucoure, 2011); 3) amount handled/area treated values take from ExpoSAC SOP No. 9.1, 

“Standard Values for Daily Acres Treated in Agriculture”; 4) standard values for the days per 

year an individual is exposed (private growers = 10 days per year and commercial applicators = 

30 days per year); 5) a standard value for years per lifetime of exposure (35 years over a 

lifetime); and 6) a standard value for lifetime expectancy of 78 years taken from the Exposure 

Factors Handbook 2011 Edition Table 18-1 (U.S. EPA, 2011).

Table 8.1.2 presents the estimated dermal and inhalation cancer occupational handler risk 

estimates for the currently registered uses of clofentezine at currently labeled PPE (i.e., baseline 

attire plus chemical resistant gloves). Clofentezine cancer occupational handler risk estimates 

for ranged from 1.8 X 10-6to 7.2 X 10-9and 5.3 X 10-6to 2.2 X 10 -8for private growers and 

commercial applicators, respectively.
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Table 8.1.2: Cancer Occupational Exposure and Risk Estimates for Clofentezine (at label PPE1)

Crop Exposure Scenario

Typical 

Application Rate2

(lb ai/A)

Total LADD Cancer Risks

Private Handler3 Commercial Handler4Private Handler3 Commercial Handler4

LADD5

(mg/kg/day)

LADD5

(mg/kg/day) Risk Estimate6 Risk Estimate6

Almond, peach, walnut

Mixing /loading airblast

0.17

6.22 x 10-71.88 x 10-62.3 x 10-87.0 x 10 -8

Applying airblast 2.15 x 10-56.45 x 10-58.1 x 10-72.4 x 10-6

Mixing, Loading Applying mechanically 

pressurized handwand

0.0034 lb ai/gallon

4.08 X 10-61.22 X 10-51.5 X 10-74.6 X 10-7

Mixing, Loading Applying manually 

pressurized handwand 7.17 X 10-7

2.15 X 10-62.7 X 10-88.1 X 108

Mixing, Loading Applying backpack 

sprayer

5.26 X 10-61.58 X 10-52.0 X 10-75.9 X 10-7

Apple

Mixing/loading airblast

0.15

5.49 x 10-71.65 x 10 -62.1 x 10-86.2 x 10-8

Applying airblast 1.89 x 10-5

5.68 x 10-57.1 x 10-72.1 x 10-6

Mixing, Loading Applying mechanically 

pressurized handwand

0.003 lb ai/gallon

3.59 X 10-61.08 X 10-51.4 X 10-74.1 X 10-7

Mixing, Loading Applying manually 

pressurized handwand 6.33 X 10-7

1.9 X 10-62.9 X 10-87.1 X 10-8

Mixing, Loading Applying backpack 

sprayer

4.65 X 10-61.39 X 10-51.8 X 10-75.2 X 10-7

Cherry

Mixing loading airblast

0.22

8.05 x 10-72.42 x 10-63.0 x 10-89.1 x 10-8

Applying airblast 2.79 x 10-5

8.37 x 10-51.1 x 10-63.2 x 10-6

Mixing, Loading Applying mechanically 

pressurized handwand

0.0044 lb ai/gallon

5.29 X 10-61.59 X 10-52.0 X 10-76.0 X 10-7

Mixing, Loading Applying manually 

pressurized handwand 9.28 X 10-7

2.79 X 10-63.5 X 10-81.1 X 10-7

Mixing, Loading Applying backpack 

sprayer

6.81 X 10-62.04 X 10-52.6 X 10-77.7 X 10-7

Applying airblast 2.04 x 10-5

6.12 x 10-57.7 x 10-72.3 x 10-6

Mixing, Loading Applying mechanically 

pressurized handwand

0.0032 lb ai/gallon

3.84 X 10-61.15 X 10-51.4 X 10-74.3 X 10-7

Mixing, Loading Applying manually 

pressurized handwand 6.75 X 10-7

2.03 X 10-62.5 X 10-87.6 X10-8

Mixing, Loading Applying backpack 

sprayer

4.95 X 10-61.49 X 10-51.9 X 10-75.6 X 10-7

Christmas tree, nectarine, persimmon, Mixing loading airblast 0.25 9.15 x 10-7

2.74 x 10-63.4 x 10-81.0 x 10-7
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Table 8.1.2: Cancer Occupational Exposure and Risk Estimates for Clofentezine (at label PPE1)

Crop Exposure Scenario

Typical 

Application Rate2

(lb ai/A)

Total LADD Cancer Risks

Private Handler3 Commercial Handler4Private Handler3 Commercial Handler4

LADD5

(mg/kg/day)

LADD5

(mg/kg/day) Risk Estimate6 Risk Estimate6

apricot, grape Applying airblast 3.17 x 10-5

9.52 x 10-51.2 x 10-63.6 x 10-6

Mixing, Loading Applying mechanically 

pressurized handwand

0.005

(lb ai/ gallon)

