Clofen t e zin e Human Hea l th Ris k Assessmen t D P N o. D 4 0 1 6 11

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

M E MORA N D UM

D a te: J une6

, 2013

SUBJ ECT : Cl ofentezin e. Pr e lim i nary Hum a n Hea lth Risk A ssess m e n t fo r R eg istrati o n
R ev i ew

P C Code: 125501

Decision N o. : 464564

Petition N o.: NA DP Barcode: D40161 1

R e gistration N o.: NA Regulatory A ction: Registration R ev i ew C a se N o.: 7602 Ri s k A s sessment Ty pe : Si n gle

Chem i cal/ Aggrega t e
T XR No.: NA

M RI DN o.: NA C AS N o.: 74 11 5-24-5

40 C FR: 1 8 0.4 4 6

F ROM: C h arles S m i th

, Se nior Environme n ta l Scie nti st/ Ri sk Assessor

# ~ R i sk Assess m e n t Br a n c h I**(l~**

and

Sheila Piper, Senior

# Chemist**~~(?~~ ~**  Yung Ya n g, Ph.D

., Seni o r T ox i co l ogis t 

## '71 6 

# r; U

B r id gett Bo b ow i e c
, Biolo g i st**13~** 

## /

S h a lu S h e l at, Indu s tr i al

### en**t~/L** R i sk Assessment Branch VI

Health Effec t s Di v i s i on (7509P) ( /)

T H RO U GH: F elecia Fort, Branch Chief 

# .i,Jl.!tNe jf);;;/1

T O: Risk Assessment B ranch VI 

## f"'

Health Effec t s Di vision (7509P)

W il hel m e n a L iv ing s ton , C hem ical R e vi e w Man ager Ri s k M anage m e nt and Im p l e m e n tat i o n B r anch IV

P est i cide R e

- eva lu a t io n Di vision (750 8P )

P age 1 of 47Clofentezine Human Health Risk Assessment DP No

. D401611

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

esti mating the risk to human health f rom exposure to pesticides

. As part of Registration Revi ew, the Pesticide Re-evalu at ion Divis ion (PRD) of OPP has requested that HED eval uate 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 re su lt from the registered

u ses of clofentezin e

.

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. Ba sed on this assessment, HED has determined that there are no potential risk estimates of concern for the currently registered uses of clofentezine.

A summa r y of the findings and an assessment of human h ea l th risk resultin g from th e currently registered u ses of clofentezine are provided in this document. The HED team members contributing to thi s risk assessment include Charles Smith (risk assessment), Bridgett Bobowie c and Shalu Shelat (occupational and residential assessment), Yung Yang (hazard assessment), and

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

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

Page 2 of47Clofentezine Human Health Risk Asses sment DP No. D401611

Page 3 of 47 1.0 Executive Summary

................................ ................................ ................................ ................... 5

2.0 Ingredient Profile

................................ ................................ ................................ ....................... 7

2.1 Struct ure 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 Yo ung 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 Recomm endations

................................ .. 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 Di etary 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 Charact erization

................................ ................................ ........ 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

................ 29Clofentezine Human Health Risk Asses sment DP No. D401611

Page 4 of 47 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

................................ ................................ .... 46Clofentezine Human Health Risk Asses sment DP No. D401611

Page 5 of 47 1.0 Execu tive Summary

As part of Registration Review, t he Pesticide Re

- evaluation Division ( P RD) 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, cher ries, 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, t he HED Haza rd 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 (fina l report pending).

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

fects on the thyroid

. Orally

- administered clofentezine is rapidly absorbed, metabolized, and eliminated while d ermal 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, on e in rat and on e 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

eviden ce (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 af ter 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, c lofentezine h as 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. E stimated 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 wasClofentezine Human Health Risk Asses sment DP No. D401611

Page 6 of 47 0.04 ppb. Clofen tezine 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

Examin ation Survey, What We Eat in America, (NHANES/WWEIA)

. Acute: An acute dietary exposure assessment was not performed as n o 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 (chil dren 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 Q 1 * of 0.0376 (mg/kg/day) - 1 to the exposure value results in a

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

Residential Exposure : There are currently no registered residential uses associated with clofentezine; therefore, a residential/non

- occupational exposu re 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 a s 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 expos ure 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 - 6 to 7. 2 X 10 - 9 and 5. 3 X 10 - 6 to 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 intermedi ate

- 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 - 6 to
9.38 X 10 - 8

.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 7 of 47 Th e restricted entry interval s (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 w eak 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 ingredi ents 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 exp osures 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 r eview of their ethical conduct and a ll

of the studies utilized in this assessment have received the appropriate review.

2 .0 Ingredient Profile

Clofentezine is a n 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 3 mole - 1 ) indicate that the compound is

non

- vo latile 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 u se pattern and environmental fate parameters, there is the potential for clofentezine to reach water resources.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 8 of 47 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 in clude 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 walnu ts. The pre

harvest 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 ornam entals in greenhouses, saran and shade houses, outdoor containers and field

grown 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 applica tions 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 pr otection 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 use s and application

ra te s 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) PHI 1

(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 C A ) NA

Grapes (except NY) 21 days (10 days C A Nectarines

Peaches 21 days (10 days C A )

Pears 21 days

Persimmons 140 days

Walnuts 30 daysClofentezine Human Health Risk Asses sment DP No. D401611

Page 9 of 47 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) PHI 1

(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 reso urces 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. T here is a potential for occupational handler and post

- application e xposures.

