### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: October 1

, 2015 OFFICE OF
CHEMICAL SAFETY AND

POLLUTION PREVENTION



### SUBJECT: Ethephon: Human Health Risk Assessment for Registration Review of Ethephon.

P C Code: 09980 I DP Barcode: 423165

Deci s ion No.: 495942 Regi s tration No.: NA

P etit ion No.: NA Regulator y Action: Reg Review

Ri sk Assessment Type: Human H ea lt h Ri sk Assessment Case No. : 0382

TXR No.: NA CAS No.: 16672-87-0

MRID No.: NA // 

# l /J

,_**/~ R:**  § 180.300



### FROM: Thurston G

. Morton, Chemist

# tf:({~ 

# /.1lf.f.!**() '~**  Kelly O ' Rourke

, Biologist 

# I 

# "'"'J /) 

# /?71

- /

_ A bdallah Khasawinah

, PhD.

, Toxicologist / /**~** 

### Health Effects Division (7509P)



### THROUGH: Elissa R eaves, PhD

, Branch Chief

Risk Assessment Branch IV

Health Effects Division (7509P)



### TO: Marquea King

# ~~

Risk Management and Impl e mentation Branch 5

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

P age 1of59

### 1.0 E xecutive S umm ary

... . .. ...... .. . ... . ... .. ........................................................ .. ........ . .. .. .. .. ........ 4

2.0 H E D Recommendation s

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

2.1 Data Deficienci es

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

2.2 Tolerance Co n s iderations

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

2.2.1 E nforcement An a lytic a l Method

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

2

. 2.2 International Harmoniz a tion

...... .. .. ................. .. .. .. . .. ... . ....................... .. .. . .. .. . .. .......... 8

2.2.3 R e commended To lerance s

............................... .. .................................. . .. .. . .. .. . ........... 8

2.3 Label Recomm e nd a tion s

..................................... .. . ... .................................. .. . .. .. . .. .. ....... 9

2

. 3

. 1 R e commendation s from Re s idu e R ev i ews

................................................................ 9

2 .3.2 Recommendation s from Oc c upation a l Assessment

................................................. 9

2.3.3 Recommend a tion s from Re s idential A ss essment

.. ........................ . ... . .. .. . ..... .......... I 

### 0

3.0 Int ro duction

........................................................ . .. ... . ... . .. .. .. .. .. . ......... ......... ....... .. . ... . .. . .. .. . I 

### 0

3.1 C hemical Identity

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

### IO

3.2 Ph ys ical /C hemical C haracteri s tic s

...................... . ................................... . .. . ............... l 0

3.3 Pesticide Use Patt e rn

... .. . .. .. .. .. .. .................................................................................... l 0

3.4 Anticipated E xpo s ure Pathwa ys

.................... .. .. .. .. . ......... ................... ........... . .. . ......... I 0

3

. 5 Consideration of Environmental Ju s tic e

............................................ ................ ........ l l

4.0 Hazard C hara c t e riz a tion and Do se- Re s pon s e Assessme nt

.......................................... I 

### 1

4.1 Toxicology Stu di es Available for Anal ys i s

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

### 11

4.2 Absorption

, Di st ribution

, Metabolism, & 

### E xcretion (ADME)

................................. 1 2



### 4.2.1 D e rmal Absorption

. .. .. . ... . ... . ......... .. .......... ........... ............. . ......... ... . .. ................... .. . .. 1 2



### 4.3 Toxicolo g ical Effects

. ....... . .. .. .. ... .. .. .. ......................................... .. . ...... . ...... . .. ................ 1 2



### 4.4 S afety Factor for Infants and C hildr e n ( FQPA Safety Factor)

................. . .. . ... . .. .. . . 14



### 4.4.1 Co mpletene ss of the Toxicolo gy Dat a ba se

........ . ................... ................... ............... 14



### 4.4.2 Ev id e nce of N eurotoxicity

...... ........... .. .. ....................... ............... .......................... ... 14