6.0 X 10-61.8 X 10-52.3 X 10-76.8 X 10-7

Mixing, Loading Applying backpack 

sprayer

7.75 X 10-62.23 X 10-52.9 X 10-7 8.7 X 10-7

Mixing, Loading Applying manually 

pressurized handwand 1.06 X 10-6

3.16 X 10-64.0 X 10-81.2 X 10-7

Ornamentals grown in greenhouses 

and shade houses

Mixing, Loading Applying manually 

pressurized handwand

0.0021

(lb ai/gallon)

4.43 X 10-7

1.33 X 10-61.7 X 10-85.0 X 10-8

Mixing, Loading Applying mechanically 

pressurized handwand 4.68 X 10-5

1.4 X 10-4 1.8 X 10-65.3 X 10-6

Mixing, Loading Applying backpack 

sprayer

3.27 X 10-69.8 X 10-61.2 X 10-73.7 X 10-7

Field-grown nursery ornamental crop

Mixing loading groundboom

0.104

3.80 x 10-71.14 x 10-61.4 x 10-84.3 x 10-8

Applying groundboom 1.16 x 10-6 1.44 x 10-6

4.4 x 10-85.4 x 10-8

Nursery (ornamentals, vegetables, 

trees, container stock) and 

Greenhouse (ornamentals, roses, cut 

flowers, container stock, vegetables)

Mixing loading groundboom

0.104

5.72 X 10-71.72 X 10-62.2 X 10-86.5 X 10-8

Applying groundboom 4.79 X 10-7

1.44 X 10-61.8 X 10-85.4 X 10-8

Nursery (ornamentals, vegetables, 

trees, container stock)

Mixing loading airblast

0.104

1.91 X 10-7

5.72 X 10-7

7.2 X 10-92.2 X 10-8

Applying airblast 6.60 X 10 -21.98 X 10-52.5 X 10-77.5 X 10-7

1 All estimates are at label PPE mitigation of long-sleeved shirt, long pants, shoes plus socks, and pair of chemical-resistant gloves. 

2 Typical rates for some of the crops were supplied by a BEAD memo (Doucoure, 2011). Crops for which typical rates were not included are assessed at the maximum rate of 0.25 lb ai/A or 0.005 lbs 

ai/gallon.

3

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. 

4 Commercial applicators are assessed assuming 30 days of exposure per year. Commercial applicators means the applicators are completing multiple applications for multiple clients.

5 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).

6 Cancer risk estimates = LADD * Q1*

, where Q1

*

= 3.76 X 10 -2(mg/kg/day)-1.
Clofentezine Human Health Risk Assessment DP No. D401611

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8.2 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.

8.2.1 Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for clofentezine at this time primarily because clofentezine’s 

vapor pressure (9.75 x 10-10 mm Hg @ 25.0°C) and Henry's Law Constant (3.9 x 10-10, atmm

3mole-1

) indicate that the compound is non-volatile under field conditions. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication 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 is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for clofentezine.

Although a quantitative postapplication 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 postapplication exposure. Therefore, it is expected that these handler inhalation exposure 

estimates would be protective of most occupational postapplication inhalation exposure 

scenarios.

8.2.2 Postapplication Dermal Exposure and Risk

8.2.2.1 Short-/Intermediate-Term Non-Cancer Postapplication Exposure and Risk

Short- and intermediate-term non-cancer dermal postapplication 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 
Clofentezine Human Health Risk Assessment DP No. D401611

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(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.

A summary of the short- and intermediate-term postapplication exposure and risk estimates 

resulting from use of clofentezine is provided in Table 8.2.2.1. The short- and intermediate-term 

risk estimates for all activities do not exceed HED’s level of concern (MOEs > 100) using 

predicted Day 0 residue values from the DFR study. 

Table 8.2.2.1: Summary of Short-and Intermediate-term Occupational Post-application NonCancer Risk Estimates for Clofentezine

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

DFR1

Dermal Dose 

at day 0 of 

application

(mg/kg/day)2

MOE3

Almond, Walnuts Scouting 580

0.515 ug/cm2

0.000299 6700

Apples

Thinning Fruit 3,600 0.00185 1100

Apricots

Cherries

Nectarines

Peaches

Pears

Persimmons

Christmas Trees Irrigation (hand set) 1,900 0.000979 2000

Grape Wine Tying/Training

Hand Harvesting/Leaf pulling 10,100 0.0052 380

Grape Juice

Grape Raisin Tying Training 5,500 0.00283 710

Grape Table Girdling 19,300 0.00994 200

Nursery Crop Ornamentals Irrigation (hand set) 1,900 0.00098 2,000

Greenhouse Crop 

Ornamentals Pruning hand 230 0.00012 17,000

1. DFR taken from MRID (43898901); Dissipation of Clofentezine Foliar Dislodgeable Residues Following Application of 

Apollo SC to Apples Grown in Washington State

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

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

8.2.2.2 Cancer Postapplication Exposure and Risk

Cancer dermal postapplication 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 = 0.515 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 10 days a year at day 0 residues; 6) a standard 
Clofentezine Human Health Risk Assessment DP No. D401611

Page 31 of 47

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).