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 cons umption, 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 categor ized by subgroups based on age and ethnic group

. Additionally, OPP is able to assess dietary exposur e 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 tod dlers, 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

consi der 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 inClofentezine Human Health Risk Asses sment DP No. D401611

Page 10 of 47 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 Requirement s

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

, 6 /2 7 /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 requir ed 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 av ailable hazard and exposure information for clofentezine , including: (1) t he toxicology

database for clofentezine does not reveal any evidence of treatment

- relat ed effects on the immune system; (2) t he known target organs of clofent ezine are the liver and thyroid; (3) t he most sensitive endpoint (hepatotoxicity) is currently used to assess exposure risk and is considered protectiv e of any potential immunotoxicity; and (4) i mmunotoxicity is not the most sensitive endpoint of clofentezine toxicity.

The av ailable 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) studiesClofentezine Human Health Risk Asses sment DP No. D401611

Page 11 of 47 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), m ale and female rats given clofentezine technical at 1000 mg/kg manifested peak plasma levels of between 14 and 16 ppm at 6

- 8 hours po st dosing which then declined to 3 ppm at 24 hours post dosing. Plasma half life was appr oximately 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 m ajor 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 14 C

clofentezine of 50 SC formulation was applied to the skin of male rats at dose levels of 0.18, 1.69, or 6.92 mg/cm 2 (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. B ased on the amount of combined

clofentezine found in the urine, feces, GI tract and carcass, t he 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 rate s w ere estima ted to be 1.22%, 0.16%, and 0.18% at the 4.8, 44, or 180 mg/kg do se 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 po rtion 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 con clusion 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/cm 2

. 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 amountClofentezine Human Health Risk Asses sment DP No. D401611

Page 12 of 47 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/cm 2 vs mg/cm 2 ) 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 P rofile

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

fects on the thyroid

. Body weight and body weight gai n decreases were decreased

whereas liver weights were increased and hepatocellular enlargement was reported along with

other observations (i ncreases in plasma cholesterol and triglyceride levels )

. The induction of the liver enzyme, UDPGT and the subsequent increase in the metabolism and the e xcretion of the thyroid hormone T4 reduced t he 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 o f 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 exposu re 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, c lofentezine has been classified as a possible human carcinogen based on male rat thyroid follicular cell adenoma an d/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 an d inhalation routes of exposure (Categories III and IV). It is a mild eye irritant , a weak dermal sensitizer, and is not considere d

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 reason ably account for potential exposures. There was no evidence of qualitative or quantitative susceptibility inClofentezine Human Health Risk Asses sment DP No. D401611

Page 13 of 47 developmental and reproduction studies and there was no evidence of neurotoxicity in the submitted studies. The dietary assessment is based on re liable 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, t here is no evidence of neurotoxicity following subchronic or chronic dosing in multiple speci es 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 /2 7 /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 stud y in rats.

3 .4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary exposure. C onservative, 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 Assessmen t

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 th e rabbit developmental studies.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 14 of 47 Chronic Dietary Endpoint : Quantification of chronic dietary risks was performed using a one

year feeding study in dog s 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 ( c PAD ) was calculated

to be 0.01 3 mg/kg /day

.

Short

- and Intermediate

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

clofentezine. Quantification of dermal risks was performed using a 90

- day rat feeding study

with a NOAEL of 2 mg/kg/day based on increased cholesterol, increased liver weights, thyroid colloid depletion and thyroid follicular cell hypertrophy (LOAEL = 20 mg/kg/day)

. Since an oral dose was selected, a dermal absorption factor of 1 % should be used in estima ting dermal risks (see Section 3 .2.1). A n MOE of 1 00 is required which includes interspecies extrapolation (10X) and intraspecies variability (10X)

.

Shor t

- and Intermediate

- term Inhalation Endpoints : No route specific inhalation study is

available for clofentezine. Quantification of inhalation risks was performed using a 90

- day rat feeding study with a NOAEL of 2 mg/kg/day based on increased cholesterol, increased liver weights, thyroid colloid depletion and thyroid follicular cell hypertrophy (LOAEL =

20 mg/kg/day)

. Since an oral study was selected

, abs orption via inhalation is presumed to be equivalent to oral absorption. A n 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 Rec ommendations

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, c lofentezine 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 Q 1 * val ue 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

.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 15 of 47 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 Non

Occupational Human Health Risk Assessments

Exposure/Scenario Point of Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxi cological

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 UF A = 10X

UF H = 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 study

LOAEL = 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. UF A = extrapol ation from animal to hu man (inter species), UF H = potential variation in sensitivity among membe rs of the human population (intra species).