### 4.4.3 Ev id e nc e of Se n s itivity /S u sce ptibili ty in the Developin g or Young Animal..

...... 14



### 4.4.4 Re s idual U ncertain ty in the E xpo s ur e D a taba se

................................................... l 5

4.5 Toxicity E ndpoint a nd Point of D e parture Se l ec tion s

.............................................. 15



### 4.5.1 Do s e-Re s pon se Assessment

............................. . ........................................................ 1 5



### 4.5.2 Recommendation for Combining Routes of E xposure s for Ri s k Assessment

.. . .. 1 6



### 4.5.3 Cancer C la ss ification and Ri sk Assessment Recomm e ndation

...... .. . .. . .. .. .. . .. .. . .. .. 1 6



### 4

. 5.4 Summary of Point s of Departur e and Toxicity Endpoints Used in Human Ri s k

Asse ss ment

................................................................... .. .. .. ...................................................... 1 7



### 4.6 Endocrine Di s ruption

.. . . ... .. .. .................................... . ............................ . ..... .. . ... . .. ........ 17



### 5.0 Dietary Ex p os ure and Ri s k A ss e ss ment

................. . ................................... .. .. .... ............ 18



### 5.1 Metabo lit e/ D eg radat e R es idue Profile

.............................................. ..... .................... 18



### 5.1.1 Summary of Plant and Animal Metabolism S tudie s

.......................... .. . ... . .. .. . .. .. ... 18



### 5.1.2 Summary of Environmental De gr adation

............................. .. . ........... . .. ... ............. 1 9



### 5.1.3 Comparison of Metabolic Pathw ays

........... . ........ . .. .. ...... . ... . .. . .. .. . .................... .... ... 1 9



### 5.1.4 R es idu es of Co ncern Summary and Rationale

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

### 1 9

5.2 Food Re s idue Profile

.......................... .. ... . .. .. .. ... . ... . ... . ... . ... . .. .. .. . ... ................ ................ 20

5.3 Water Re s idue Profile

... . .. . ................................. .. .. .. .. .. .. .. ........................... .. . .. .. . .. .. ..... 20

5.4 Di etary Ri s k Assess ment

.. .. ......................................................................... . .. . .. .. ......... 22



### 5

. 4.1 De scr ipti o n o f R es idue D ata Use d in Dietary Assess ment

...................... . ............. 22

5.4.2 Percent C r o p Treated Us ed in Di etary Assess ment

.............................................. 22

5.4.3 Acute Dietary Ri s k Assessment

..................... .. ... . ............................ .. .. .. .. .. . .. .. .. ....... 22

Pa ge 

### 2 of 59

### Page 3 of 59

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 23

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 23

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 24

6.1 Residential Handler Exposure

................................ ................................ .................... 24

6.2 Post

- Application Exposure

................................ ................................ .......................... 25

6.3 Residential Risk Estimates for Use in Aggregate Assessme nt

................................ .. 27

6.4 Residential Bystander Post

- application Inhalation Exposure

................................ . 27

6.5 Spray Drift

................................ ................................ ................................ .................... 28

7.0 Aggregat e Exposure/Risk Characterization

................................ ................................ .. 29

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 29

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 29

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 30

7.4 Chronic Aggregate Risk

................................ ................................ .............................. 30

7.5 Cancer Aggregate Risk

................................ ................................ ................................ 30

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 30

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 31

9.1 Short

- and Intermediate

- term Handler Risk

................................ ............................. 31

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 35

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

.................. 35

9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

....................... 35

10.0 References

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

................................ .................. 37

A.1 Toxicology Data Requirements

................................ ................................ ................... 37

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 38

A.3 Ha zard Identification and Endpoint Selection

................................ .......................... 44 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 46 Appendix C. Ethephon Use Pattern

................................ ................................ ......................... 47 Appendix D.