A summary of the cancer postapplication exposure and risk estimates resulting from use of 

clofentezine is provided in Table 8.2.2.2. The postapplication cancer risk estimates for all 

activities ranged from 1.3 X 10-6to 9.4 X 10-8.

Table 8.2.2.2: Summary of Occupational Post-application Cancer Risk Estimates for Clofentezine

Crop Activity

Transfer 

Coefficient 

(cm2/hr)

Typical 

application rate

lbs ai/a

DFR1 Dermal LADD 

(mg/kg/day)2

Cancer Risk 

Estimate3

Almond, Walnuts Scouting 580 0.17

0.515 

ug/cm2

2.50X 10 -69.4 X 10-8

Apples

Thinning Fruit 3,600

0.15 1.36 X 10-55.1 X 10-7

Apricots 0.25 2.27 X 10-5

8.6 X 10-7

Cherries 0.22 2.00 X 10-5

7.5 X 10-7

Nectarines 0.25 2.27 X 10-5

8.6 X 10-7

Peaches 0.17 1.55 X 10-5

5.8 X 10-7

Pears 0.16 1.46 X 10-55.5 X 10-7

Persimmons

0.25

2.27 X 10-58.6 X 10-7

Christmas Trees Irrigation (hand set) 1,900 1.203 X 10-54.5 X 10-7

Grape Wine Tying/Training

Hand Harvesting/Leaf pulling 10,100 5.57 X 10-7

2.1 X 10-8

Grape Juice

Grape Raisin Tying Training 5500 3.48 X 10-51.3 X 10-6

Grape Table Girdling 19,300 3.23 X 10-6

1.2 X 10-7

Nursery Crop 

Ornamentals Irrigation (hand set) 1, 900 0.104 5.00 X 10-6

1.9 X 10-7

Greenhouse Crop 

Ornamentals Pruning hand 230 0.104 6.05 X 10-7

2.3 X 10-8

1 DFR taken from MRID (43898901) was adjusted for typical application rates supplied by BEAD (Doucoure, 2011). 

2 Dermal LADD = Dermal dose * 10 Day per year of exposure x 78 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

Restricted Entry Interval

The restricted entry interval (REI) listed on the existing clofentezine labels is based on the acute 

toxicity of the technical material. 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 post-application risk estimates were not a concern on day 0 (12 

hours following application) for all post-application activities. Under WPS for agricultural 

pesticides, active ingredients classified as Acute III or IV for acute dermal, eye irritation and 

primary skin irrigation are assigned a 12-hour REI. Therefore, the REI of 12 hours on current 

clofentezine labels is adequate to protect agricultural workers from post-application exposures to 

clofentezine.
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References

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

Calculations

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

Human Health Assessments; PC Code: 125501; DP Number: D336110. January 31, 2007. 

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. 
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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

no1

yes

yes

no

no

no

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

no

no

no

870.7485 General Metabolism

870.7600 Dermal Penetration 

870.7800 Immunotoxicity

yes

no

yes3

yes

yes

no

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 (final report pending).
Clofentezine Human Health Risk Assessment DP No. D401611

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A.2 Toxicity Profiles

Table A . 2 . 1: Acute Toxicity of Clofentezine

Guideline No. Study Type MRIDs # Results Toxicity Category

81-1 Acute Oral- Rats 00159071 LD50 >3230 mg/kg III

81-2 Acute Dermal- ats 00105902 LD50 >1332 mg/kg III (Suppl)1

81-3 Acute Inhalation- Rats 00138753* LC50 >11.35 mg/L (6hr.) IV

81-4 Primary Eye Irritation- Rabbits 00105907* mild irritant IV

81-5 Primary Skin Irritation- Rabbits 00159073 not a skin irritant IV

81-6 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

Study Type MRID No. Results

21-Day Dermal Toxicity-Rat none no study available

Subchronic-Feeding-Mouse none incorporated into the two year mouse oncogenicity study

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).

Subchronic 13 Week-Feeding-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 enlargment.

Subchronic 13 Week-Feeding 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.

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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Chronic toxicity/Carcinogenicity-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).

Carcinogenicit Evidence of carcinogenicity in male rats [thyroid tumors] y-Mouse 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.

Developmental Toxicit No evidence of carcinogenicity y-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 enlargment

of the centrilobular hepatocytes.