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 UF A = 10X

UF H = 10X

Total UF = 100X

Dermal Absorption = 1% Occupational LOC =

100 13

- week rat study

LOAEL= 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 UF A = 10X

UF H = 10X

Total UF = 100X Occupational LOC =

100 13

- week rat study

LOAEL= 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. UF A = extrapol ation from animal to human (in ter species), UF H = potential variation in sensitivity among membe rs of the human population (intra species).Clofentezine Human Health Risk Asses sment DP No. D401611

Page 16 of 47 3. 6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemi cals. 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

suscept ible 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 Endo crine Disr uptor 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 occurrin g 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 stag e 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 relati onship between the do se 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 contai ns 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 5 1 pesticide active ingredients

. Clofentezine is among the group of 51 pesti cide activ e 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 t he 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. AlthoughClofentezine Human Health Risk Asses sment DP No. D401611

Page 17 of 47 clofentezine under laboratory conditions appears to be more persistent in aerobic soil (t 1/2 = 4 weeks in clay, 6 weeks in loamy sand and 8 weeks in clay loam), abiotic hydr olysis and/or direct photolysis are likely to control the degradation of clofentezine in the environment. However, extensive mineralization (i.e., CO 2 formation, up to 56% in aerobic soil after one year) was

found in the a erobic 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 CO 2 , only trace amount s 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 residu e 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 combin ed

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 th e Risk

Assessment an d Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Clofentezine Clofentezine

Livestock Ruminant C lofentezine and 3

- (2

- chloro

- 4

- hydroxyphenyl)

- 6

- (2

- chlorophenyl)

- 1,2,4,5

- tetrazine metabolite C lofentezine 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).Clofentezine Human Health Risk Asses sment DP No. D401611

Page 18 of 47 4

. 2 Food Residue Pr ofile

Crop Field Trials Adequate crop field trial data are available for clofentezine in/on almonds, peaches, nectarines, persimmons, and grapes following application of a S C 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

T he 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 translate d 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 clofente zine 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 e xamining c onfined 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

T here are no monitoring data currently available for clofentezine or its residues of concern in drinking water

. E stimated 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;

D 404287 ; 0 8/03/2012 ) . The surface water EDWCs are based on the USEPA Pesticide Root Zone Model (PRZM) and E xposure 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.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 19 of 47 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 1 0.062 2

Groundwater SCI

- GROW

-- 0.041

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

1 Represents North Carolina apple scenario

2 Represents California grape scenario

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 res idues (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 fi gures (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.

D efault processing factors were assumed for all existing crop use s with the exception of apple and pear juice (0.105 processing factor), raisins (0.3 processing factor), and grape juice (0. 0 9 processing factor). The residue file crea ted using the DEEM TM software for these dietary exposure analyses reflects these processing factors.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 20 of 47 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 crop s 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 n o 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 year s old ) resulted in an estimated risk of <1 % of the chronic population adjusted dose (c PAD ). 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 Q 1 * of 0.0376 (mg/kg/day) - 1 to the exposure value results in a

cancer r isk estimate of 2.8 x 10 - 7 to 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. 0000 08 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 <1Clofentezine Human Health Risk Asses sment DP No. D401611

Page 21 of 47 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 metho d 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 information 1 ). 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 data base 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 airbla st 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 Po stapplication 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 3 mole - 1 ) indicate that the compound is non

- volatil e 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

id entify 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 inha lation exposure assessment

for clofentezine

.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmClofentezine Human Health Risk Asses sment DP No. D401611

Page 22 of 47 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 regi stered residential uses

associated with clofentezine; therefore, a residential/non

- occupational exposure assessment is not required. As a result, the clofent ezine aggregate risk assessment includes only dietary exposure (food and water). An acute dietar y exposure assessment was not performed as n o appropriate endpoints were identified from the available clofentezine toxicity studies for the acute dietary

scenario

. The c hronic d ietary exposure estimates from food and drinking water do not exceed

HED’s le vel 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 tre e nut crops as well for use on C hristmas 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 ev ent.

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 han dlers is based on the following

scenarios:Clofentezine Human Health Risk Asses sment DP No. D401611

Page 23 of 47 1) Mixing/loading liquids for airblast a nd groundboom; 2) Applying sprays via airblast and ground boom equipment ; 3 ) Mixing/loading/applying liquids via mechanica lly

- pressurized handgun;

4 ) Mixing/loading/applying liquids vi a 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 Forc e (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. T he 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

- exposure

data.html

.

8 .1.1 Short

- /Intermediate

- Term Non

- Cancer Handler Exposure and Risk

H andler exposure is expected to be short

- or intermediate

- term in duration based on information provided o n the proposed labels. T he 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 duration s

. Long

- term exposures are not expected ; therefore, a long

- term assessment was not conducted.

Short

- and i ntermediate

- 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 estimate s for the currently registered uses of clofentezine at baseline personal protective equipment (PPE)

. The short

- and intermediate

- term combined risk estimates for all occupation al handler scenarios do not exceed HED’s level of concern (MOEs > 100 )

. HED

notes that current c lofentezine 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 t he addition of waterproof chemical resistant gloves required on the current labels.Clofentezine Human Health Risk Asses sment DP No. D401611

Page 24 of 47 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 Daily 2 Baseline Unit

Exposure ( m g/lb ai) 3 Baseline Dose

(mg/kg/day) 4 Baseline Short

- and

Intermediate

- term
MOEs 5 Combined Short

and Intermediate

term MOEs Dermal Inhalation Dermal Inhalation Dermal Inhalation

Mixer/Loader

Mixing/Loading liquids for groundboom and airblast applications (AHETF) Airblast: N ursery (ornamentals,

vegetables, trees, container stock)