................................ ................................ ................................ ................................ . 58

### Page 4 of 59

1.0 Executive Summary

Atta ched is Health Ef

fects Division’s (HED) human health risk assessment status update for ethephon as part of the Registration Review process. The most recent risk assessment for ethephon was conducted in May, 2006 in support of the Tolerance Reassessment Eligibility

Decisio n (TRED) which was issued in June, 2006. A Reregistration Eligibility Decision document (RED) was issued in April, 1995.

Ethephon

, an organophosphonate

, is a plant growth regulator. It regulates phases of plant growth and development by application at various growth stages

. Ethephon is registered on a number of terrestrial food, feed, and nonfood crops, greenhouse nonfood crops, and outdoor plants. Ethephon is used to promote fruit ripening, abscission, flower induction, and breaking of apical

domina nce (inhibition of the growth of lateral buds by the terminal bud of a shoot). Ethephon reacts to form ethylene gas which is an important component of the plant hormone complex. The production of ethylene by the plant occurs naturally as crops mature; et hylene triggers production of an enzyme that breaks down cellulose. Ethylene production by the plant can be slow during periods of unfavorable weather. Ethephon is used as a source of ethylene gas which is absorbed by the plant tissues and moderates the g rowth process. Ethephon formulations

include emulsifiable concentrates and soluble concentrates. Application is by broadcast to plant foliage by either ground or aerial equipment. Ethephon may also be applied by hand sprayer to select home garden veget ables ( i.e. , tomatoes).

Hazard Characterization

Ethephon is an organophosphorus/ phosphonate compound ; i t is not an organo phosphate . It does not have a leaving group as in the organo phosphates which is required for the insecticidal mode

of action. H umans appear to be more susceptible to the clinical toxicity of ethephon than experimental animals. Ethephon i nhibit s red blood cell and plasma cholinesterase (ChE) activities in experimental animals and may not be accompanied by clinical signs of toxicit y until a high threshold level of exposure is reached. Brain ChE activity is not inhibited in vivo

. In human subjects, p lasma and RBC cholinesterase activities were slightly elevated in treated subjects but fell within the normal range. Because humans ap pear to be more susceptible to ethephon ’s clinical toxicity than animals, a toxicity endpoint for risk assessment was selected from a human study.

The toxicology database for ethephon is complete for risk assessment. There is no quantitative or qualitative evidence of increased susceptibility following in utero or postnatal exposure in any of the developmental or reproductive studies. Developmental and post natal toxicity occurred at doses causing maternal/parental tox icity. Ethephon did not produce acute delayed neurotoxicity in hens after being dosed with nearly lethal doses

. It produced clinical toxicity in rats following acute or subchronic neurotoxicity testing, but no n eurobehavioral or neuropathological effects

were seen . Ethephon was mutagenic in bacteria but not in cultured mammalian cells. It was negative for cytogenic effects both in vitro and in vivo and did not cause unscheduled DNA synthesis. There was, however, evidence of mitotic gene conversion in y east. Ethephon is rapidly absorbed from the gut and eliminated in the urine with minimum metabolic

transformation.

### Page 5 of 59

Ethephon was not carcinogenic in rats or mice at doses that were considered adequate. It was initially classified in 1994 as Group D for carcinogenicity based on insufficiency of the weight of

the evidence ( TXR # 0011195 )

. However, based on the lack of carcinogenicity in rats and mice

and mostly negative mutagenic effects, the HIARC in 2002, reclassified ethephon as a "Not Likely to be Car cinogenic to Humans ” ( TXR # 0051308 ). Ethephon exhibits low acute toxicity via the oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. Ethephon is dermally corrosive and is a skin and eye irritant (Toxicity Category I). It is not a dermal sensitizer.