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

Limit Dose)

LOAEL >3200 mg/kg/day

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.

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

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
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Dominant Lethal Rat 00130764 (1983)

0, 4, 40, or 400pm

Non-mutagenic

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 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. 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.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: None

MRID No.: N/A

Executive Summary: None

Comments about Study/Endpoint/Uncertainty Factor(s): No appropriate endpoint 

attributable to a single exposure (dose) was identified from the oral toxicity studies including 

developmental toxicity studies in rats and rabbits. Therefore, an acute RfD was not established.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: None

MRID No.: N/A

Executive Summary: None

Comments about Study/Endpoint/Uncertainty Factor(s): No appropriate endpoint 

attributable to a single exposure (dose) was identified from the oral toxicity studies including 

developmental toxicity studies in rats and rabbits. Therefore, an acute RfD was not established.

A.3.3 Chronic Reference Dose (cRfD) `

Study Selected: One-year chronic dog study

MRID No.: 00149491

Executive Summary: See appendix, 

Dose and Endpoint for Risk Assessment: NOAEL= 1.25 mg/kg; LOAEL= 25 mg/kg/day based 

on increased liver weights, hepatocellular enlargement, and increased serum cholesterol, 

triglycerides and alkaline phosphatase levels.

Comments about Study/Endpoint/Uncertainty Factor(s): The uncertainty factor (UF)

includes a 10X for intraspecies extrapolation and a 10X for interspecies extrapolation.
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A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: none

MRID No.: N/A 

Executive Summary: None 

Comments about Study/Endpoint/Uncertainty Factor(s): As there are no registered or 

proposed residential uses for clofentezine, short- and intermediate-term incidental oral endpoints 

have not been selected.

A.3.5 Dermal Exposure (Short- and Intermediate-Term)

Study Selected: 13-week rat feeding study 

MRID No.: 00105911 

Executive Summary: See appendix. 

Dose and Endpoint for Risk Assessment: NOAEL= 2.0 mg/kg; LOAEL= 20.0 mg/kg/day 

based on increased cholesterol, increased liver weights, thyroid colloid depletion and thyroid 

follicular cell hypertrophy.

Comments about Study/Endpoint/Uncertainty Factor(s): This study was selected because of 

(1) the absence of a 21 day dermal toxicity study, and (2) the LOAEL and endpoint is supported 

by a comparable LOAEL and endpoint seen in the 28 day rat feeding study. Since an oral 

NOAEL was selected, the dermal absorption factor of 1% should be used for this risk 

assessment. Long-term dermal exposure is not expected based on maximum of one application 

per year as prescribed by the label.

A.3.6 Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Study Selected: 13-week rat feeding study

MRID No.: 00105911

Executive Summary: See appendix. 

Dose and Endpoint for Risk Assessment: NOAEL= 2.0 mg/kg; LOAEL= 20.0 mg/kg/day 

based on increased cholesterol, increased liver weights, thyroid colloid depletion and thyroid 

follicular cell hypertrophy.

Comments about Study/Endpoint/Uncertainty Factor(s): Except for an acute inhalation 

toxicity study (MRID# 00138753) for which clofentezinewas placed in toxicity Category IV 

(LC50 > 11.5 mg/L); no other studies are available via this route. HEDs level of concern (LOC) 

for clofentezine inhalation exposure is 100 (i.e., a margin of exposure (MOE) less than 100 

exceeds HED’s level of concern) for occupational scenarios. The level of concern includes a 

10X uncertainty factor (UF) for intraspecies extrapolation and a 10X for interspecies 

extrapolation.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

Executive Summary #1: In a 90-day feeding study (MRID 00105911, 00159079, 40467905), 

Charles River COBS CD Sprague-Dawley rats (25/sex/group) were fed Clofentezine Technical 
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(99 % a.i. batch # CR 20099/5) in the diet at concentrations of 0, 40, 400 or 4000 ppm (doses of 

0, 2, 20 or 200 mg/kg/day). 5/sex/dose of these were sacrificed after a 6 week recovery period 

(received no chemical). Additional 10 animals per sex were sacrificed pre test to establish pretest blood values. 

At 400 and 4000 ppm, there was elevated cholesterol levels (13-18%, 24-50% above controls for 

the mid and high dose males at 4, 8, 12 weeks, similar effects in females), increased liver 

weights (10, 40 % greater than controls for mid and high dose animals), liver-to-body-weight 

ratios, and centrilobular hepatocellular enlargement. There was also depletion of thyroid colloid 

(3/20, 2/19, 4/20, 12/19, controls to high dose) and follicular cell hypertrophy in mid (slight) and 

high (moderate) group males (all thyroid effects were reversible after the recovery period). 

