### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D

. C

. 20460



### MEMORAN D U M

D ate : February IO, 2016 OFFICE OF C HEMI C AL SAFETY AND POLLUTIO N PREVENTION



### SUBJECT: C l ofe nt ez in e

. H uman-Health Risk Assess m e nt to S upp ort a Sec ti o n 

### 3 R egistration Requ es t to Add ew Us es on Avocado and Papaya

, and New Uses for 

### Pome Fruit Group 11-10

, Cherry sub-group l 2- I 2A, Peach s ub-group 12-128. and Small Fruit Vine C lim bing except Fuzzy Kiwifruit Subgro up l 3-07F based on Existing Tolerances on Representati ve Commodities

.



### P C C ode: 12550 l 

### D ec i s ion No. : 495217 

### Pet ition No.: NA 

### Risk A ss e ss m e nt Ty p e: Sing l e Chem i cal/ Aggregate 

### TXR No. : NA 

### M RJD No.: NA 

### DP Barcode: 0423333 

### R eg i s tr at ion No.: NA 

### R eg ul atory Actio n : Section 3 

### Regi s trat i on 

### Case No.: NA



### CAS N o.: 74115-24-5 4 0 

### CF R : 180.572



### FROM: Evisabel Craig. Ph.D., DABT. Risk assesso r / Toxicologist

# ·**~** Bridgett B obow i ec

.

## Biologist**~ ~** **~** () P. Yvonne Barnes, Chem i s t**~** 

### Ri s k Assessment Branch V l Health E ffects Division (7509 P )



### THRO UG H: Donna Da v is, Acting Branch Chief Ri s k Assessment Branch VI H ealth Effec ts Division ( 7509P)



### TO : And y Ertman

, Chemical R ev i ew Ma na ger Barbara Madden, T earn L ea der Marion Johnson

, Branch Chief Minor Use and Emergency R es pon se Branch Registration Divi s ion (7505P)

Pa ge I of 43

### Clofentezine Hum a n-H ea l th Ri sk Assessment DP No. 423333



### Th e H ea lth E ffe c t s Division ( H E D ) of th e Offic e of P es ti cide Prog r a m s (O PP ) i s charged with

es tim a tin g th e ri s k to human h ea lth from ex p os ur e t o p es ticide s. The R eg i st r a ti o n Di v i s ion ( RD )

o f the Offic e of P es ticide Program s ha s reque sted that H E D eva luat e ha zard and ex po s ure dat a and

co ndu c t dietary

, occ upational

, r esidential, and aggregate exposu r e assessme nt s , as n ee d e d. to

es tim a t e th e ri s k to human h ea lth that will re su lt from t h e existing and proposed n ew u ses of the acaric id e cl o f e nt ez ine.

A 

### s umm ary of the findin gs and an assess m e nt of hum a n health risk resulting from the exist in g and proposed n ew us es of c lofente z in e are provided in thi s d oc um ent. The risk assessment, h aza rd

c h a ra cte ri zat i o n and endpoint se l ec tion were provided by Evisabel Craig ( R A B 6); the di eta r y exposure assess m e nt and r es idue chemistry assessment by Yvonne B a rne s ( RAB6) ; the

occ upati o n a l and re s id e ntial expos ur e assess m e nt b y B1id ge tt B obowiec (RAB6); a nd th e drinking
water expos ur e assessment by Ro sa nna Louie-Ju zw iak of the E n v ironm e ntal F a te and Effects Di vis ion (E FED ).

Page 2 of43Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 3 of 43 

### Table of Contents 1.0 Executive Summary

................................ ................................ ................................ .............. 5 2.0 HED Recommendations

................................ ................................ ................................ ....... 7 2.1 Da ta Deficiencies

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

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

................................ ................................ ............................ 8 2.2.3 Revisions to Petitioned

- For Tolerances

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

................................ ................................ ........................ 9 2.3 Label Recommendations

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

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

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

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

................................ ................................ ................................ ....... 10 3.4 Anticipated Exposure Pathways

................................ ................................ .................... 11 3.5 Consideration of Environmental Justice

................................ ................................ ....... 12 4.0 Hazard Characterization and Dose

- Response Assessment

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

................................ ................................ .... 12 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

................................ 13 4.2.1 Dermal A bsorption

................................ ................................ ................................ ...... 13 4.3 Toxicological Effects

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

................................ ................................ .............. 14 4.4 Safety Factor for Infants and Children (FQPA SF)

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

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

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

........... 15 4.4.4 Residu al Uncertainty in the Exposure Database

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

................................ ................. 15 4.5.1 Dose

- Response Assessment

................................ ................................ ......................... 15 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

............................... 16 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

................................ ................................ ................................ ................................ .. 16 5. 0 Dietary Exposure and Risk Assessment

................................ ................................ ........ 17 5. 1 Residues of Con cern Summary and Rationale

................................ ............................. 17 5.2 Food Residue Profile

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

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

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

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

................................ ................. 18 5.4.3 Acute Dietary Risk Assessment

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

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

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

................................ ................................ ................................ ............ 19 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ 19 6.1 Spray Drift

................................ ................................ ................................ ....................... 20 6.2 Residential Bystander Post

- Application Inhalation Exposure

................................ ... 20Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 4 of 43 

### 7.0 Aggregate Exposure/Risk Characterization

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

................................ ................................ .. 20 9.0 Occupational Exposure/Risk Characterization

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

................................ ................................ ... 21 9. 2 Occupational Postapplication Expossure and Risk

................................ ...................... 30 10.0 References

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

................................ ..................... 37 Appendix B. Review of human research

................................ ................................ ..................... 40 Appendix C. Physical/Chemical Properties

................................ ................................ ................ 41 Appendix D. Summary of Occupational Exposure Algorithm s

................................ ................ 41 Appendix E

. International Re s idue Limits ...............................................................43Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 5 of 43 

### 1.0 Executive Summary

Clofentezine [3

- 6

- bis(2

- chlorphenyl)

- 1,2,4,5

- tetrazine] is an acaricide currently registered for occupational foliar applications to almonds, apples, apricots, cherries, Christmas trees plantations (except California), grapes (except New York), peaches, pears, persimmo ns, nectarines, and walnuts. In addition to traditional agricultural crops, clofentezine is registered for use on commercial ornamentals in greenhouses, saran and shade houses, outdoor containers

, and field

grown nursery stock. There are no registered or proposed residential uses associated with clofentezine at this time.

This assessment addresses dietary exposure, occupational exposure and risk associated with the proposed new uses of clofentezine , as well as the proposed ne w crop groups . A Section 3 registration was requested by the Interregional Research Project No. 4 (IR

- 4), in cooperation with the registrant, Makhteshim Agan of North Americ a, I nc. for use of technical clo fentezine (EPA Reg. No. 74054

- 1 ) and the suspensio n concentrate (SC) formulation APOLLO ® 

### SC Ovicide/Miticide (EPA Reg. No. 66222

- 47) containing 42% active ingredient on avocado, and papaya, as well as new groups for stone fruit (12

- 12A and 12

- 12B), pome fruits (11

- 10), and small fruit vines except fuzzy s ubgroup (13

- 07F) based on existing tolerances for the respective representative commodities

.

The proposed label recommends that clofentezine be applied only one time per year at first sign of mite activity. The maximum single application rate for all cr ops using ground and handheld equipment is 0.25 pound active ingredient per acre (lb ai/A) or 0.005 lb ai/gallon of spray. Aerial and chemigation application of clofentezine is prohibited. Clofentezine personal protective equipment (PPE) on the proposed labels includes baseline dermal (long sleeved shirt, long pants, shoes plus socks) as well chemical resistant gloves (i.e., such as barrier laminate, butyl rubber, neoprene rubber, poly

- vinyl chloride (PVC), or Viton ®)



### . The toxicology database for clofentezine is complete for risk assessment purposes

. In June 2012, the HED Hazard and Science Policy Council (HASPOC) waived the requirement for a neurotoxicity battery and a route specific inhalation toxicity study

. More rec ently, in June 2013, HASPOC waived the requirement for an immunotoxi city stu d y.
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 rapi dly absorbed,
met abolized, and eliminated

. HED had reconsidered the available der mal absorption data for clofente z in e, and has revised the dermal absorption factor to 10%

, consistent with current policy.

The FQPA Safety Factor can be reduced to 1X because there is an adequate toxicity database for clofentezine and exposure data are complete or are estimated based on data that reasonably account for potential exposures

. Two pre

- natal developmental toxicity studies were available, one in rat s and one in rab bit s but n o evidence (quantitative or qualitative) of increased susceptibility was seen in either study. There was no evidence (quantitative or qualitative) of increased susceptibility following pre

- an d/or post

- natal exposure in rats for two generations i n the reproduction study (NOAEL set at the highest dose tested). Also, there was no evidence of neurotoxicity in the clofentezine database.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 6 of 43 

### C lofentezine has been classified as a possible human carcinogen based on male rat thyroid follicular cell adenoma and/or carcinoma combined tumor rates. The Q 1 

### * value for clofentezine using the 3⁄4 inter species scaling factor is 3.76 x 10

- 2 

### (mg/kg/day)

- 1



### . Clof entezine is not considered a mutagen

. The residue chemistry data base is complete to support the proposed actions that are the subject of this memorandum. The nature of the residue in plants is well understood a nd the residue of concern is the parent compound only for both risk assessment and tolerance setting purposes. T here are no new livestock feedstuffs associated with this petition; therefore a discussion of livestock metabolism is not relevant to this action. Adequate residue data, in terms of both number of trials and geographic representation, developed by a validated method and supported by storage stability data have been provided to support the new uses on avocado and papaya. No new data was submitted , or are required to support the new crop group s /subgroup s since tolerances are already established based on all the relevan t representative commodities and the use pattern for the new crop groups/subgroups is identical to the use patterns for the representative commodities. There is an adequate analytical enforcement method available to enforce the proposed tolerances.

Mode lled e stimated drinking water concentrations (EDWCs) were generated by the Environmental Fate and Effects Division (EFED)

. Clofentezine chronic and cancer dietary risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Vers ion 3.16 which uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).