Endpoints and Uncertainty Factors for Risk Assessment

The point of departure for all exposure scenarios is derived from a 28

- day human study with a LOAEL of 1.8 mg/kg/day and an uncertainty factor of 30 (10x for intraspecies variation, interspecies variation reduced to 1x for use of a human study and 3x for extrapolating from LOAEL to a NOAEL) (TXR 0051308 )

. The clinical signs of toxicity in this human study occurred at 1.8 mg/kg/day (signs and symptoms are summarized in Table 4.5.4 ) . This endpoint is conservative and is protective of any effects exhibited in experimental animals. This 28

- day human study was reviewed by the Human Studies Review Board in 2006 and found acceptable

.

Dietary ( Food and W

ater) Exposure and Risk

The established ethephon tolerance levels are adequate except for several where levels need revised to account for 2 significant figures

. The tolerance expression for ethephon has been

reviewed and should be should be updated based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

The tolerance expression for ethephon is harmonized with both Canada and Codex. There is harmonization with the Canadian ethephon Maximum Residue Level ( MRL ) levels f or cantaloupe, grape, and pineapple. There is harmonization with the Codex ethephon MRL levels for apple, blueberry, cherry, and pineapple. Harmonization with the remaining commodity MRLs is not possible due to differences in the Good Agricultural Practi ces ( GAP ) or field trial

residue levels used for MRL calculation.

Adequate field trial data for ethephon, following maximum application rates, have been submitted for all registered use sites. PDP data were available and used for grape and apple

commo dities. Processing factors from processing studies were used with the PDP monitoring

data. Maximum percent crop treated (CT) was used in the acute dietary exposure analysis while the average percent CT was used in the chronic dietary exposure analysis. Use of PDP data, field trial data and calculated livestock anticipated residues (ARs) results in a dietary risk (food and water) estimate of 39 % of the acute population adjusted dose (aPAD) for the U.S. Population

and 170 % for children 1

- 2 years, the most highly exposed population subgroup. Estimated chronic dietary (food and water) exposure is below HED’s level of concern for the general population and all subpopulations. Use of anticipated residues and %CT data results in a

### Page 6 of 59

maximum risk estimate of 3.5 % of the cPAD for the U.S. Population and 2 4 % of the cPAD for

children 1

- 2 years, the most highly exposed subpopulation.

Aggregate risks from ethephon are of concern for Children 1

- 2 years old. For adults, the short

term residential handler inhalation MO E estimated for Backpack Sprayer to Gardens /Trees, when aggregated with dietary exposure, is 99 0, which does not exceed HED’s level of concern (LOC = 30 ) . For children, the aggregated MOE (incidental oral + dietary) MOE was 24 which

exceed s HED’s level o f concern (LOC = 30).

Spray Drift

T he turf post

- application assessment is considered protective of spray drift exposure based on the maximum application rate on crops and the existing turf application rates; therefore, a separate quantitative spray drift assessment was not conducted.

Occupational Exposure and Risk

In the absence of systemic dermal toxicity, dermal handler and post

- application exposure assessments were not conducted, and there is no risk associated with dermal exposure to

workers. The re are no occupational handler inhalation risk estimates of concern for the registered uses of ethephon at baseline (i.e., no respirator). Occupational inhalation margins of exposure (MOEs) ranged from 150 to 42,000 (LOC = 30) at baseline attire. The REI is based on the acute toxicity of ethephon and a 48 hour REI is adequate for the registered uses.

Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for ethephon at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational

post

- application inhalation exposure assessment for ethephon

.

Residential Exposure

There are no residential handler inhalation risk estimates of concern for the registered uses of ethephon; the MOEs range from 2,600 to 120,000 (LOC = 30). Regarding post

- application exposure, the lowest incidental oral risk estimate for children (1 to < 2 year old) playing on treated turf (i.e., parks) is an MOE of 30, which does not exceed HED’s level of concern (LOC = 30)

.

Human Studies Review

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exp osed to a pesticide or other chemical. These data, which include the human

tox icity study (MRID 00036510 ) and studies from PHED 1.1; and the AHETF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have

### Page 7 of 59

included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1



### .

2.0 HED Recommendations

No additional residue chemistry data are required for registration review. No label changes are required based on residue ch emistry. Current tolerances need to be updated as previously

discussed

.