0.25 lbs

ai/ A 20 A

0.22 0.00022 0.00014 0.000014 14000 140000 13000

A irblast: Almonds, Apples, Apricots,

Cherries Christmas Trees (except C A ), Grapes (except NY ), Nectarines, Peaches, Pears, Persimmons, Walnuts

G roundboom : field

- grown ornamental s 40 A 0.00028 0.000027 7300 73000 6600

G roundboom : greenhouse and nursery

ornamentals 60 A 0.00041 0.00004 4800 49000 4400

Applicator Applying Sprays

Ground via Groundboom (AHETF) Field

- g rown o rnamental s 0.25 lbs

ai/ A 40 A 0.0786 0.00034 0.000098 0.000043 20000 47000 14000

G reenhouse 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

A lmonds, 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 n ursery (ornamentals,

vegetables, trees, container stock)

, Almonds, Apples, Apricots, Cherries Christmas Trees (except C A ), Grapes (except NY ), Nectarines, Peaches, Pears, Persimmons, Walnuts 0.005 lbs ai/g al 40 gals 13.2 0.14 0.00033 0.00035 6100 5700 2900

Mixing/Loading/ Applying Liquids with Manually

- pressurized Handwand (PHED) Greenhouse and n ursery (ornamentals,

vegetables, trees, container stock)

, Almonds, Apples, Apricots, Cherries

Christmas Trees (except C A ), Grapes (except NY ), Nectarines, Peaches, Pears, Persimmons, Walnuts 0.005 lb ai/gal 40 gals 100 0.03 0.0025 0.000075 800 27000 780Clofentezine Human Health Risk Asses sment DP No. D401611

Page 25 of 47 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 Daily 2 Baseline Unit

Exposure ( m g/lb ai) 3 Baseline Dose

(mg/kg/day) 4 Baseline Short

- and

Intermediate

- term
MOEs 5 Combined Short

and Intermediate

term MOEs Dermal Inhalation Dermal Inhalation Dermal Inhalation

Mechanically

pressurized Handgun (PHED) Almonds, Apples, Apricots, Cherries

Christmas Trees (except C A ), 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 n ursery (ornamentals, vegetables, trees, container stock) 0.005 lb ai/gal 1000 gal s 3.5 0.12 0.00219 0.0075 910 270 210

1. Applic ation Rate = Maximum rate listed from labels.

2. T aken from “Standard Values for Daily Acres Treate d in Agriculture”; ExpoSAC SOP No. 9.1. Revised September 25, 2001.

3. Unit Exposures are taken from “Occupational Pesticide Handler Unit Expos ure 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

Page 26 of 47 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 fr o m the Exposure

Factors Handbook 2011 Editio n 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 - 6 to 7. 2 X 10 - 9 and 5. 3 X 10 - 6 to 2. 2 X 10 - 8 for private growers and commercial applicators, respectively

.Clofentezine Human Health Risk Assessment DP No. D401611

Page 27 of 47 T able 8.1.2: Cancer Occupational Exposure and Risk Estimates for Clofentezine (at label PPE 1 )