An acute dietary exposure assessment was not performed as no appropriate endpoints were identified from the available clofentezine toxicity studies indicating that clofente zine does not pose an acute dietary hazard. Partially refined chronic dietary as well as cancer dietary exposure and risk assessment s w ere perfo rmed that directly incorporated average field trial residues

, percent crop treated information, and modelled drinking water estimated residues. The estimated exposure to the highest population subgroup (children 1 < 2 years old) resulted in an estimated r isk of <1% of the chronic population adjusted dose (cPAD). The estimated exposure to the general U.S. population resulted in an estimated risk of <1% of the chronic population adjusted dose (cPAD). . Applying the Q 1 

### * of 3.76 x 10

- 2 

### mg/kg/day to the expos ure value result ed in a cancer risk estimate of 3.8 x 10

- 7 

### to the general U.S. population.

There are no registered residential uses of cl ofente zine; therefore, the aggregate assessment includes food and water only and, as noted above, is not of concern.

There is potential for occupational exposure associated with handler activities (i.e., mixing, loading, and applying) as well as with post

- application activities (i.e., re

- entering treated areas). Based on the proposed use pattern (i.e., one application p er season) the duration of exposure for the proposed uses is expected to be short

- term (ST) 1 to 30 days and intermediate

- term (IT) 1 to 6 months. Long

- term exposures greater than 6 months are not anticipated. Combined MOEs at baseline PPE (long sleeve s hirt, socks, shoes and no respirator) are not of concern (MOE s >100) for the proposed crop s except for airblast application to avocados and papayas (MOE=97) and handheld manual and mechanically pressurized handgun applications (MOEs 80 and 52)

. ManualClofentezine Human

- Health Risk Assessment DP No. 423333

Page 7 of 43 

### and mechanically pressurized handgun applications are not of concern with the current proposed label PPE of gloves (MOEs are 11,000 and 150 respectively). The addition of double layer dermal protec tion and gloves brings the risk estimate for airblast appl ications to 110 . This PPE is currently not on the proposed label . In summary the c ombined dermal and inhalation MOEs ranged from 52 to 1,900 with baseline dermal PPE and no respirator, 88 to 11,000 with the addition of gloves, and 110 to 120,000 with dou ble layer dermal protection and gloves. Clofentezine combined dermal and inhalation cancer risk estimates at baseline for private handlers ranged from 1.77E

- 05 to 4.78E

- 07 and 1.07E

- 05 to 8.46E

- 08 with the addition of chemical resistant gloves, 8.08E

- 06 t o 7.67E

- 8 with double layer dermal protection and gloves for proposed uses. Clofentezine combined dermal and inhalation cancer handler risk estimates at baseline for commercial handlers ranged from 5.34E

- 05 to 1.43E

- 06 baseline dermal and no respirator an d 3.2E

- 05to 2.54 E

- 07 with the addition of chemical resistant gloves, and 2.43E

- 05 to 2.3E

- 07 with double layer dermal protection, gloves, and no respirator.

The non

- cancer post

- application exposure estimates do not exceed HED’s level of concern (MOEs ≥ 100) at day 0 after treatment (DAT) using the highest post

- application transfer coe fficients for the proposed crops (avocado and papaya) and the representative commodities of the new crop group s 11

- 11 and 12

- 12 A and 12

- 12B

. However in considering the pro posed new use on crop subgroup 13

- 07F, in light of the revised dermal absorption factor, HED has reevaluated the post

application exposure and risk associated with the existing registered use on grapes, the representative commodity for subgroup 13

- 07F. T here are grape activities, such as tying training, hand harvest, hand

- leaf pulling and girdling/turning that exceed HED’s level of concern at day 0 after treatment . Hand harvesting floriculture also exceeds HED’s level of concern until day 3 after application

. The proposed new uses include a 12 hour reentry interval (REI) consistent with previously registered labels. The cancer post

- application risk estimates for the proposed crops and crop groups/subgroups calculated ranged from 1.34

- 04 to 6.92E

- 07 at day 0 after treatment (DAT0) and 9.52 E10

- 5 to 4.93E

- 07 using the average 30 day dose.

There are issues with respect to international harmonization raised by these actions contained in this memorandum. While t here are no issues with respect to avoca do, papaya, and pome fruit

, establishing the recommended tolerances on stone fruit (12

- 12A and 12

- 12B) does raise an issue with harmonization relative to the currently established Codex MRLs for stone fruit. Further, should the Agency determine that worker risk issues associated with the request to establish a subgroup 13

- 07F tolerance are resolved, there would be issues of harmonization with the currently established Codex MRL on grapes, the representative commodity for the subgroup 13

- 07F. There are no i ssues with respect to Canadian MRLs raised by the establishment of the tolerances in this memorandum.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Thes e studies (listed in Appendix B ) have been determined to require a review of their ethical conduct and all of the studies utilized in this assessment have received the appropriate review.

2.0 HED RecommendationsClofentezine Human

- Health Risk Assessment DP No. 423333

Page 8 of 43 

### HED has no objection to the establishment of tol erances for residues of clofente zine in/on avocado and papaya, and the new uses on crop group/subgroups 11

- 10, 12

- 12A, and 12

- 12B. However, HED has identified worker risks of concern associated with the current registered use on grapes, the representative crop for the 13

- 07F crop subgroup; and therefore cannot recommend in favor of establishing that tolerance at this time.

2.1 Data Deficiencies

There are currently no deficiencies in the toxicology, ORE

, or residue chemistry databases for clofentezine.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An HPLC analytical method for the determination of clofentezine residues in/on fruit was submitted with PP# 3F3392 (MRID# 44202401). Brie fly, fruit samples are extracted into acetone and filtered. An aliquot of the extract is removed and partitioned with hexane. The organic extract is rotary evaporated to dryness then reconstituted in hexane for clean up through a silica solid phase extrac tion cartridge. The clofentezine is eluted from the silica, evaporated to dryness, adjusted to the final volume and quantified using high performance liquid chromatography with UV detection at 268 nm. The limit of quantitation (LOQ) and limit of detec tion (LOD) were determined to be 0.01 ppm and 0.003 ppm, respectively. Although the method was initially validated on apples which was the initial registered commodity, it was developed for all fruit. A petition method validation (PMV) was successfully co mpleted by the EPA Analytical Chemistry Laboratory, and the method was found acceptable.

While this method was originally developed for fruit matrices, the data collection method used to determine residues in avocado employed extraction with the same so lvent, acetonitrile, and showed acceptable recoveries; therefore HED concludes that th is method is suitable as an enforcement method for avocado, papaya, as well as all the new commodities associated with the proposed crop groups.

2.2.2 Recommended Tolerances

The tolerance expressions established under 40 CFR §180.446 comply with the HED Interim Guidance on Tolerance Expressions (S. Knizner, 05/27/2009); no revisions are necessary. A tolerance summary is presented in Table 2.2.2 below.

Table 2.2.2 T olerance Summary for Clofentezine

Commodity Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition/Comments

To be established under 40 CFR §180.446 (a) General. (1) Cherry, subgroup 12

- 12A 1.0 1.0 Established tolerance for cherry (1.0 ppm) should be removed from the 40CFR andClofentezine Human

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Page 9 of 43 Table 2.2.2 T olerance Summary for Clofentezine

Commodity Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition/Comments

To be established under 40 CFR §180.446 (a) General. (1) replaced by this subgroup tolerance. Fruit, pome, group 11

- 10 0.5 0.50 Established tolerance for apple and pear (0.5 ppm) should be removed from 40CFR and replaced by this group tolerance. Peach, subgroup 12

- 12B 1.0 1.0 Established tolerance for peach should be removed from the 40CFR and replaced by this group tolerance. Fruit, small, vine climbing, except fuzzy kiwifruit, Subgroup 13

- 07F 1.0 1.0 Established tolerance for grape (1 ppm) should be removed from the 40CFR and replaced by this subgroup tolerance. Avocado 0.3 0.30 N/A Papaya 0.3 0.30 N/A



### 2.2.3 Revisions to Petitioned

- For Tolerances

No revisions are needed.

2.2.4 International Harmonization

The International Residue Limit (IRL) Status Sheet for clofent e zine is attached in Appendix E

. The tolerance expression in plant commodities is harmonized between the US, Codex and Canada. In all three countries, the residue of concern in plants is the p arent compound, only.

The recommended tolerance for residues of clofente zine in/on avocado and papaya in the U.S. is 0.30 ppm. There are no Codex

, Canadian , or Mexican MRLs for residues on avocado and papaya. Therefore, there are no issues with respect to harmonization raised by the new avocado and papaya tolerances.

The US is recommending a tolerance of 0.5 ppm for pome fruit. There are MRLs for both Codex and Canada at 0.5 ppm for pome fruit. Since the US tolerance matches the Codex and Canadian MRL S, there are no international harmonization issues for pome fruit.

The US is recommending a tolerance of 1.0 ppm in stone fruit (12

- 12A and 12

- 12B). There are Canadian MRLS at 1.0 ppm for stone fruit and a Codex MRL for stone fruit at 0.5 ppm. The clofentezine residues in/on representative stone fruit crops , cherry and peach

, from the submitted US field trial data are greater than 0.5 ppm and setting the tolerances for 12

- 12A and 12

- 12B at 0.5 ppm to harmonize with Codex could result a tolerance exceedance for US growers. The refore, the US tolerance is harmonized with the Canadian MRL, but cannot be harmonized with Codex MRL for stone fruit at this time

.

The recommended US tolerance of 1.0 ppm for the crop subgroup fruit, small, vine climbing, except fuzzy kiwifruit, 13

- 07F does not harmonize with the Codex MRL of 2.0 ppm

. There is no Canadian MRL for these commodities. The petitioner proposes to establish the 13

- 07F subg roupClofentezine Human

- Health Risk Assessment DP No. 423333

Page 10 of 43 

### tolerance at 1.0 ppm, which would leave the tolerance on grapes at 1.0 ppm, the current US grape tolerance level

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

. Therefore, HED is recommending that the tolerance of 1.0 ppm be established and notes that there are issues of international harmonization created by this approach.

2.3 Label Recommendations

No label revis ions are needed based on the residue chemistry , occupational or residential exposure review s

.