Although present in females, the thyroid effects were less marked. The NOAEL is 40 ppm (2 

mg/kg/day. The LOAEL is 400 ppm (20 mg/kg/day) based on increased cholesterol, increased 

liver weights, thyroid colloid depletion and thyroid follicular cell hypertrophy.

This study is acceptable/guideline and satisfies the guideline requirements for a subchronic 

feeding study in rats.

Executive Summary #2: In a 90-day feeding study (MRID 00105910,40467904), Charles River 

COBS CD Sprague-Dawley rats (20/sex/group) were fed Clofentezine Technical (99% a.i. batch 

# CR 20099/5) in the diet at concentrations of 0, 3000, 9000 or 27,000 ppm (doses of 0. 150, 450 

or 1350 mg/kg/day). Rats (5/sex/dose) were sacrificed at 2 months, 10/sex/dose at 3 months and 

the remaining 5/sex/dose after a 4 week recovery period (received no chemical). Blood 

parameters were evaluated at 4, 6 12 weeks and after recovery. Additional 10 animals per sex 

were sacrificed pre test to establish pre-test blood values.

Treatment related effects occurring in both sexes at all doses, included hair loss, primarily during 

the first 30 days (e.g., males 0/20, 5/20, 9/20 and 16/20, controls to high dose), increased plasma 

cholesterol (not progressive over time) (ranging from 40-80, 70-100, 80-125 % over controls 

from low to high dose and increased blood triglycerides (at 6 weeks) in both sexes in a dose 

related manner. There was increased liver weight (40, 50, 70% greater than controls from the low 

to high dose) and centrilobular hepatocellular enlargement was present on all treated rats at both 

the 9 and 12/13 week sacrifice. In addition there was a depletion of thyroid colloid and follicular 

cell hypertrophy in males and females at all treatment levels at weeks 9 and 13 (severity 

increasing with time). All the above effects regressed to normal following the 4 week recovery 

period. In the male 27,000 ppm group there were 2 treatment related deaths (day 6 and day 90), 

and the group mean body weights were decreased 13-14 % from week 8 to 13 (returned to 

normal following the recovery period). Males and females in the high dose group also had gross 

changes in the liver (reversible following recovery). 

The NOAEL is equal to or less that 3000 ppm (150 mg/kg/day). The LOAEL is less than 3000 

ppm based on increased cholesterol and triglycerides, increased liver weight and hepatocellular 

enlargement.
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This study is acceptable/non-guideline and provides special information on characterization of 

thyroid effects. It does not satisfy the guideline requirements for a subchronic feeding study in 

rats.

Executive Summary #3: In a 28 day feeding study (MRID 40975503), male Charles River COBS 

CD Sprague-Dawley rats (20/group) were fed Clofentezine Technical (batch # CR 20099/15) in 

the diet at concentrations of 0, 10, 400, 3,000 or 30,000 ppm (0. 1, 40, 300 or 3000 mg/kg/day). 

Blood samples evaluation and necropsies were conducted at 4, 7, 14 and 28 days of test.

At 400 ppm or higher, increased liver enzyme activity (UDPGT) (all time points), increased liver 

weight and increased thyroid activity (hypertrophy (by day 7), hyperplasia (by day 14) and 

mitotic activity (day 4 and 7) of follicular cells, colloid depletion (by day 4) and an increase in 

thyroid weight (start day 15) were noted. The thyroid changes appeared to diminish in frequency 

and severity during the study based on microscopic examination of serially sacrificed rats. The 

NOAEL is 10 ppm (1 mg/kg/day). The LOAEL is 400 ppm (40 mg/kg/day) based on thyroid 

activity as early as day 4.

This study is acceptable/non-guideline due to limited study design, and although it does provide 

useful information, it does not satisfy the guideline requirements for a subchronic feeding study 

in rats.

Executive Summary #4: In a 90-day subchronic feeding study (MRID 00105912, 00126844), 

Clofentezine Technical (99.7-99.9 % a.i., Batch# not given) was administered in the diet to 

beagle dogs (4/sex/group) at concentrations of 0, 3200, 8000 or 20,000 ppm (doses of 0, 80, 200 

or 500 mg/kg/day).

At 20,000 in males there were effects (stat. sig.) on the electrocardiograms including reduced 

PR-intervals and/or increased QRS-complex values; and in females the QT-intervals were 

decreased (this was increased at 8000 ppm as well but not stat. sig.). There were statistically 

significant dose-related increases in liver weights in both sexes at all doses. The NOAEL is less 

than 3200 ppm (80 mg/kg/day). LOAEL is less than or equal to 3200 ppm (80 mg/kg/day) based 

on increased liver weight in both sexes and electrocardiographic changes in females.

This study is acceptable/guideline and satisfies the guideline requirements for a subchronic

feeding study in dogs.