Crop Exposure Scenario Typical Application Rate 2

(lb ai/A) Total LADD Cancer Risks

Private Handler 3 Commercial Handler 4 Private Handler 3 Commercial Handler 4

LADD 5

(mg/kg/day) LADD 5

(mg/kg/day) Risk Estimate 6 Risk Estimate 6

Almond, peach, walnut Mixing /loading airblast

0.17 6.22 x 10

- 7 1.88 x 10

- 6 2.3 x 10

- 8 7.0 x 10

- 8

Applying airblast 2.15 x 10

- 5 6.45 x 10

- 5 8.1 x 10

- 7 2.4 x 10

- 6

Mixing, Loading Applying mechanically pressurized handwand

0.0034 lb ai/gallon 4.08 X 10

- 6 1.22 X 10

- 5 1.5 X 10

- 7 4.6 X 10

- 7

Mixing, Loading Applying manually pressurized handwand 7.17 X 10

- 7 2.15 X 10

- 6 2.7 X 10

- 8 8.1 X 10 8

Mixing, Loading Applying backpack

sprayer 5.26 X 10

- 6 1.58 X 10

- 5 2.0 X 10

- 7 5.9 X 10

- 7

Apple Mixing/loading airblast 0.15 5.49 x 10

- 7 1.65 x 10

- 6 2.1 x 10

- 8 6.2 x 10

- 8

Applying airblast 1.89 x 10

- 5 5.68 x 10

- 5 7.1 x 10

- 7 2.1 x 10

- 6

Mixing, Loading Applying mechanically pressurized handwand

0.003 lb ai/gallon 3.59 X 10

- 6 1.08 X 10

- 5 1.4 X 10

- 7 4.1 X 10

- 7

Mixing, Loading Applying manually pressurized handwand 6.33 X 10

- 7 1.9 X 10

- 6 2.9 X 10

- 8 7.1 X 10

- 8

Mixing, Loading Applying backpack

sprayer 4.65 X 10

- 6 1.39 X 10

- 5 1.8 X 10

- 7 5.2 X 10

- 7

Cherry Mixing loading airblast 0.22 8.05 x 10

- 7 2.42 x 10

- 6 3.0 x 10

- 8 9.1 x 10

- 8

Applying airblast 2.79 x 10

- 5 8.37 x 10

- 5 1.1 x 10

- 6 3.2 x 10

- 6

Mixing, Loading Applying mechanically pressurized handwand

0.0044 lb ai/gallon 5.29 X 10

- 6 1.59 X 10

- 5 2.0 X 10

- 7 6.0 X 10

- 7

Mixing, Loading Applying manually pressurized handwand 9.28 X 10

- 7 2.79 X 10

- 6 3.5 X 10

- 8 1.1 X 10

- 7

Mixing, Loading Applying backpack

sprayer 6.81 X 10

- 6 2.04 X 10

- 5 2. 6 X 10

- 7 7.7 X 10

- 7

Applying airblast 2.04 x 10

- 5 6.12 x 10

- 5 7. 7 x 10

- 7 2.3 x 10

- 6

Mixing, Loading Applying mechanically pressurized handwand

0.0032 lb ai/gallon 3.84 X 10

- 6 1.15 X 10

- 5 1.4 X 10

- 7 4.3 X 10

- 7

Mixing, Loading Applying manually pressurized handwand 6.75 X 10

- 7 2.03 X 10

- 6 2.5 X 10

- 8 7.6 X10

- 8

Mixing, Loading Applying backpack

sprayer 4.95 X 10

- 6 1.49 X 10

- 5 1.9 X 10

- 7 5.6 X 10

- 7

Christmas tree, n ectarine, persimmon, Mixing loading airblast 0.25 9.15 x 10

- 7 2.74 x 10

- 6 3.4 x 10

- 8 1.0 x 10

- 7Clofentezine Human Health Risk Assessment DP No. D401611

Page 28 of 47 T able 8.1.2: Cancer Occupational Exposure and Risk Estimates for Clofentezine (at label PPE 1 )

Crop Exposure Scenario Typical Application Rate 2

(lb ai/A) Total LADD Cancer Risks

Private Handler 3 Commercial Handler 4 Private Handler 3 Commercial Handler 4

LADD 5

(mg/kg/day) LADD 5

(mg/kg/day) Risk Estimate 6 Risk Estimate 6

apricot , grape Applying airblast 3.17 x 10

- 5 9.52 x 10

- 5 1.2 x 10

- 6 3.6 x 10

- 6

Mixing, Loading Applying mechanically pressurized handwand

0.005
(lb ai/ gallon) 6.0 X 10

- 6 1.8 X 10

- 5 2.3 X 10

- 7 6.8 X 10

- 7

Mixing, Loading Applying backpack

sprayer 7.75 X 10

- 6 2.23 X 10

- 5 2.9 X 10

- 7 8.7 X 10

- 7

Mixing, Loading Applying manually pressurized handwand 1.06 X 10

- 6 3.16 X 10

- 6 4.0 X 10

- 8 1.2 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

- 6 1.7 X 10

- 8 5.0 X 10

- 8

Mixing, Loading Applying mechanically pressurized handwand 4.68 X 10

- 5 1.4 X 10

- 4 1.8 X 10

- 6 5.3 X 10

- 6

Mixing, Loading Applying backpack

sprayer 3.27 X 10

- 6 9.8 X 10

- 6 1.2 X 10

- 7 3.7 X 10

- 7

Field

- grown nursery ornamental crop Mixing loading groundboom

0.104 3.80 x 10

- 7 1.14 x 10

- 6 1.4 x 10

- 8 4.3 x 10

- 8

Applying groundboom 1.16 x 10

- 6 1.44 x 10

- 6 4.4 x 10

- 8 5.4 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

- 7 1.72 X 10

- 6 2.2 X 10

- 8 6.5 X 10

- 8

Applying groundboom 4.79 X 10

- 7 1.44 X 10

- 6 1.8 X 10

- 8 5.4 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

- 9 2.2 X 10

- 8

Applying airblast 6.60 X 10

- 2 1.98 X 10

- 5 2.5 X 10

- 7 7.5 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 c ompleting multiple applications for multiple clients.

5 T otal LADD = total absorbed dose [Dermal dose + Inhalation Dose] * Days per year of exposure x Years per lifetime of exposure / (36 5 days/year x Lifetime expectancy).

6 Cancer risk estimates = LADD * Q 1 * , where Q 1 *

= 3.76 X 10 - 2 (mg/kg/day)

- 1

.Clofentezine Human Health Risk Assessment DP No. D401611

Page 29 of 47 8. 2 Occupat ional 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 re

entry 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 acti vities, 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 , atm

m 3 mole - 1 ) indicate that the compound is non

- volatil e under field conditions. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its 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 appro priate, 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 performe d 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 wo uld 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 d ermal 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,

201 1 ; 2) the maximum clo fentezine label application rates ; 3 ) a dislodgeable foliar residueClofentezine Human Health Risk Assessment DP No. D401611

Page 30 of 47 (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 ) t he 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 f

or all activities do not exceed HED’s level of concern (MOEs > 10 0) using

p redicted Day 0 residue values f r o m the DF R study.