3.0 Introduction

3.1 Chemical Identity

Table 3.1: Clofentezine Nomenclatur e

Chemical Structure

Common Name Clofentezine IUPAC name 3,6

- bis(2

- chlorophenyl)

- 1,2,4,5

- tetrazine CAS Name 3,6

- bis(2

- chlorophenyl)

- 1,2,4,5

- tetrazine CAS Registry Number 74115

- 24

- 5



### 3.2 Physical/Chemical Characteristics Clofentezine’s vapor pressure (9.75 x 10

- 10 

### mm Hg @ 25 °C) and Henry's Law Constant ( 0.168 Pa×m3/mol ) indicate that the compound is non

- volatile under field conditions. Clofentezine has a low solubility (34.2 mg/L) in water; however, clofentezine is fairly persistent in the e nvironment. Based on the use pattern and environmental fate parameters, there is the potential for clofentezine to reach water resources. The octanol/water partition coefficient for clofentezine indicates that it may have the potential to accumulate into fatty tissues.

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

.

3.3 Pesticide Use Pattern

Clofentezine is formulated as a suspension concentrate containing 42% active ingredient or 1.0 lb active ingredient per quart (i.e., 4.0 lbs a.i/gallon). Two end

- use products are registered: Apollo ® 

### SC Ovicide/Miticide (EPA Reg. No. 66222

- 47) and Clofentezine SC (EPA Reg. No. 66222

- 53). HED notes that only the Apollo® SC Ovicide/Miticide label includes the agricultural us es of clofent e zine. Clofentezine is applied at the first sign of mites by ground equipment through airblast, groundboom machinery, and handheld equipment once per year. It may not be applied aerially or through any type of irrigation system. There are n o registered residential uses for clofentezine.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 11 of 43 

### The Section 3 registration requested by IR

- 4, in cooperation with the registrant, Makhteshim Agan of North America, Inc. proposes the use of Apollo ® 

### SC Ovicide/Miticide on avocado, papaya, as well as the f

ollowing crop subgroups expansions : cherry subgroup (12

- 12A), peach subgroup (12

- 12B), pome fruit group (11

- 10), and small fruit vine climbing except fuzzy subgroup (13

- 07F).

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

- harvest interval (PHI) as the previously registered crops. The PHI for avocado and papaya is 3 days. The PHI for the pome fruit group is 45 days. The PHI for the cherries, small fruit, vine climbing except fuzzy kiwi and peaches is 21 days and (10 days for peaches in California). The proposed uses and application rates are further described in Table 3.3.

Table 3.3. Summary of Directions for Proposed Use for Clofentezine

APOLLO ® Suspension Concentrate (SC)

- EPA Reg. No. 66222

- 47

- 4 lbs a.i/gal Application. Equipment Crop s Maximum Application Rate PHI (days) Use Directions and Limitations

Airblast, Groundboom, and Handheld Equipment Avocado

8 oz. product/A 0.25 lb a.i/A 3 Apply at first sign of mite activity

. Do not apply via aerial or chemigation. Do not make more than one applications of product per year. PPE includes baseline attire (a long

- sleeved shirt and long pants, and shoes plus socks) and gloves. Do not graze livestock in treated areas or harvest t he

cover crop for livestock feed. Papaya Fruit, pome, group 11

- 10 45 Pears and Asian pear 21 and (10 days Peaches California) Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F Cherry, subgroup 12

- 12A Peach, subgroup 12

- 12B



### Conclusions: Adequate use directions have been provided for the new uses on avocado and papaya. The petitioner has requested new uses for several crop groups based on the current uses and tolerances for the respective representative commodities

. The proposed use instructions for the pome fruit group 11

- 10, the cherry subgroup 12

- 12A, the peach subgroup 12

- 12B, and the fruit, small, vine climbing, except fuzzy kiwifruit , subgroup 13

- 07F are identical to the use pattern for the current ly registered representative commodities

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

3.4 Anticipated Exposure Pathways Humans may be exposed to clofentezine in food and drinking water, since clofentezine may be applied directly to growing crops and application s may result in clofentezine reaching surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application and upon re

- entry into the field after application. There are currently no residential uses of clofentezine, so exposure in residential and non

- occupational settings is not likely

. This risk assessment considers all of the exposure pathways based on the proposed new uses of clofentezine , but also considers the existing registered uses

.Clofentezine Human

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Page 12 of 43 

### 3.5 Consideration of Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” (http:// epa.gov/compliance/ej/ resources/policy/exec_order_12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA u nder the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home us e of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assess ment
4.1 Toxicology Studies Available for Analysis The studies available for consideration of clofentezine toxicity provide a comprehensive and complete database for risk assessment purposes

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

, 6 /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 o ral neurotoxicity studies in the rat are not required at this time. This approach considered all the available hazard and exposure information for clofentezine, including: (1) the lack of neurotoxicity in the available toxicity studies for clofentezine; (2) the known target organs of clofentezine are the liver and thyroid; (3) the most sensitive endpoint (hepatotoxicity) is currently used to assess exposure risk and is considered protective of any potential neurotoxicity; and (4) neurotoxicity is not the most sensitive endpoint of clofentezine toxicity.

Use of an oral NOAEL for inhalation risk assessment was also discussed at the June 2012 HASPOC meeting. The HASPOC concluded that based on a WOE approach, that a subchronic inhalation toxicity study fo r 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 thyr oid 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.Clofentezine Human

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### More recently, in June 2013, HASPOC waived the requirement for an immunotoxicity study (TXR 0056690, 06/07/2013 ) . The HASPOC concluded that based on a WOE approach, that an immunotoxicity study for clofentezine is not required at this time. This approach considered all of the available hazard and exposure information for clofentezine , including: (1) t he toxicology database for clofentezine does not reveal any evidence of treatment

- relat ed effects on the immune system; (2) t he know n 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 available toxicity studies for clofentezine are listed in Table A. 1 in Appendix A. The data from the following studies were used to evaluate the hazard potential of clofen tezine (see Appendix A: Tables A.2 and A.3 ) :

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

 Subchronic oral toxicity studies (rat and dog)

 Developmental (rat and rabbit) and reproductive t oxicity (rat) studies

 Chronic oral toxicity studies (rat and dog)

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

 Metabolism studies (rat)

 Mutagenicity battery

 Dermal penetration

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

O rally

- 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 pos t 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.

4.2.1 Dermal Absorption Two dermal absorption studies have been submitted for clofentezine. In the first study (MRID 00159102; Campbell et al., 1986), clofentezine was applied at doses of 36, 338, and 1,380 μg/cm 2 

### for 10 hours. Following 10 hours of exposure, 0.61, 0.13, and 0.08% of the dose was absorbed, respectively (amount in urine, feces, and carcass). High amounts of radioactivity were identified remaining at the skin site (>30%) and on the dressing (~40

- 60%) in all dose groups.

A second dermal study (MRID 49705401; Challis, et al., 1989) was conducted utilizing a more thorough washing procedure and analysis up to 120 hours post

- exposure to determine if continuedClofentezine Human

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### absorption occurred after washing. In this s tudy, clofentezine was applied at doses of 0.38, 3.8, and 38 μg/cm 2 

### for 10 hours. The total absorbed dose at 24 hours after exposure was 1.44%, 4.66, and 8.66% with 2.63, 1.79, and 1.67% remaining on the skin site after washing, respectively. At 120 hours, the total absorbed dose was 1.44, 3.81, and 9.69% with less than 0.1% remaining on the skin site in all groups.

In the two available studies, the percentage of chemical absorbed increased with decreasing amount applied indicating saturation of the d ermal absorption process or “dermal loading” in the higher application groups. This is also supported by the increased amount of chemical absorbed over time at the low doses in both studies as well as decreased amounts remaining at the skin site at the ex tended time periods. In the second study at 24 hours, the amount of chemical absorbed in the 38 μg/cm 2 

### group was nearly double (1.44% vs. 0.61 %) the amount at 10 hours in the 36 μg/cm 2 

### group in the first study (low dose). Additionally, the lowest dose te sted in the second study (0.38 μg/cm 2 

### ), which appeared to have minimal to no dermal loading, showed continued absorption from 24 to 120 hours (7.45 to 9.69%, respectively) and a non

- detectable amount of chemical remaining at the skin site. Although the pr evious risk assessment used a DAF of 1% based on the first study (1986), the methodology employed in this study does not conform to current policy. Therefore, based on the available data, the dermal absorption of clofentezine is considered to be 10% (round ed from 9.69% obtained from the 1989 study) for this risk assessment. This value was chosen as it represents a dose which did not appear to have significant dermal loading and takes into account the continued absorption over time demonstrated when evaluati ng the data across both studies.

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects Subchronic and chronic studies indicate the liver is the primary target organ for clofentezine with secondary ef

fects on the thyroid

. Body weight and body weight gai n 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 subseque nt increase in the metabolism and the e xcretion of the thyroid hormone T4 reduced the availability of T4 required for the general metabolism and the maintenance of homeostasis. The decreased levels of plasma T4 resulted in the stimulation of the thyroid b y the pituitary gland to raise the plasma T4 levels. Thyroid changes in the form of colloid depletion, thyroid follicular cell hypertrophy and hyperplasia were observed as a means to regain the homeostasis.

Two pre

- natal developmental toxicity studies we re 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 q ualitative) of increased susceptibility seen following pre

- and/or post

natal exposure in rats for two generations in the reproduction study (NOAEL set at the highest dose tested).

Clofentezine does cause thyroid tumors in male rats after long

- term high exposure resulting in progressive effects on the thyroid that leads to hyperplasia and eventual tumor formation. No mechanism or mode of action has been submitted to the Agency at this time for clofen tezine. As aClofentezine Human

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### 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). Clofentezine is not considered to be a muta gen . 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.

4.4 Safety Factor for Infants and Children (FQPA SF) The risk assessment team has concluded that the FQPA SF should be reduced to 1x because there is an adequate toxicity database for clofentezine and exposure data are complete or are estimated based on data that reasonably account for po tential exposures. There was no evidence of qualitative or quantitative susceptibility in developmental and reproduction studies and there was no evidence of neurotoxicity in the submitted studies. The dietary assessment is based on reliable data and doe s not underestimate exposure.

4.4.1 Completeness of the Toxicology Database The toxicity database is considered complete. With the exception of the guideline studies which have been waived by the HASPOC, all required guideline studies have been submitted including the developmental toxicity studies in rats and rabbits, and the two

- g e ne r ation reproduction study in
rats.

.