A.4.2 Prenatal Developmental Toxicity

Prenatal Developmental Toxicity Study - Rat

In a developmental study (MRID 00114270, 00159095), 38 female Charles River COBS CD 

Sprague-Dawley strain rats were treated by gavage with Clofentezine Technical (100% pure a.i., 

Batch # CR 20099/8) for days 7 through 20 of gestation at doses of 0, 320, 1280 or 3200 

mg/kg/day (controls had 37 rats).
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In the dams, there was differential staining and slight enlargement of the centrilobular 

hepatocytes at 3200 mg/kg/day. The maternal NOAEL is 1280 mg/kg/day (above the limit test 

of 1000.0 mg/kg/d). The maternal LOAEL is 3200 mg/kg/day.

There were no developmental effects on offspring at any dose. The developmental LOAEL is 

greater than 3200 mg/kg/day (above the limit test). The developmental NOAEL is at or above 

3200 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 

prenatal developmental toxicity study in rats.

Prenatal Developmental Toxicity Study - Rabbit

In a developmental study (MRID 00130761), female New Zealand strain rabbits (16/group) were 

treated by gavage with Clofentezine Technical (98.5% a.i.) for days 7 through 29 of gestation at 

doses of 0, 250, 1000 or 3000 mg/kg/day.

Evidence of maternal toxicity included body weight reduction (24 % lower than controls) 

throughout treatment and reduced food intake (ranging from 20-50% lower than controls) which 

occurred at 3000 mg/kg/day. The maternal LOAEL is 3000 mg/kg/day. The maternal NOAEL 

is 1000 mg/kg/day.

Evidence of developmental toxicity included a reduced mean fetal weight reduction of 13%

which occurred at 3000 mg/kg/day. The developmental LOAEL is 3000 mg/kg/day. The 

developmental NOAEL is 1000 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 

prenatal developmental toxicity study in rabbits.

A.4.3 Reproductive Toxicity- Rats

In a 3-generation reproduction study (MRID 00147884, 00159070), F0 Charles River Crl:CD

Sprague-Dawley BP strain rats (30/sex/group) were given Clofentezine Technical (purity 

unspecified, batch # CR 20099/12) in the diet at concentrations of 0, 4, 40 or 400 ppm (0, 0.2, 

2.0 or 20.0 mg/kg/day). Forty/sex F0 rats were exposed to 400 ppm (20 mg/kg/day). There were 

25/sex/group in the F1 generation for all treatment groups. F0 parents produced 2 litters (F1A, 

F1B). The F1A litter was used as the F1 parents to produce the F2A and F2B litters. Ten 

F2A/sex/group were given test diet for 82-84 days prior to sacrifice. 

Systemic effects observed at 400 ppm were limited to minimal centrilobular hepatocyte 

hypertrophy in adult male rats. The parental LOAEL is greater than 400 ppm (20 mg/kg/day). 

The parental NOAEL is at or above 400 ppm (20 mg/kg/day).

There were no reproductive effects and no effects on offspring observed in this study at any dose 

level. The reproductive LOAEL is greater than 400 ppm (20 mg/kg/day). The reproductive 

NOAEL is at or above 400 ppm (20 mg/kg/day).
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This study is acceptable/guideline according to guidelines for a reproductive toxicity study in 

rats.

A.4.4 Chronic Toxicity

One-Year Chronic Toxicity – Dog

In a 1 year chronic feeding study (MRID 00149491), Clofentezine Technical (98.2 % a.i., Batch 

# CR 20099/14) was administered in the diet to beagle dogs (6/sex/group) at concentrations of 0, 

50, 1000 or 20,000 ppm (doses of 0, 1.25, 25 or 500 mg/kg/day).

Treatment related effects were present in dogs given levels of 1000 and 20,000 ppm. These 

effects included liver changes with hepatocyte enlargement concurrent with eosinophilic 

cytoplasm; increased liver weight (both sexes), thyroid weight (high dose males only) and 

adrenal weight (high dose females only). At 1000 and 20,000 ppm there were also elevated 

serum cholesterol (30-40% above controls) and triglycerides (primarily during the first 4 weeks 

of study, 30-50% above controls). There was a statistically significant increase in alkaline 

phosphatase in males and females at the high dose primarily during the early part of the study 

and again at term in high dose males and mid and high dose females (40-75 % above controls).

The NOAEL was 50 ppm (1.25 mg/kg/d); the LOAEL was 1000 ppm (25.0 mg/kg/d) based on 

liver changes and elevated serum cholesterol, triglycerides, and alkaline phosphatase.

The study is classified as acceptable/guideline and satisfies the guideline requirement for a oneyear dog study.