Table 8.2.2.1: Summary of Short

- and Intermediate

- term Occupational Post

- application Non

Cancer Risk Estimates for Clofentezine

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) DFR 1 Dermal Dose at day 0 of application (mg/kg/day) 2 MOE 3

Almond , Walnuts Scouting 580

0.515 ug/cm 2 0.000299 6700

Apple s

Thinning Fruit 3,600 0.00185 1100 Apricot s

Cherr ies

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 2,0 00

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/cm 2 ) × 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 d ermal 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 T ransfer Coefficients, June 3, 201 1; 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) t he 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 standardClofentezine 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 c ancer 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 - 6 to 9. 4 X 10 - 8

.

Table 8.2.2.2 : Summary of Occupational Post

- application Cancer Risk Estimates for Clofentezine

Crop Activity Transfer

Coefficient (cm 2 /hr) Typical

application rate

lbs ai/a DFR 1 Dermal LADD (mg/kg/day) 2 Cancer Risk

Estimate 3

Almond, Walnuts Scouting 580 0.17

0.515 ug/cm 2 2.50X 10 - 6 9.4 X 10 - 8

Apples

Thinning Fruit 3

, 600 0.15 1.36 X 10 - 5 5.1 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 - 5 5.5 X 10 - 7

Persimmons

0.25 2.27 X 10 - 5 8.6 X 10 - 7

Christmas Trees Irrigation (hand set) 1

, 900 1.203 X 10 - 5 4.5 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 - 5 1.3 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 * Q 1 * , where Q 1 * = 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 w eak skin sensitizer.

Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following ap plication) 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 hour s on current
clofentezine labels is adequate to protect agricultural workers from post

- application exposures to

clofentezine

.Clofentezine Human Health Risk Assessment DP No. D401611

Page 32 of 47 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. J une 27 , 2012, TXR No. 0056333

.Clofentezine Human Health Risk Assessment DP No. D401611

Page 33 of 47 A ppendix 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

no 1 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

yes 2

yes 2

no no

no

no

no

no

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no

yes 3 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 201 2

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

3 In June 201 3

, the HASPOC waived the requirement for an immunotoxicity study ( final report pending ).Clofentezine Human Health Risk Assessment DP No. D401611

Page 34 of 47 A.2 Toxicity Profiles

Table A . 2 . 1 : Acute Toxicity of Clofente z in e

Guideline No. Study Type MRIDs # Results Toxicity Category

81

- 1 Acute Oral

- Rats 00159071 L D 50 >3230 m g/kg III

81

- 2 Acute Der m al

- ats 00105902 LD 50 >1332 m g/kg III (Suppl) 1

81

- 3 Acute Inhalation

- Rats 00138753* LC 50 >11.35 m g/L (6hr.) IV

81

- 4 Pri m ary Eye Irritation

- Rabbits 00105907* m ild irritant IV

81

- 5 Pri m ary Skin Irritation

- Rabbits 00159073 not a skin irritant IV

81

- 6 Der m al 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 To xicity Profile for Clofentezine

Study T y pe M RID No. Results

21

- Day Dermal Toxicit y

- Rat none no study available

Subchronic

- Feeding

- Mouse none incorporated i n to the two y ear mouse oncogenicity study

Subchronic 28 day Feeding in

Male Rats 40975503 (1989) Accep ta b l e/non

- gu i d elin e 0, 10, 400, 3000, or 30000

ppm M: 0, 1, 40, 300 or 3000 mg/kg/day (> Limit Dose) NOAEL (s y stemic) = 1.0 mg/kg/day [10 ppm]

LOAEL (s y stemic) = 40.0 mg/kg/day [400 ppm ]

, based on increased enz y me activity (uridine diphosphate glucuron y ltransferase; UDPGT), and th y roid activity (h y pertroph y
, h y perplasia, and mitotic activity of follicular
cells, colloid d e pletion and an increase in th y roid weight).

Subchronic 13 Week

- Feeding

- Rat 00105911 (1981)

00159079

40467905 Accep ta b l e/gu i d elin e 0, 40, 400, or 4000 ppm

M & F: 0, 2, 20, or 200 mg/kg/day NOAEL (s y stemic) = 2.0 mg/kg/day [40 PPM]

LOAEL (s y stemic) = 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 Accep ta b l e/gu i d elin e 0, 3200, 8000, or 20000 ppm
M & F: 0, 80, 200 or 500 mg/kg/day NOAEL was not e stablished. LOAEL (s y stemic) < 80.0

mg /kg/day [<3200 ppm ]

, based on increased liver weights in both sexes and electrocardiographic changes

in fe m a les.

Chronic Feeding

- One Year Dog 00149491(1983) Accep ta b l e/gu i d elin e 0, 50,1000 or 20000 ppm
M & F: 0, 1.25, 25, or 500 mg/kg/day NOAEL (s y stemic) = 1.25 mg/kg/day [50 ppm]

LOAEL (s y stemic) = 25.0 mg/kg/day [1000 ppm ]

, based on increased liver weights, hepatocellular enlarge m ent, and

increased serum cholesterol, trigl y ceride s
, and alkaline phosphatase levels.Clofentezine Human Health Risk Assessment DP No. D401611

Page 35 of 47 Chronic toxicit y /Carcinogenicit y

- Rat 00147883 (1985)

00159081

40289801 Accep ta b l e/gu i d elin e 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 (s y stemic) = 1.72 mg/kg/day [40 ppm]

LOAEL (s y stemic) = 17.3 mg/kg/day [400 ppm ]

, based on increased liver weights and liver

- to

- body weight ratios and

increased th y roxin levels; and centrilobular hepatocellular

h y pertrophy and vacuolation, focal c y stic degeneration of hepatoac y tes, and diffuse distribution of fat deposits in liver (M).