4.4.2 Evidence of Neurotoxicity

As discussed in Section 4 .1, neither an acute nor a subchronic neurotoxicity study has been conducted for clofentezine

. However, 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 w aived the requirement for a neurotoxicity battery (TXR 0056333

, 6 /2 7 /2012)

.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal There is no evidence of increased susceptibility of offspring following pre

- or postnatal exposure to clofentezine in rats or rabbits.

4.4.4 Residual Uncertainty in the Exposure Database There are no residual uncertainties with regard to exposure. C onservative, upper

- bound assumptions were used to determine exposure through dietary sources (food and d rinking water )

, such that these exposures have not been underestimated. There are currently no residential uses and no outstanding exposure data requirements for clofentezine.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response As sessment Acute Dietary Endpoint : No acute population adjusted dose (PAD) was selected for the general U.S. population (including females 13

- 49 years of age ) or any population subgroups. NoClofentezine Human

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### appropriate toxicological endpoint attributable to a single exposure was identified in the available toxicology studies including the rat and the rabbit developmental studies.

Chronic Dietary Endpoint : Quantification of chronic dietary risks was performed using a one year feeding study in 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) , and FQPA (1x)

. 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 perfor med 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 a bsorption factor of 1 0 % should be used in estima ting dermal risks (see Section 3 .2.1). A n UF of 100 is appli ed 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 depl etion and thyroid follicular cell hypertrophy (LOAEL = 20 mg/kg/day)

. Since an oral study was selected

, absorption via inhalation is presumed to be equivalent to oral absorption. A n UF of 100 is appli ed which includes interspecies extrapolation (10X) and intraspecies variability (10X)

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For clofentezine

, dermal and inhalation exposures can be combined since the same oral study was used to select endpoints and doses for dermal and i nhalation risk assessment

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Clofentezine can cause thyroid tumors in male rats after long

- term high exposure resulting in progressive effects on the thyroid that leads to hyperplasia and eventual tumor formation. No mechanism or mode of action has been submitted to the Agency for clofentezine at thi s 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 * 

### value for use in clofentezine risk assessment using the 3⁄4 inter species scaling factor is 3.76 x 10

- 2 

### (mg/kg/day)

- 1



### . Clofentezine is not considered to be a mutagen

.

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

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Page 17 of 43 Table 4.5.4.1: Toxicological D oses and Endpoint for Use in Clofentezine Dietary and Non

- Occupational Human Health Risk Assessments
Exposure/Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary (All populations) No appropriate endpoint was identified including developmental toxicity studies in rats and rabbits.

Chronic Dietary (all populations) NOAEL =

1.25 mg/kg/day 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 alkalin e 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 human (inter spec ies), UF H = potential variation in sensitivity among membe rs of the human population (intra species).

Table 4.5.4.2: Toxicological Doses and Endpoint for Use in Clofentezine Occupational Human Health Risk Assessments Exposure/Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal Short

- Term (1

- 30 days) Intermediate

– Term (1

- 6 months) Oral

NOAEL = 2.0 mg/kg/day UF A = 10X

UF H = 10X

Total UF = 100X

Dermal Absorption = 1 0 % Occupational LOC for MOE =

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) Inter mediate

– Term (1

- 6 months) Oral

NOAEL = 2.0 mg/kg/day UF A = 10X

UF H = 10X

Total UF = 100X Occupational LOC for MOE = 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 h uman (inter species), UF H = potential variation in sensitivity among membe rs of the human population (intra species).



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

No new metabolism data was submitted or required to support this petition. The nature of the residue has been adequately delineated in plants . In plant crops, the residue of concern is the parent, c lofentezine (A. Smith, 04/26/1988; RCB Nos. 3190 and 3191). Table 5.1 provides a
summary.

Table 5.1. Sum mary of Clofentezine residues to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Clofentezine Clofentezine Water Clofentezine ClofentezineClofentezine Human

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### 5.2 Food Residue Profile Clofentizine is typically applied to growing crops as a foliar application. Given information in the metabolism studies that suggest that c lofentezine is unlikely to be absorb ed by the roots of plants and does not translocate throughout the p lant, it is likely that clofente zine residues will be primarily the parent compound and will be found as surface residues on fruits and leaves. Clofente zine is not likely to concentrate in processed commodities. Clofentezine is solid at room temperature with a vapor pressure such that losses through volatilization/sublimation are expected to be minimal, it is considered non

- volatile.

5.3 Water Residue Profile The drinking water assessment for clofentezine conducted in 2012 is a ppropriate to support new uses on papaya and avocado, based on communication with EFED (D 423336, R. Louie

- Juzwiak, May 27, 2015) . T he residues of concern for clofentezine in drinking water is the parent compound, clofentezine only

. Tier II Estimated Drink ing Water Concentrations (EDWCs) were generated to support clofentezine use on almonds, apples, Christmas trees, nectarines, containerized plants, peaches, pears, pecans, persimmons and walnuts. The surface water EDWCs are based on the USEPA Pesticide Root Zone Model (PRZM) and Exposure Analysis Modeling System (EXAMS) using the EXPRESS shell, Version 1.03.02. The highest surface water EDWCs values are 7.59 ppb (1

- in

- 10 year acute) and 0.062 ppb (1

- in

- 10 year annual average). These concentration values were produced by the EFED North Carolina apple scenario and corrected for the required 100 buffer. The SCI

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

Table 5.3. Maximum Estimated Surface Water and Groundwater C oncentrations for Clofentezine

Drinking Water Source Model Use rate (lbs a.i/A/season) Acute

(ppb) Chronic

(ppb) Parent only

Surface water FIRST 0.26 7.59 1 0.062 2

Groundwater SCI

- GROW

-- 0.041
Note: Bolded value was used for the chronic dietary assessment.
1 Represents North Carolina apple scenario

2 Represents California grape scenario



### 5.4 Dietary Risk Assessment Clofentezine chronic and cancer dietary exposure and risk assessments were conducted using the DEEM

- FCID, Version 3.16, which incorporates 2003

- 2008 consumption data from USDA’s NHANES/WWEIA.

5.4.1 Description of Residue Data Used in Dietary Assessment Average crop field trial residues were used for all commodities in the dietary assessment. Livestock calculated secondary residues were also included in these assessments.

5.4.2 Percent Crop Treated Used in Dietary AssessmentClofentezine Human

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### The Biological and Economics Analysis Division (BEAD

, 12 /09/14 ) provided updated estimated % CT information for several commodities. The average percent crop treated estimates were used in the chronic and cancer dietary risk assessments for the following crops that are currently registered for clofentezine: almonds: 5%; apples: 2.5%; apricots: 2.5%; cherries: 5%; grapes: 1%; nectarines: 5%; peaches 5%; pears 5%; and walnuts: 5%.

5.4.3 Acute Dietary Risk Assessment An acute dietary exposure assessment was not performed as n o appropriate endpoints were identified from the available clofentezine toxicity studies which indicates that clofente zine does not pose an acute dietary risk.

5.4.4 Chronic Dietary Risk Assessment

A partially refined chronic dietary exposure assessment was performed that directly incorporated average field trial residues , percent crop treated, and modelled drinking water estimated residues

. The estimated exposure to the highest population subgroup (children 1 < 2 years old) resulted in an estimated risk of <1% of the chronic population adjusted dose (cPAD). The estimated exposure to the general U.S. population resulted in an estimated risk of <1% of the chronic population adjusted dose (cPAD).

5.4.5 Cancer Dietary Risk Assessment

A partially refined cancer dietary exposure assessment was performed that d irectly incorporated average field trial residues , percent crop treated

, and modelled drinking water estimated residues as clofentezine has been classified as a possible human carcinogen. Applying the Q 1 

### * of 3.76 x 10

- 2 

### mg/kg/day to the exposure value res ults in a cancer risk estimate of 3.8 x 10

- 7 

### to the general U.S. population.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Clofentezine 1

Population Subgroup cPAD (mg/kg/day) Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

Q* = 3.76 x 10

- 2 General U.S. Population

0.013 0.000 0 10 <1 0.000010 3.8 x 10

- 7 All Infants (< 1 year old) 0.000029 <1

N/A N/A Children 1

- 2 years old 0.000039 <1 Children 3

- 5 years old 0.000024 <1 Children 6

- 12 years old 0.000013 <1 Youth 13

- 19 years old 0.000006 <1 Adults 20

- 49 years old 0.000008 <1 Adults 50

- 99 years old 0.000008 <1 Females 13

- 49 years old 0.000008 <1

1 Population with the greatest exposure is in bold.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization There are no registered or proposed residential uses and/or commercial uses at residential sites of clofentezine at this time. Therefore, a residential exposure assessment is not required.Clofentezine Human

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### 6.1 Non

- Occupational Spray Drift Exposure Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., airblast) employed for clofentezine. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more informat ion). 1 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

- Residential Exposure Assessm ent Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

occupational exposure to drift.

6.2 Non

- Occupational Bystander Post

- Application Inhalation Exposure Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has develope d a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux
st udies, route

- specific inhalation toxicological studies) or further analysis is required for clofentezine.

7.0 Aggregate Exposure/Risk Characterization Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and
any non

- occ upational (residential) uses. There are currently no registered residential uses associated with clofentezine; therefore, the clofentezine aggregate risk assessment includes only dietary exposure (food and water). An acute dietary exposure assessment was not performed as clofente zine does not pose an acute dietary risk. The chronic d ietary exposure estimates from food and drinking water do not exceed HED’s level of concern . The cancer dietary exposure estimates from food and drinking water result in a cancer risk estimate of 3 .8 x 10

- 7



### . Sections 5 .4. 4 and 5 .4. 5 discuss the chronic and cancer dietary (food and water) exposure assessments.

8.0 Cumulative Exposure/Risk Characterization Unlike other pesticides for which EPA has followed a cum ulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmClofentezine Human

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Page 21 of 43 

### 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 EP A’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa. gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Characterization The proposed uses for clofentezine are on possible commercial agricultural crops; therefore, there is potential for occupational handler and post

- application exposure.

9

. 1 Occupational Handler Exposure and Risk HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (i.e., amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application ev ent.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for o ccupational handlers is bas ed on the following scenarios: 1. Mixing/loading liquid concentrates to support airblast applications, 2. Mixing/loading liquid concentrates to support groundboom applications, 3. Applying sprays with airblast equipment, 4. Applying sprays with groundboom equipment, 5. Mixing/loading/applying liquid concentrates to support mechanically and manually

pressurized handgun applications, and 6. Mixing/loading/applying liquid concentrates to support backpack sprayer applications.