A.4.5 Carcinogenicity

Combined Chronic/Carcinogenicity Study – rat

In a 27 month chronic carcinogenicity study, (MRID 00147883, 00159081, 40289801,

40467906, 40467910) Clofentezine Technical (98.7 % al., batch # CR 20099/12) was 

administered in the diet to Charles River Crl:CD Sprague-Dawley BR strain rats at 

concentrations of 0, 10, 40 or 400 ppm (doses of M: 0, 0.43, 1.72 or 17.3; F: 0, 0.55, 2.18 or 22.1 

mg/kg/day). There were 70 rats/sex/dose with 20/sex/dose of these sacrificed at 12 months.

There was a slight increase in free thyroxine levels in males at 27 months. Liver weights and 

weight ratios for high dose group males were increased above controls (20 %) and for high dose 

group females (10%), both statistically significant. Histological changes occurred in the liver of 

males in a dose-related manner, and included centrilobular hepatocyte hypertrophy and 

vacuolation, focal cystic degeneration of hepatocytes, and diffuse distribution of fat deposits in 

the livers of high dose males (38% compared to 22% in controls). The systemic NOAEL is 40 

ppm (1.72 mg/kg/day). The systemic LOAEL is 400 ppm (17.3 mg/kg/day) based on increased 

liver weights and increased liver-body weight ratio (males); increased thyroxine levels; 
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centrilobular hypertrophy and vacuolation of hepatocytes, focal cystic degeneration of 

hepatocytes and diffuse distribution of fat deposits in liver (males).

Doses were considered below the maximum tolerate dose (MTD) based on the subchronic 

studies as well as little evidence of toxicity even at the high dose (confirmed in the Toxicology 

Branch Cancer Peer Review, Document dated 6 June l 988). A new study, however, is not 

required since tumors were present in male rats.

The corresponding tumor rates in males were 2/68, 2/65, 2/66, and 8/63, respectively. The male 

rats had a significant dose-related increasing trend at p <0.01, and a significant difference in the 

pair-wise comparison of the 400 ppm dose group with the controls at p <0.05, for thyroid 

follicular cell adenomas and/or carcinomas combined. The upper bound estimate of unit risk, 

Q1* (mg/kg/day)-1, of clofentezine based upon male rat thyroid follicular cell adenoma and/or 

carcinoma combined tumor rates is 3.76 x 10-2in human equivalents. This Q1* has been 

converted from animals to humans by use of the 3/4 scaling factor and obtained by the 

application of the Multi-Stage model (Tox Risk program, Version 3.5, K. Crump, 1994).

This study is acceptable/guideline and satisfies the guideline requirements for the combined 

chronic/ carcinogenicity feeding study in rats.

Carcinogenicity (feeding) – Mouse

In a 105 week carcinogenicity study (MRID 00147885, 00159094, 40302001), Clofentezine 

Technical (98.7 % al., batch # CR 20099/12) was administered in the diet to CD-1 Swiss mice 

(52/sex/dose) at concentrations of 0, 50, 500 or 5000 ppm (doses of M: 0, 5.0, 50.7 or 543.0; F:

0, 5.3, 56.9 or 557.1 mg/kg/day).

Clofentezine treatment was associated with statistically significant reductions in group mean 

body weight (approximately 7 % below controls) and body weight gains (approximately 15 -

22% less than controls) for males at 5000 ppm. These differences were observed during the first 

three months of the feeding period. A statistically significant increase in mortality (81% 

compared to 52% in controls) was observed in the high dose group females when compared to 

controls for the last six months of the study. Amyloidosis was considered a contributing factor to 

those deaths. The 5000 ppm males increased incidence (stat. sig.) of altered hepatocytes (areas or 

foci of eosinophilic hepatocytes), Female mice at 5000 ppm had stat. sig. increases in liver 

weights and the incidence of altered hepatocytes (eosinophilic and/or basophilic areas of foci). 

The NOAEL was 500 ppm (M: 50.7; F: 56.9 mg/kg/day). The LOAEL was 5000 ppm (M: 543.0; 

F: 557.1 mg/kg/day) based on reversible decreases in body weight and weight gain, increased 

incidences of eosinophilic areas or foci of hepatocytes in males; in females increased incidence 

of basophilic and/or eosinophilic foci or areas of hepatocytes, and an increased mortality in 

females with amyloidosis identified as a contributing factor.

Doses were adequately high based on mortality in females and a transient decrease in body 

weight gain in males at 5000 ppm. In addition, the highest dose tested is above 1/2 the limit dose 

of 1 gm/kg.
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Although liver tumors were elevated in both sexes of mice, no biologically relevant doseresponse relationship occurred in male mice, while that in female mice was flat over the dose 

range of 0 ppm (i.e., 4 tumors were observed) to 5000 ppm (i.e., 7 tumors were observed).

The study is classified as acceptable/guideline and satisfies the guideline requirement for a 

carcinogenicity study in mice.

A.4.6 Mutagenicity

Clofentezine is not considered to be a mutagen based on the available database.