Evide n ce of carcinoge n icity in male rats [th yr oid tumors] Carcinogenicit y

- Mouse 00147885 (1985)

00159094

40302001 Accep ta b l e/gu i d elin e 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 (s y stemic) = 50.70 mg/kg/day [500 ppm]

LOAEL (s y stemic) = 543.0 mg/kg/day [5000 ppm ]

, based on decreased body weights and body weight gains, increased

incidence of eosinophilic areas in hepatoc y tes of m a les; in

fe m a les increased incidence of basophilic and/or eosinophilic

foci or areas of hepatoc y te alterations, m ortality w ith

a m y loidosis as a contributing factor for increased m ortalit y

.

No evide n ce of carcin oge n i city Developmental Toxicit y

- Ra t 00114270 (1982)

00159095 Accep ta b l e/gu i d elin e 0, 320, 1280, or 3200 mg/kg/day Maternal NOAEL = 1280 mg/kg/day (above the Limit Dose)

LOAEL = 3200 mg/kg/da y
, based on differential staining and slight enlargment

of the centrilobular hepatoc y tes. Developmental NOAEL >3200 mg/kg/day (above the

Li m i t Dos e )

LOAEL >3200 mg/kg/day

Developmental Toxicit y

- Rabbi t 00130761 (1983) Accep ta b l e/gu i d elin e 0, 250, 1000, or 3000 mg/kg/day Maternal NOAEL = 1000 mg/kg/day (Limit Dose)

LOAEL = 3000 mg/kg/da y
, based on decreased body weight and food consumption Developmental NOAEL= 1000 mg/kg/day (Limit Dose)

LOAEL = 3000 mg/kg/da y
, based on

decreased m ean fetal weight. Reproductive Toxicit y

- Rat 00147884 (1984)

00159070 Accep ta b l e/gu i d elin e 0, 4, 40, or 400 ppm
M & F: 0, 0.2, 2.0 or 20.0 mg/kg/day Parental/S y ste m ic 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 S accharo m y ces cerevisiae

gene conversion/mitotic

reco m bination 00130765 (1983) Non

- m utagenic and negative for m itotic reco m bination

Gene Mutation

- Salmonella 00105909 (1980)

Doses: 3.3 to 33 μg/plate Non

- mutagenic (±) activation.

Mouse L y mphoma 00159096 (1982)

40958301 Accep ta b l e/gu i d elin e
Doses: 0, 15, 30, 70, 100, or 128 μg/ml

- S9 or 0, 2, 10,
30, 80, 100, or 128 μg/ml

+ S 9. Non

- mutagenic (±) activation.

Micronucleus Assay Mice 00114269(1982)

Doses: 0, 800, 1600, or 3200 mg/kg Non

- mutagenicClofentezine Human Health Risk Assessment DP No. D401611

Page 36 of 47 Dominant Lethal Rat 00130764 (1983)

0, 4, 40, or 400pm Non

- mutagenic

Metabolism

- Rat 40942001(1985)

00159099

00159132

00105925 Accep ta b l e/gu i d elin e Male and female rats given c l ofentezine technical at 1000 mg/kg m a nifested peak plas m a 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 a pproximately 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 m e tabolites were 3

- (2'

- m e th y l

- thio

- 3' h y droxy phen y l)

- 6

- (2 '

- chloro

- phen y l)

- 1 ,2,4,5

- tetrazine and 3

- ,4

- , and 5

- h y drox y clofentezine. 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 s erum 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

.Clofentezine Human Health Risk Assessment DP No. D401611

Page 37 of 47 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 Asses sment : NOAEL= 2.0 mg/kg; LOAEL= 20.0 mg/kg/day

based on i ncreased 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 f or 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 i ncreased 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 (LC 50 > 11.5 mg/L); no other studies are available via this route. HEDs level of co ncer n (LOC)

for clofentezine inhalation exposure is 100 (i.e., a margin of exposure (MOE) less than 10 0 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 TechnicalClofentezine Human Health Risk Assessment DP No. D401611

Page 38 of 47 (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 pre

test 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

- weig ht ratios, and centrilobular hepatocellular enlargement. There was also depletion of thyroid colloid (3/20, 2/19, 4/20, 12/19, c ontrols to high dose) and follic ular 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 depleti on and thyroid follicular cell hypertrophy.

This study is acceptable/guideline and satisfies the guideline requirements for a subchron ic feeding study in rats

.

Executive Summary #2 : In a 90

- day feeding study (MRID 00105910,40467904), Charles River

COBS C D Sprague

- Dawley rats (20/sex/group) were fed Clo fentezine 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. A dditional 10 animals per sex were sacrificed pre test to establish pre

- test blood val ues.

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 centr ilobular 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 no rm al 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 % f rom 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 l ess than 3000 ppm based on increased cholesterol and triglycerides, increased liver weight and hepatocellular enlargement.Clofentezine Human Health Risk Assessment DP No. D401611

Page 39 of 47 This study is acceptable/non

- guideline and provides special information on characterization of thyr oid effects. It does not satisfy the guideline requirements for a subc hronic feeding study in

rats

.