It is the policy of HE D to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) databa se, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that ar e used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 2 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 3



### .

2 Available: http://www2.epa.gov/sites/production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf

3 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlClofentezine Human

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### 9. 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 on 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 Ref erence Table” ; 2) the maximum clofentezine label application rates ; and 3) amount handled/area treated values take from ExpoSAC SOP No. 9.1, “Standard Values for Daily Acres Treated in Agriculture ”.

Combined ST and IT occupational handler dermal and inhalation MOEs ranged from 52 to 1,900 with baseline dermal PPE and no respirator, 88 to 11,000 with the addition of gloves, and 110 to 120,000 with double layer dermal protection and gloves

. All occupational handler scenarios resulted in inhalation MOEs far greater than the LOC of 100 with no respirator. Airblast appli cation to avocado and papaya as well as the exiting registered orchard crops have a combined risk estimate s that exceeds HED’s level of concern at baseline dermal plus gloves and no respirator mitigation

. See the following tables 9.1.1 and 9.1.2 for occup ational noncancer handler risk estimates.Clofentezine Human

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Page 23 of 43 Table 9.1.1 Short/Intermediate Term Occupational Handler Dermal and Inhalation Noncancer Exposure and Risk Estimates for Clofentezine wit h 10% Dermal Absorption 1

Exposure Scenario Crop / Target Category Appli catio

n Rate Amount Handled 3 Dermal Dose (mg/kg/day) 4 Dermal MOE 5 Inhalation Dose (mg/kg

day) 6 Inhalati

on MOE 7

Formulation Application

Equipment SL/No G SL/G DL/G SL/N o G SL/G DL/G No

- R No

- R

Mixer/Loader

L/SC/EC Airblast Nursery (ornamentals, ve getables, trees, container )

0.25 A 20 A 0.00138 0.0002 0.0002 1400 8500 11000 0.00001 140000 Orchard/Vineyard 40 A 0.00275 0.0005 0.0004 730 4300 5500 0.00003 73000

Groundboom Nursery (ornamentals, vege tables, trees, container

stock), Greenhouse (ornamentals, ros es, cut flowers, container , vegetables) 60 A 0.00413 0.0007 0.0006 480 2800 3700 0.00004 49000

Orchard/Vineyard 40 A 0.00275 0.0005 0.0004 730 4300 5500 0.00003 73000 Field crop, typical 80 A 0.0055 0.0009 0.0007 360 2100 2700 0.00006 36000 Applicator

Spray (all starting formulation s) Airblast Nursery (ornamentals, ve getables, trees, container )

0.25 A 20 A 0.0111 0.0099 0.0093 180 200 220 0.0003 6800 Orchard/Vineyard 40 A 0.0221 0.0199 0.0185 90 100 110 0.00053 3400

Groundboom Nursery (ornamentals, vegetables, trees, container

stock)

, Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 60 A 0.0015 0.0003 0.0002 1400 6600 8500 0.00006 31000

Orchard/Vineyard 40 A 0.001 0.0002 0.0002 2000 10000 13000 0.00004 47000 Field crop, typical 80 A 0.002 0.0004 0.0003 1000 5000 6300 0.00009 24000 Mixer/Loader/Applicator

L/SC/EC Backpack Greenhouse (ornamentals, ros es, cut flowers, container , vegetables)

0.005 lb ai/gal lon 40 0.0033 0.0028 0.0016 610 710 1300 0.00035 5700 Nursery (ornamentals, vegetables, trees, conta iner ) And Christmas Tree Farms, 0.0146 0.0076 0.0042 140 260 470 0.00017 12000 Manually

pressurized Handwand Greenhouse (ornamentals, roses, cut flowers,

container stock, vegetables), and nurs ery (ornamentals, vegetables, trees, container stock) 40 A 0.025 0.0001 0.0001 80 19000 22000 0.00008 27000

Mechanically

- pressurized Handgun Orchard/Vineyard, Nursery (ornamentals, ve getables,

trees, container ) And Christmas Tree Farms, and Field crop, typical 1000 A 0.0379 0.0129 0.0085 53 160 240 0.00054 3700

Mechanically

- pressurized Handgun Greenhouse (ornamentals, roses, cut flowers,

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

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

. 2. Based on registered or proposed label (EPA Reg. No. 66222

- 47). Formulated clofentezine products are liquid concentrates, soluble concentrates, or emulsifiable concentrates (L/SC/EC) 3. Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure (mg/lb ai) * Application Rate * Area treated or Amount handled * Absorption Factor (10 % ))  Body Weight ( 8 0 kg). 5 Dermal MOE = Derma l NOAEL (2 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/A) × Area T reated or Amount Handled (A or gal/day) ÷ BW (80 kg). 7. Inhalation MOE = Inhal ation NOAEL (2 mg/kg/day) ÷ Inhalation Dose (mg/kg/day)Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 24 of 43 Table 9.1.2 Short/Intermediate Term Combined Occupational Handler Noncancer Exposure and Risk Estimates for Clofentezine with 10 % Dermal Absorption 1 Exposure Scenario Crop / Target Category Applic a tion Rate Amount Handled /

Area Treated 3 Combined Dose (mg/kg

- day) Combined MOE 4

Formulation Application

Equipment SL/No G + No

- R SL/G +

No

- R DL/G +

No

- R SL/No G

+ No

- R SL/G +

No

- R DL/G +

No

- R Mixer/Loader

L/SC/EC Airblast Nursery (ornamentals, vegetables , trees, container)

0.25 A 20 A 0.00139 0.00025 0.000197 1400 8000 10000 Orchard/Vineyard 40 A 0.00278 0.0005 0.000391 720 4100 5100

Groundboom Nursery (ornamentals, vegetables, trees,

container stock) and Greenhouse (ornamentals,

roses, cut flowers, container stock, vegetables) 60 A 0.00417 0.00075 0.000587 480 2600 3400

Orchard/Vineyard 40 A 0.00278 0.0005 0.000391 720 4100 5100 Field crop, typical 80 A 0.00555 0.001 0.000783 360 2000 2500 Applicator

Spray (all starting formulations) Airblast Nursery (ornamentals, vegetables, trees, container stock) 0.25 20 A 0.0114 0.0102 0.00955 180 190 210 Orchard/Vineyard 0.25 40 A 0.0227 0.0205 0.0191 88 97 110

Groundboom Nursery (ornamentals, vegetables, trees,

container stock) and Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.25 60 A 0.00154 0.00037 0.0003 1300 5400 6700

Orchard/Vineyard 0.25 40 A 0.00103 0.00024 0.000201 1900 8200 10000 Field crop, typical 0.25 80 A 0.00205 0.00049 0.0004 960 4100 5000 Mixer/Loader/Applicator

L/SC/EC Backpack Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables)

0.005 lb ai/ gallons 40 gallons 0.00365 0.00315 0.00191 550 630 1100

Backpack Nursery (ornamentals, vegetables, trees,

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

pressurized Handwand Greenhouse (ornamentals, roses, cut flowers,

container stock, vegetables) and Nursery (ornamentals, vegetables, trees, container stock) 40 gallons 0.0251 0.00018 0.000166 80 11000 12000

Mechanically

- pressurized Handgun Orchard/Vineyard and Nursery (ornamentals,

vegetables, trees, container stock) and Field crop, typical 1000 gallons 0.0384 0.0134 0.00904 52 150 230

Mechanically

- pressurized Handgun Greenhouse (ornamentals, roses, cut flowers,

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

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2015 ); Level of mitigation: Baseline , PPE, and Eng . Controls. SL/No G (Single layer dermal protection consisting of long sleeve shirt, long pants, and socks and shoes) no gloves; SL/G (single layer dermal protection) plus the addition of glo ves, No

- R (no r espirator). DL/G (double layer dermal protection with gloves ) 2. Based on registered or proposed label (EPA Reg. No. 66222

- 47). Formulated clofentezine products are liquid concentrates, soluble concentrates, or emulsifiable concentrates (L/SC/EC) 3. Exposure Science Advisory Council Policy #9.1. 4 Combined MOE = 1/ ((1/Dermal MOE) + (1/Inhalation MOE)) 5 . Orchard crops include the registered crop s almonds, apricots, cherries, C hristmas trees, grapes, peaches, pears, persimmons, nectarines, walnuts. Nursery includes c ommercial ornamentals grown in greenhouse, outdoor saran and shade houses, and field grown nursery stock.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 25 of 43 

### 9. 1.2 Cancer Handler Exposure and Risk Cancer risk estimates were calculated using a linear low

- dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q 1 

### * that has been calculated for clofentezine based o n dose response data in the appropriate toxicology study (Q 1 

### * = 3.76 x 10

- 2 

### (mg/kg/day)

- 1 

### ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values. Dermal and inhalation ADD values were first added together to obt ain combined ADD values. LADD values were then calculated and compared to the Q 1 

### * to obtain cancer risk estimates.

The risk estimates were calculated using the maximum rate of 0.25 lb ai/A as a typical rates were not available for the avocado and papay a. Crops subgroups were also presented with the maximum rate of 0.25 lb ai/A. Cancer risk estimates are presented for private and commercial handlers with dermal baseline PPE as well as dermal baseline plus gloves PPE. Inhalation cancer risk estimates a re presented with no respirator. Clofentezine combined dermal and inhalation cancer risk estimates at baseline for private handlers ranged from 6.43E

- 07 to 1.16E

05 and 1.15E

- 07 to 9.48E

- 06 with the addition of chemical resistant gloves for proposed uses. Clofentezine combined dermal and inhalation cancer risk estimates at baseline for private handlers ranged from 1.77E

- 05 to 4.78E

- 07 and 1.07E

- 05 to 8.46E

- 08 with the addition of chemical resistant gloves, 8.08E

- 06 to 7.67E

- 8 with double layer dermal protection and gloves for proposed uses. Clofentezine combined dermal and inhalation cancer handler risk estimates at baseline for commercial handlers ranged from 5.34E

- 05 to 1.43E

- 06 baseline dermal and no respirator and 3.2E

- 05to 2.54 E

- 07 with the addition of chemical resistant gloves, and 2.43E

- 05 to 2.3E

- 07 with double layer dermal protection, gloves, and no respirator. See table 9 .1.2 and 9.1.3 for further d escription of handler occupational cancer risk estimates.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 26 of 43 Table 9.1.2 Occupational Private/Farmer Handler Cancer Exposure and Risk Estimates for Proposed Use of Clofentezine Registered Uses with 10% Dermal Absorption 1