Gene Mutation

Reverse gene mutation assay [Bacterial 

strains of S. typhimurium]

MRID 00105909

Negative

Cytogenetics

Micronucleus study [Mouse]

MRID 00114269

Negative

Chromosomal aberration 

[Mouse Lymphoma]

MRID 00159096, 40958301

Negative

Dominant Lethal (Rat)

MRID 00130764

Negative

Other Genotoxicity

Gene conversion/mitotic recombination

(Saccharomyces cerevisiae)

MRID 00130765

Negative

A.4.7 Metabolism

Metabolism – Rat

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. 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.
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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 

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.
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Appendix C: Physical and 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-m

3mole-1

Octanol/water partition coefficient (25°C) log Kow = 3.1
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Appendix D: Percent Crop Treated Memo from BEAD

Clofentezine (125501)

Screening Level Usage Analysis (SLUA)

Date: February 17, 2012 

What is a Screening Level Usage Analysis (SLUA)?

Available estimates of pesticide usage data for a particular active ingredient that is 

used on agricultural crops in the United States.

Pesticide usage data obtained from various sources. The data are then merged, 

averaged, and rounded so that the presented information is not proprietary, business 

confidential, or trade secret. 

What does it contain?

Pesticide usage data for a single active ingredient only.

Agricultural use sites (crops) that the pesticide is reported to be used on.

Available pesticide usage information from U.S. states that produce 80% or more of a 

crop, in most cases, or less than 80%, in rare cases, depending on the scope of the 

survey and available resources.

Annual percent of crop treated (average & maximum) for each agricultural crop.

Average annual pounds of the pesticide applied for each agricultural crop (i.e., for the 

states surveyed, not for the entire United States).

What assumptions can I make about the reported data?

Average pounds of active ingredient applied - Values are calculated by merging 

pesticide usage data sources together; averaging across all observations, then 

rounding. Note: If the estimated value is less than 500, then that value is labeled 

<500. Estimated values between 500 & <1,000,000 are rounded to 1 significant 

digit. Estimated values of 1,000,000 or greater are rounded to 2 significant digits.)

Average percent of crop treated - Values are calculated by merging data sources 

together; averaging by year, averaging across all years, & rounding to the nearest 

multiple of 5. Note: If the estimated value is less than 2.5, then the value is labeled 

<2.5. If the estimated value is less than 1, then the value is labeled <1.

Maximum percent of crop treated - Value is the single maximum value reported 

across all data sources, across all years, & rounded up to the nearest multiple of 5. 

Note: If the estimated value is less than 2.5, then the value is labeled <2.5.

What are the data sources used?

USDA-NASS (United States Department of Agriculture’s National Agricultural 

Statistics Service) – pesticide usage data from 2003 to 2010.

Private pesticide market research – pesticide usage data from 2003 to 2010.

California Department of Pesticide Regulation (DPR) Pesticide Use Reporting

(PUR) data for 2003 to 2010.

What are the limitations to the data?

Additional registered uses may exist but are not included because the available 

surveys do not report usage (e.g., small acreage crops).

Lack of reported usage data for the pesticide on a crop does not imply zero usage.
Clofentezine Human Health Risk Assessment DP No. D401611

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Usage data on a particular site may be noted in data sources, but not quantified. In 

these instances, the site would not be reported in the SLUA.

Non-agricultural use sites (e.g., turf, post-harvest, mosquito control, etc.) are not 

reported in the SLUA. A separate request must be made to receive these estimates.

Some sites show some use, even though they are not on the label. This usage could 

be due to various factors, including, but not limited to Section 18 requests, existing 

stocks of the chemical, data collection errors, and experimental use permits (EUPs). 

Table 4. Screening Level Estimates of Agricultural Uses of Clofentezine (125501) Sorted 

Alphabetically

Crop

Lbs. A.I.

Percent Crop Treated

Average Maximum

1 Almonds 3,000 <2.5 5

2 Apples 1,000 <2.5 10

3 Apricots <500 <2.5 <2.5

4 Cherries 1,000 5 10

5 Grapes <500 <1 <2.5

6 Nectarines <500 5 10

7 Peaches 1,000 5 15

8 Pears <500 5 10

9 Plums/Prunes+ <500 <2.5 <2.5

10 Walnuts 2,000 5 10

All numbers rounded.

<500 Less than 500 pounds of active ingredient

<2.5 Less than 2.5 percent of crop treated

<1 Less than 1 percent of crop treated

** California data only. No information available about use of this chemical on this crop in 

other states.

+ Crops not known to be listed on active end use product registrations or as Section 18 

emergency

exemptions when this report was run

SLUA data sources include: 

USDA-NASS (United States Department of Agriculture's National Agricultural Statistics 

Service) 

Private Pesticide Market Research

California DPR (Department of Pesticide Regulation)

These results reflect amalgamated data developed by the Agency and are releasable to the 

public.