Executive Summary #3: In a 28 day feeding study (M RID 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 (b y day 7), hyperplasia (by day 1 4) and mitotic activity (day 4 and 7) of follicular cells, colloid depletion (by day 4) and an increase in thyroid w eight (start day 15) were noted . The thyroid changes appeared to dim inish in frequency and severity during the study based on microscopic examination of serially sacrificed rats. Th e 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 subchron ic feeding study

in rats

.

Executive Summary #4: In a 90

- day subchronic feeding study (M RI D 00105912, 00126844), Clofentezine Technical (9 9.7

- 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 20,0 00 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

th an 3200 ppm (80 mg/kg/day). LOAEL is less than or equal to 32 00 ppm (80 mg/kg/day) based

on i ncreased liver weight in both sexes and electroc ardiographic 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, 12 80 or 3200 mg/kg/day (controls had 37 rats).Clofentezine Human Health Risk Assessment DP No. D401611

Page 40 of 47 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 mater nal 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 redu ced 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. F 0 parents produced 2 litters (F 1A , F 1B ). The F 1A litter was used as the F 1 parents to produce the F 2A and F 2B litters. Ten

F 2A /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/k g/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).Clofentezine Human Health Risk Assessment DP No. D401611

Page 41 of 47 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 (MR ID 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 li ver 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 c holesterol (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 ear ly part of the study and again at term in high dose males and mid and high dose females (40

- 75 % above controls).

The NOAEL w as 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, triglyceri des, and alkaline phosphatase.

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

year dog study

.

A.4.5 Carcinogenicity

Combined Chronic/Carcinogenicity Study

– rat

In a 27 month chronic carcinogenicity study, (MRI D 00147883, 00159081, 40289801, 40467906, 40467910) Clofentezine Technical (98.7 % al., batch # CR 20099/12) was

administered in the diet to Charles River Cr l :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 le vels in males at 27 months. Live r weights and weight ratios for high dose group males were increased above controls (20 %) and fo r high dose group females (10% ), both statistically significant. Histological changes occurred in the liver of

males in a dose

- related manner, and included centrilobula r 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 LOA EL is 400 ppm (17.3 mg/kg/day) based on increased liver weights and increas ed liver

- body weight ratio (males ); increased thyroxine levels;Clofentezine Human Health Risk Assessment DP No. D401611

Page 42 of 47 centrilobular hypertrophy and vacuolation of hepatocytes, focal cystic degeneration of hepatocytes and diffuse distri bution of fat deposits in liver (males).

Do ses were considered below the maximum tolerate dose ( MT D ) based on the subchronic

studies as well as little evidence of toxicit y even at the high dose (confirm ed in the Toxicology

Branch Cancer Pe er Review, Docu ment 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, Q 1 * (mg/kg/day) - 1 , of c lofent ezine based upon male rat thyroid follicular cell adenoma and/or

carcinoma co mbined tumor rates is 3.76 x 10 - 2 in human equivalents. This Q 1 * 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 i n rats

.

Carcinogenicity (feeding)

– Mouse

I n a 105 week carcinogenicity study (MRID 00147885, 00159094, 40302001)

, Clofentezine Technical (98.7 % al., b atch # CR 20099/12) was admini stered 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 g ains (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 signif icant 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 m onths 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 eosi nophilic 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 fo ci). The NOAEL was 500 ppm (M: 50.7 ; F: 56.9 mg/kg/day). The LOAEL was 5000 ppm (M: 543.0;

F: 55 7.1 mg/kg/ day) based on reversible decreases in body weight and weight gain, increased

inci dences of eosinophilic areas or foci of hepatocytes in males; in females increased incidence of basophilic and/ or eosinophilic foci or areas of hepatocy tes, 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, th e highest dose test ed is above 1/ 2 the limit dose of 1 gm/kg.Clofentezine Human Health Risk Assessment DP No. D401611

Page 43 of 47 Although liver tumors were elevated in both sexes of mice, no biologically relevant dose

response relationship occurred in male mice, while that in female mice was flat over the dose range of 0 ppm (i.e., 4 tumo rs 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 a berration
[Mouse Lymphoma ]

MRID 00159096, 40958301 Negative

Dominant Lethal (Rat)

MRID 00130764 Negative

Other Genotoxicity

Gene conversion/mitotic reco m bination (Saccharomyces cerevisiae)

MRID 00130765 Negative

A.4.7 Metabolism

Metabolism

– Rat

In a metabolism study (MRID 4092001), m ale 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 appr oximately 3.5

hours. Wh ole 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.Clofentezine Human Health Risk Assessment DP No. D401611

Page 44 of 47 Appendix B: Review of Human Research

This risk assessment relies in part on data fr om 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 Agricult ural 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.Clofentezine Human Health Risk Assessment DP No. D401611

Page 45 of 47 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 3 mole - 1

Octanol/water partition coefficient (25°C) log Kow = 3.1Clofentezine Human Health Risk Assessment DP No. D401611

Page 46 of 47 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 roun ded 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 a pplied

- 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 val ue 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 Agric ulture’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 no t imply zero usage.Clofentezine Human Health Risk Assessment DP No. D401611

Page 47 of 47 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

rep orted 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.