Exposure Scenario

Crop / Target Category Dermal Dose (mg/kg/day) Inhalation

Dose (mg/kg

day) Lifetime Average Private/Farmer Lifetime Average Combined Dose (mg/kg

- day) 2 Private/Farmer

Handler Cancer Risk 3 Dermal Dose (mg/kg/day) Inhalation

Dose (mg/kg

day)

Formulat ion Application

Equipment SL /N

o G S L/ G DL /G No

- R SL

/N

o G SL /G DL /G No

- R SL/N

o G + No

- R SL/ G + No

R DL/ G + No

R SL/N o G + No

- R SL/ G + No

R DL/ G + No

R Mixer/Loader

L/SC/EC Groundboom Nursery (ornamentals, vegetables, trees, container stock) and Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0 04 1 0. 00 07 0.0 00 6 4.11E

- 05 5.0

8E

- 05 8.6 7E

- 06 6.7 1E

- 06 5.05E

- 07 5.13E

- 05 9.17 E

- 06 7.22 E

- 06 1.93E

- 06 3.45 E

- 07 2.71 E

- 07

Orchard/Vineyard 0.0 02 8 0. 00 05 0.0 00 4 2.74E

- 05 3.3

8E

- 05 5.7 8E

- 06 4.4 7E

- 06 3.37E

- 07 3.42E

- 05 6.11 E

- 06 4.81 E

- 06 1.29E

- 06 2.3E

- 07 1.81 E

- 07

Field crop, typical 0.0 05 5 0. 00 09 0.0 00 7 5.48E

- 05 6.7

6E

- 05 1.1 6E

- 05 8.9 5E

- 06 6.74E

- 07 6.82E

- 05 1.22 E

- 05 9.63 E

- 06 2.56E

- 06 4.59 E

- 07 3.62 E

- 07
Applicator

Spray (all starting formulati ons) Groundboom Nursery (ornamentals, vegetables, trees, container stock) and Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0 01 5 0. 00 03 0.0 00 2 6.38E

- 05 1.8

2E

- 05 3. 7 2E

- 06 2.9 E

06 7.84E

- 07 1.89E

- 05 4.51 E

- 06 3.69 E

- 06 7.11E

- 07 1.7E

- 07 1.39 E

- 07

Orchard/Vineyard 0.0 01 0. 00 02 0.0 00 2 4.25E

- 05 1.2

1E

- 05 2.4 7E

- 06 1.9 4E

- 06 5.22E

- 07 1.27E

- 05 0.00 0003 2.47 E

- 06 4.78E

- 07 1.13 E

- 07 9.29 E

- 08

Field crop, typical 0.0 02 0. 00 04 0.0 00 3 0.0001 2.4

1E

- 05 4.9 5E

- 06 3.8 7E

- 06 1.04E

- 06 2.52E

- 05 0.00 0006 4.92 E

- 06 9.48E

- 07 2.26 E

- 07 1.85 E

- 07 Mixer/Loader/Applicator

L/SC/EC Backpack Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0 03 0. 00 28 0.0 01 6 0.0004 4.0

6E

- 05 3.4 4E

- 05 1.9 2E

- 05 4.3E

- 06 4.49E

- 05 3.87 E

- 05 2.35 E

- 05 1.69E

- 06 1.46 E

- 06 8.84 E

- 07

Nursery (ornamentals, vegetables, trees, container stock) and Christmas Tree farm 0.0 14 6 0. 00 76 0.0 04 2 0.0002 0.0

00 18 0.0 00 1 0.0 00 05 0.000002 0.000

182 0.00 0096 0.00 0054 6.84E

- 06 3.61 E

- 06 2.03 E

- 06 Manually

pressurized Handwand Greenhouse (ornamentals, roses, cut flowers,

container stock, vegetables) and Nursery (ornamentals, vegetables, trees, container stock) 0.0 25 0. 00 01 9.1 3E

- 05 0.0001 0.0

00 3 1.3 3E

- 06 1.1 2E

- 06 9.22E

- 07 0.000

309 2.25 E

- 06 2.04 E

- 06 1.16E

- 05 8.46 E

- 08 7.67 E

- 08

Mechanicall
y

pressurized Handgun Orchard/Vineyard and Nursery (ornamentals,

vegetables, trees, container stock) and Christmas Tree Farm and Field crop, typical 0.0 37 9 0. 01 3 0.0 08 5 0.00054 0.0

00 5 0.0 00 16 0.0 00 10 4 0.000007 0.000

472 0.00 0165 0.00 0111 1.77E

- 05 6.20 E

- 06 4.17 E

- 06Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 27 of 43 Table 9.1.2 Occupational Private/Farmer Handler Cancer Exposure and Risk Estimates for Proposed Use of Clofentezine Registered Uses with 10% Dermal Absorption 1

Exposure Scenario

Crop / Target Category Dermal Dose (mg/kg/day) Inhalation

Dose (mg/kg

day) Lifetime Average Private/Farmer Lifetime Average Combined Dose (mg/kg

- day) 2 Private/Farmer

Handler Cancer Risk 3 Dermal Dose (mg/kg/day) Inhalation

Dose (mg/kg

day)

Formulat ion Application

Equipment SL /N

o G S L/ G DL /G No

- R SL

/N

o G SL /G DL /G No

- R SL/N

o G + No

- R SL/ G + No

R DL/ G + No

R SL/N o G + No

- R SL/ G + No

R DL/ G + No

R

Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0 21 9 0. 01 6 0.0 1 0.0075 0.0

00 3 0.0 00 2 0.0 00 12 3 9.22E

- 05 0.000

361 0.00 0284 0.00 0215 1.36E

- 05 1.07 E

- 05 8.08 E

- 06

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

grower. 2 Total LADD = Total Absorbed Dose [Dermal Dose + Inhalation Dose] * Days per year of exposure X years per lifetime of exposure / (365 days/year x Lifetime expectancy. 3 Cancer risk estimates = LADD * Q 1 * , where Q 1 * = 3.76 X 10 - 2 (mg/kg/day)

- 1

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

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

long pants, and socks and shoes) no gloves; SL/G (single layer dermal protection) plus the addition of gloves, DL/G (Double layer dermal protection plus the addition of gloves), No

- R (no respirator),Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 28 of 43 Table 9.1.3 Short/Intermediate Term Occupational Commercial Handler Cancer Exposure and Risk Estimates Clofentezine with 10 % Dermal Absorption 1

Exposure Scenario

Crop / Target Category Dermal Dose (mg/kg/day) Inhalatio n Dose (mg/kg

day Lifetime Average

Dermal Dose (mg/kg/day) Lifetim

e Averag

e Inhalati

on Dose (mg/kg

day) Contract/Commercial

Handler Lifetime Average Combined Dose (mg/kg

- day) 2 Contract/ Commercia l Handler Cancer Risk (mg/kg

day) 2

Formula tion Application

Equipment SL/No G SL/G DL/

G No

- R SL/N

o G SL/G DL/

G No

- R SL/No

G + No

- R SL/

G + No

R DL/ G + No

R SL/N o G + No

- R SL/ G + No

R DL/ G + No

R Mixer/Loader

L/SC/E C Groundboo

m Nursery (ornamentals, vegetables, trees,

container stock) and Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0041 0.0007 0.00 055 4.11E

- 05 0.000

15 0.000 03 2.01 E

05 1.52E

06 0.0001

5 2.75 E

05 2.16 E

- 05 5.79E

- 06 1.03 E

06 8.12 E

- 07

Orchard/Vineyard 0.0028 0.0005 0.00 036 2.74E

- 05 0.000

10 1.73 E

- 05 1.34 E

05 1.01E

06 0.0001

0 1.83 E

05 1.44 E

- 05 3.87E

- 06 6.88 E

07 5.41 E

- 07

Field crop, typical 0.0055 0.001 0.00 073 5.48E

- 05 0.000

20 3.47 E

- 05 2.68 E

05 2.02E

06 0.0002

1 3.67 E

05 2.89 E

- 05 7.71E

- 06 1.38 E

06 1.09 E

- 06 Applicator

Spray (all starting formulat ions) Groundboo

m Nursery (ornamentals, vegetables, trees,

container stock) AND Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0015 0.0003 0.00 024 6.38E

- 05 5.46

E

- 05 1.12 E

- 05 8.7 E

06 2.35E

06 5.68E

05 1.35 E

05 1.11 E

- 05 2.14E

- 06 5.08 E

07 4.17 E

- 07

Orchard/Vineyard 0.001 0.0002 0.00 016 4.25E

- 05 3.63

E

- 05 7.41 E

- 06 5.83 E

06 1.57E

06 0.0000

4 0.00 001 7.41 E

- 06 1.43E

- 06 3.38 E

07 2.79 E

- 07

Field crop, typical 0.002 0.0004 0.00 032 0.00009 7.23

E

- 05 1.49 E

- 05 1.16 E

05 3.13E

06 7.56E

05 0.00 002 1.48 E

- 05 2.84E

- 06 6.77 E

07 5.56 E

- 07 Mixer/Loader/Applicator

L/SC/E C Backpack Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0033 0.0028 0.00 156 0.00035 0.000

12 0.000 10 5.75 E

05 1.29E

05 0.0001

4 0.00 012 7.04 E

- 05 5.08E

- 06 4.36 E

06 2.65 E

- 06

Nursery (ornamentals, vegetables, trees, container stock) and Christmas Tree farm 0.0146 0.0077 0.00 423 0.0002 0.000

54 0.000 28 0.00 016 0.00001 0.0005

5 0.00 029 0.00 016 2.05 E

- 05 1.08 E

05 6.09 E

- 06Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 29 of 43 Table 9.1.3 Short/Intermediate Term Occupational Commercial Handler Cancer Exposure and Risk Estimates Clofentezine with 10 % Dermal Absorption 1

Exposure Scenario

Crop / Target Category Dermal Dose (mg/kg/day) Inhalatio n Dose (mg/kg

day Lifetime Average

Dermal Dose (mg/kg/day) Lifetim

e Averag

e Inhalati

on Dose (mg/kg

day) Contract/Commercial

Handler Lifetime Average Combined Dose (mg/kg

- day) 2 Contract/ Commercia l Handler Cancer Risk (mg/kg

day) 2

Formula tion Application

Equipment SL/No G SL/G DL/

G No

- R SL/N

o G SL/G DL/

G No

- R SL/No

G + No

- R SL/

G + No

R DL/ G + No

R SL/N o G + No

- R SL/ G + No

R DL/ G + No

R Manually

pressurized Handwand Greenhouse (ornamentals, roses, cut

flowers, container stock, vegetables) and Nursery (ornamentals, vegetables, trees, container stock) 0.025 0.0001 9.13 E

05 0.00008 0.000

92 3.98 E

- 06 3.37 E

06 2.77E

06 0.0009

3 6.75 E

06 6.12 E

- 06 3.48 E

- 05 2.54 E

07 2.3E

- 07

Mechanicall
y

pressurized Handgun Orchard/Vineyard and Nursery

(ornamentals, vegetables, trees, container stock) and Christmas Tree farm, Field crop, typical 0.0081 0.0024 0.00 181 0.00024 0.000

3 0.000 09 6.68 E

05 0.000 01 0.0003

1 9.88 E

05 7.56 E

- 05 1.16 E

- 05 3.71 E

06 2.84 E

- 06

Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables) 0.0379 0.0129 0.00 85 0.0005 0.001

4 0.000 48 0.00 031 0.00002 0.0014

2 0.00 049 0.00 033 5.34 E

- 05 1.86 E

05 1.25 E

- 05

1 Commercial growers are assessed assuming 30 days of exposure per year. 2 Total LADD = Total Absorbed Dose [Dermal Dose + Inhalation Dose] * Days per year of exposure X years per lifetime of exposure / (36 5 days/year x Lifetime expectancy. 3 Cancer risk estim ates = LADD * Q 1 * , where Q 1 * = 3.76 X 10 - 2 (mg/kg/day)

- 1

. 4 Crops are assessed at the maximum rate of 0.25 lb ai/A or 0.005 lbs ai/gallon. Typical rates not provided. 5 Based on the “Occupational Pesticide H and ler Unit Exposure Surrogate Reference Table” ( September, 2015 ).Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 30 of 43 

### 9

. 2 Occupational Post

- Application Exposure and Risk HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide ( also referred to as 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 le vels 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, rela tive to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2 .1 Occupational Post

- application Inhalation Exposure/Risk Estimates There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues r elated to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological s tudies) or further analysis is required for clofentezine.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

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

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is e xpected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

9.2.2. Occupational Post

- application Dermal Exposure/Risk Estimates

A quantitative dermal post

- application e xposure assessment was conducted and noncancer and cancer risk estimates were calculated. HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. For clofentezine, based on the proposed use, ST a nd IT exposure are anticipated.

Occupational Post

- application Non

- Cancer Dermal Risk EstimatesClofentezine Human

- Health Risk Assessment DP No. 423333

Page 31 of 43 

### Short

- and intermediate

- term non

- cancer d ermal post application exposure and risks were estimated using 1) standard default values for dermal transfer coeffici ents from the Science Advisory Council for Exposure Policy Number 3.2: Agricultural Transfer Coefficients, June 3, 201 1; 2) the maximum clofentezine label application rates ; 3) a dislodgeable foliar residue (DFR) study on apples (MRID 43898901) grown in Washington State (DFR = 0.515 ug/cm2 on day of application) that was used as a surrogate for all registered crops; and 4) t he assumption that an average occupational workday is 8 hours long.

The non

- cancer post

- application exposure estimates do not exceed HED’s level of concern (MOEs ≥ 100) at day 0 after treatment (DAT) using the highest post

- application transfer coefficients for the proposed cro ps , avocado and papaya

. However there are existing grape activities included in the crop group 13

- 07F th at do exceed HED’s level of concern at day 0 after treatment. These post

- application activities include, tying training, hand harvest, hand

- leaf pulling and girdling/ turning. See table 9 .2.2 .1 for a summary of occupational post

- application risk estimates f

or clofentezine.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 32 of 43 Table 9.2.2.1 Short

- Term Occupational Post

- application Dermal Non

- Cancer Exposure and Risk Estimates for Proposed Clofentezine Uses Using the Highest Transfer Coefficients and Existing

Crop/Site Policy Crop

Group Category Activities Transfer Coefficient (cm 2 /hr.) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

0 DAT 4 7 DAT 30 DAT 0 DAT 7 DAT 30 DAT Avocado 99 Hand

- Harvesting 1,400

0.5 ug/cm 2 0.007 0.006 0.003 290 340 590 Papaya Floriculture NA 4,800 0.0239 0.02 0.011 84 99 170 Cherry (12

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

- 12B) Pome Fruits (11

- 10)
Grape, Wine And Grape, Juice (13

- 07F) Tying/Training, Hand

Harvesting, Hand

- Leaf Pulling 10,100 0.051 0.043 0.025 40 47 82

Grape, Table And Grape Raisin Girdling/ Turning 19,300 0.097 0.082 0.047 21 25 4 3 Tying/Training, Hand

Harvesting, Hand

- Leaf Pulling 5,500 0.028 0.023 0.013 73 86 150 6

1. DFR = MRID (43898901) Brady, S.; Kelly, I. (1991) Dissipation of Clofentezine Foliar Dislodgeable Residues Following Application of Apollo SC to Apples Grown in Washington State, 1989: Lab Project Number: R152.03.89: 1322

- 89

- 101

- 05

- 02B

- 01: 38292,38293. Unpublished study prepared by Northwest Agricultural Research, Inc.; Landis International, Inc.; and Analytical Bio

- Chemistry Labs, Inc. 65 p MRID (43898901) Brady, S.; Kelly, I. (1991) Dissipation of Clofentezine Foliar Dislodgeable Residues Following Application of Apollo SC to Ap ples Grown in Washington State, 1989. 2 D aily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 10 %)]  BW (80 kg). 3 MOE = POD (2.0 mg/kg/day) / Daily Dermal Dose. 4. Day after treatment (DAT) 5 .Bolded number are risk estimates that exceed concern 6 DAT14 table and raisin grapes has a post

- application MOE of 100.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 33 of 43 

### Occupational Post

- application Cancer Dermal Risk Estimates Cancer d ermal post application exposure and risks were estimated using 1) standard default values for dermal transfer coefficients from the Science Advisory Council for Exposure Policy Number 3.2: Agricultural Transfer Coefficients, June 3, 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 = 0.51 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 30 days a year at day 0 residues; 6 ) a standard value for years per lifetime of exposure ( 35 years over a lifetime); and 7 ) a standard value for lifetime expectancy of 78 years ta ken from the Exposure Factors Handbook 2011 Edition Table 18

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

The cancer post

- application risk estimates with the highest transfer coefficients for the proposed crops and crop groups calculated ranged from 9.71E

- 06 to 1.0E

- 04 at d ay 0 after treatment (DAT) and 6.92E

- 06 to 1.0E

- 04 using the average 30 day dose. The existing grape post

application activity of girdling/turning is the highest cancer number. See table 9 .2.2. 2 for cancer post

- application risk estimates.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 34 of 43 Table 9.2.2.2. Occupational Post

- Application Cancer Exposure and Risk Estimates for Proposed Clofentezine Uses Using the Highest Transfer Coefficients.

Crop/Site Policy Crop

Group Category Activities Transfer Coefficient (cm 2 /hr.) DFR 1 Dermal LADD (mg/kg/day) 1 Cancer Risk Estimate 2

0 DAT 4 30 Day

Average 0 DAT 30 Day Average Avocado 99 Hand

- Harvesting 1,400

0.5
μ g/cm 2 2.58E

- 04 1.84E

- 04 9.71E

- 06 6.92E

- 06 Papaya Floriculture NA 4,800 0.000883 0.000629777 3.32E

- 05 2.37E

- 05

Stone Fruit (12

- 12) Thinning Fruit 3,600 6.64E

- 04 4.73E

- 04 2.50E

- 05 1.78E

- 05 Pome Fruits (11

- 10) Grape, Wine And Grape, Juice (13

- 07F) Tying/Training, Hand

Harvesting, Hand

- Leaf Pulling 10,100 0.0019 0.0013 7E

- 05 5E

- 05

Grape, Table And Grape Raisin Girdling/ Turning 19,300 0.0036 0.0025 1E

- 04 1E

- 04
Tying/Training, Hand

Harvesting, Hand

- Leaf Pulling 5,500 0.0010 0.0007 4E

- 05 3E

- 05

1 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)]. 2 Daily Dose (mg/kg/day)= DFR (μg/cm2) x 0.001 mg/ug x Tc (cm2/hr) x DA ( 10 %) x ET (8 hr/day)/ 8 0 kg
3 Cancer risk estimate = Dermal LADD ( 0 DAT or 30 day average doses mg/kg/day) × Q 1 * , where Q 1 * = 3.76 X 10

- 2 (mg/kg/day)

- 1

.Clofentezine Human

- Health Risk Assessment DP No. 423333

Page 35 of 43 

### Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of clofentezine. Clofentezine is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is a weak skin sensitizer. Short

- and intermediate

- term post

application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities for the proposed crop groups avocado and papaya. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protec tion Statement interim REI of 12 hours is adequate to protect agricultural workers from post

application exposures to clofentezine from application to avocado and papaya, however there were risk estimates of concern for crop group 13

- 07F and floriculture c rops , therefore HED is recommending the REI be revised on the label to address those concernsClofentezine Human

- Health Risk Assessment DP No. 423333

Page 36 of 43 

### 10.0 References

BEAD memo:

 Doucoure, 2011

. Clofentezine Usage Data to Support HED’s Lifetime Average Daily Dose Calculations

Drinking Water Memo:

 Loui e

- Juzwiak, R. 2015. Clofentezine

- Drinking Water Assessment for Proposed New Use on Avocado, Papaya, and Crop Group Expansions for Pome fruit (11

- 10), Cherry Subgroup (12

- 12A), Peach Subgroup (12

- 12B), and Small Fruit, Vine Climbing (except Fuzzy Kiwi) (S ubgroup 13

- 07F). D423336.

Dietary Memo:



#  Barnes

, Y. Clofentezine. Chronic and Cancer Dietary (Food and Drinking Water) Exposure Assessments in Support of Establishment of Permanent Tolerances and Section 3 Registration for New Use on Avocado and Papaya and Crop Group/Subgroup Expansions for Pome Fruit, Group 11

- 10; Cherry Subgroup 12

- 12A; Peach Subgroup 12

- 12B and Fruit, small, vine climbing, except fuzzy kiwi, Subgroup 13

- 07F. DP number: D429749, 11/10/2015.

HASPOC Memos:

 Rury, K. (2012). Clofentezine: Summary of Hazard and Science Policy Council (HASPOC) Meetings: Recommendations on the need for the inhalation, and acute and subchronic neurotoxicity studies. June 27, 2012, TXR No. 0056333

.

 Habiba, U. (2013). Clofentezine: Summary of Hazard and Science Policy Council (HASPOC) Meetings: Recommendations on the need for an immunotoxicity study. June 07, 2013. TXR# 0056690.

ORE Memo:

 Bobowiec

, B., Occupational and Residential Exposure Assessment for the Proposed Uses on Avocado, Papaya, and expansion of crop subgroups; Cherry (12

- 12A), Peach (12

- 12B), Pome Fruits (11

- 10), and Small Fruit Vines (13

- 07F). DP number : D429731

, 10/16 / 2015.

Previous Risk Assessment:

 Smith, C. (2013). Clofentezine. Preliminary Human Health Risk Assessment for Registration Review. PC Code: 125501; DP Number: D401611, June 06, 2013.

Registration Review Scoping Document:

 Reaves, E. and C. Smith. (2007). Clofentezine: Registration Review Scoping Document for Human Health Assessments; PC Code: 125501; DP Numb er: D336110 . January 31, 2007.

Residue Chemistry:

 Barnes, Y . Clofentezine: Petition for the Establishment of Permanent Tolerances and Registration for New Use on Avocado and Papaya and Crop Group/Subgroup Expansions for Pome Fruit, Group 11

- 10; Cherry Subgroup 12

- 12A; Peach Subgroup 12

- 12B andClofentezine Human

- Health Risk Assessment DP # 423333

Page 37 of 43 

### Fruit, small, vine climbing, except fuzzy kiwifruit, Subgroup 13

- 07F, Summary of Analytical Chemistry and Residue Data. DP number: D 429732, 11/10/2015

Attachments

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Review of Human Research Appendix C. Physical/Chemical Properties Appendix D. Summary of Occupational Algorithms

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for clofentezine are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

TABLE A.1: Toxicology Data Requirements for Clofentezine

Test Technical
Required Conducted
870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (non

- rodent) 870.3200 21/28

- Day Dermal 870.3250 90

- Day Dermal 870.3465 90

- Day Inhalation yes yes yes

no CR 1 yes

yes

no

no waived
870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent) 870.3800 Reproduction yes yes yes yes

yes yes
870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation (bacterial) 870.5300 Mutagenicity

— Gene Mutation (mammalian) 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5395 Mutagenicity

— Other Genotoxic Effects 870.5500 Mutagenicity

— Other Genotoxic Effects yes yes yes yes yes yes

yes yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity no

no yes 2
yes 2

no no

no waived

w a ived

noClofentezine Human

- Health Risk Assessment DP # 423333

Page 38 of 43 TABLE A.1: Toxicology Data Requirements for Clofentezine

Test Technical
Required Conducted

870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no yes 3 yes

yes waived

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

2 In June 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 ( TXR# 0056690 , 06/07/2013).



### A.2 Toxicity Profiles

Table A . 2 . 1: Acute Toxicity of Clofente z ine

Guideline No. Study Type MRIDs # Results Toxicity Category

870.1100 Acute Oral

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

870.1200 Acute Der m al

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

870.1300 Acute Inhalation

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

870.2400 Pri m ary Eye Irritation

- Rabbits 00105907* m ild irritant IV

870.2500 Pri m ary Skin Irritation

- Rabbits 00159073 not a skin irritant IV
870.2600 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 Toxicity Profile for Clofentezine

Guideline No/ Study type MRID No. (year)/ Classification /Doses Results

870.3100

Subchronic

- Feeding

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

870.3100

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).

870.3100

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 enlargement

.Clofentezine Human

- Health Risk Assessment DP # 423333

Page 39 of 43 870.3150

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.

870.3200 21

- Day Dermal Toxicit y

- Rat N one N o study available

870.3465

90

- Day Inhalation Toxicity None No study available

870.3700a
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 enlargement 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

870.3700b
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.

870.3800
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

870.4100a

Chronic toxicit y /Carcinogenici
t 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] 870.4100b

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 # 423333

Page 40 of 43 870.4200b

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

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

- mutagenic

Dominant Lethal Rat 00130764 (1983)

0, 4, 40, or 400pm Non

- mutagenic

870.7485

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.

870.7600 Dermal penetration 49705401 (1989)

Acceptable/non

- guideline 1.0, 0.1, and 0.01 mg/rat (equivalent to 38 .5, 3.85, and 0.385 μg/cm 2 skin ) Dermal absorption was estimated as 1.4%, 4.7%, and 10.0% 24 hours after a 10

- hour application in rats treated with 1.0, 0.1, and 0.01 mg/rat, respectively. Similar results were obtained 120 hours after a 10

- hour treatment; being 1.5%, 3.9%, and 10.6% in rats treated with 1.0, 0.1, and 0.01 mg/rat, res pectively.



### Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers E xposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database, the Agricultural Handler Exposure Task Force (AHETF), and theClofentezine Human

- Health Risk Assessment DP # 423333

Page 41 of 43 

### Agricultural Reentry Task Force (ARTF) have been determined to require a review of their ethical conduct, h ave received that review, and have been determined to be ethically conducted.

Appendix C. Physical/Chemical Properties

Appendix Table C.1: Clofentezine Physical and Chemical Properties

Parameter Value Molecular Weight 303.1 g/mol Water solubility (20°C) 2.9 x 10

- 2 mg/L Vapor pressure (25°C) 9.75 x 10

- 10 mmHg Henry’s Law Constant (25°C) 3.9 x 10

- 10 , atm

- m 3 mole

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



### App endix D. Summary of Occupational Exposure Algorithms

D.1 Occupational Non

- Cancer Algorithms

Daily Exposure: Daily handler exposures are estimated for each applicable handler task with the application rate, the amount of acres treated or gallons applied in a day, and the applicable unit exposure using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) * Application Rate (lbs ai/A) * Daily Amount Handled (A/day) * Conversion Factor (mg/1,000 μg)

Where:

Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation abso rption, Unit Exposure = Unit exposure value (μg ai/day), Application Rate = Normalized application rate based on a logical unit treatment (lb ai/A), and Daily Amount Handled = Normalized application area based on a logical unit treatment such as acres (A/day).



### Daily Dose: Daily dose (inhalation) was calculated by normalizing the daily inhalation exposure value by body weight.

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

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg body weight/day), Daily Exposure = Amount (mg ai/day) amount inhaled that is available for inhalation absorption, and Body Weight = Body weight de termined to represent the population of interest in a risk assessment.



### Margin of Exposure (MOE): The daily inhalation dose received by occupational handlers was compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers fo r each exposure route. All MOE values were calculated for inhalation exposure using the following formula:

MOE = NOAEL (mg/kg/day)/Average Daily Dose (mg/kg/day)Clofentezine Human

- Health Risk Assessment DP # 423333

Page 42 of 43 Where:

MOE = Margin of exposure value used by HED to represent risk or how close a che mical exposure is to being a concern (unitless), ADD = Average daily dose (ADD) is absorbed dose received from exposure to pesticide, and NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred in the study.



### D.2 Occupational Cancer Algorithms

After the development of the ADD values, the next step required to calculate carcinogenic risk estimates is to amortize these values over the anticipated lifetime, which results in the LADD. LADD values are calculated using the followin g equation:

LADD = ADD * Days per Year of Exposure

365 Days per Year * Years per Lifetime of Exposure Lifetime Expectancy

where:

LADD = absorbed dose over a lifetime (mg ai/kg/day), ADD = average daily dose absorbed in a given scenario (mg ai/kg/day ), Days per Year of Exposure = annual frequency of an application by an individual (days/year), Years per Lifetime of Exposure = amount of a lifetime that an individual would be expected to use pesticides (years), and Lifetime Expectancy = average l ife expectancy of an individual (years).

Cancer risk estimate calculations are completed by comparing the LADD values calculated above to the Q 1 

### * for the chemical. Cancer risk estimates are calculated using the following equation:

Total Cancer Risk Esti mate = ( Dermal LADD + Inhalation LADD ) * Q 1 

### *

where:



### Cancer Risk Estimate = probability of incidence of cancer cases over a lifetime (unitless), Dermal LADD = absorbed dose from dermal exposure over a lifetime (mg ai/kg/day), Inhalation LADD = absorbed dose from inhalation exposure over a lifetime (mg ai/kg/day), and Q 1 

### * = quantitative dose response factor used for linear, low

- dose response cancer risk estimate calculations (mg/kg/day )

- 1Clofentezine Human

- Health Risk Assessment DP # 423333

Page 43 of 43 

### Appendix E. International Residue Limits Table

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 

### Codex 40 CFR 180.446: Clofentezine

Plant: Clofentezine

Livestock: Clofentezine and 3

- (2

- chloro

- 4

- hydroxyphenyl)

- 6

- (2

- chlorophenyl)

- 1,2,4,5

- tetrazine metabolite Plant: Clofentezine

Livestock and dairy: 3,6

- bis(2

- chlorophenyl)

- 1,2,4,5

- tetrazine, including the metabolite 3

- (2

- chloro

- 4

- hydroxyphenyl)

- 6

- (2

- chlorophenyl)

- 1,2,4,5

- tetrazine P lant commodities: clofentezine Animal commodities: sum of clofentezine, and all metabolites containing the 2

- chlorobenzoyl moiety, expressed as clofentezine The residue is fat soluble.


### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex
Avocado 0.3 Papaya 0.3 Fruit pome group 11

- 10 0.5 0.5 apple, pear 0.5 Cherry, subgroup 12

- 12A 1.0 0.5 stone fruits Peach, subgroup 12

- 12B 1.0 1 nectarine, peach

Fruit, small, vine climbing, except fuzzy kiwifruit, Subgroup 13

- 07F 1.0 2.0 grapes, dried grapes = (currants, raisins and sultanas) Completed by: M. Negussie, 05/11/2015

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.