HED calculated an aggregate risk estimate of concern (MOE of 24 ; LOC of 3 0) for short

- term
risk for children 1

- 2 years old from incidental oral and food and water.

2.1 Data Deficiencies

ORE: In accordance with 40 CFR 158, turf transferable residue ( TT R) data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. The existing uses for ethephon could result in residential post

- application exposure; however, ch emical

- specific TTR data are not

available. Since the highest estimated residential post

- application exposure using default TT R

values for ethephon is not minimal in comparison to the LOC (i.e., the calculated MOE is not greater than ten times higher than the LOC, MOE = 30 compared to the LOC of 30 ); EPA is requiring the 40 CFR TT R data to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of turf transferab le pesticide residues.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods for purposes of enforcement of ethephon tolerances in plant commodities,

ruminant tissues and milk are available. The Amchem

- Plant Method (PAM, VOL. II, Method I)

is the recommended method for plant commodities and processed products other than wheat and barley straw. The Amchem

- Cereal Method (forwarded to FDA for inclusion in the PAM, VOL. II, Method II) is the recommended method for wheat and barley straw. The Union Ca rbide

Animal Method (forwarded to FDA for inclusion in the PAM, VOL. II, Method III) is the

recommended method for milk and animal tissues. The currently recommended plant and animal analytical enforcement methods use diazomethane as a methylating agent. In the 1991 Registration Update, HED required the registrant to revise the currently accepted enforcement methods to replace diazomethane with a safer methylating agent or provide documentation supporting the need for diazomethane if a suitable alternativ e is impractical. Rather than address Agency concerns about the use of diazomethane, Rhone

- Poulenc submitted new plant and animal methods for enforcement purposes which principally involve the decomposition of ethephon to ethylene to determine the residue s of ethephon in various commodities. The Agency reviewed the new proposed plant and animal enforcement methods and concluded they must also

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Page 8 of 59

undergo a successful independent laboratory validation (ILV) (PR Notice 88

- 5, 7/15/88) followed by a successful me thod validation by the Agency. The ILV has been reviewed and found adequate by HED (T. Morton, 5/2/02, D280666). The method will be forwarded to the Agency laboratory for method validation. The registrant successfully radio

- validated the animal

residue a nalytical method using samples from the new poultry metabolism study (T. Morton, D227485, 2/21/02).

2.2.2 International Harmonization

The tolerance expression for ethephon is harmonized with both Canada and Codex. There is

harmonization with the Canad ian ethephon MRL levels for cantaloupe, grape, and pineapple. There is harmonization with the Codex ethephon MRL levels for apple, blueberry, cherry, and pineapple. Harmonization with the remaining commodity MRLs is not possible due to

differences in the GAP or field trial residue levels used for MRL calculation.

2.2.3 Recommended Tolerances

The 0.1 ppm tolerance for cucumbers was previously recommended for revocation (T. Morton, D280985, 6/20/01) but still remains in the CFR. This tolerance should be revoked.

The tolerance expression for ethephon has been reviewed and should be updated as follows based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

Tolerances are established for residues of ethephon

, including its metabolites and degradates, in

or on the commodities in the table below. Tolerance values in bold represent suggested changes. Compliance with the tolerance levels specified below is to be determined by measuring only ethephon (P)

- (2

- chloroethyl) pho sphonic acid.

Table 2.2.3 . Tolerance Summary for Ethephon Commodity Tolerance (ppm) Comments; Correct Commodity Definition Apple 5.0 Apple, juice 10.0 Barley, bran 5.0 Barley, grain 2.0 Barley, straw 10.0 Blackberry 30.0 Blueberry 20.0 Cantaloupe 2.0
Cattle, fat 0.02 Cattle, kidney 1.0
Cattle, meat 0.02 Cattle, meat byproducts, except kidney 0.20 2 significant figures Cherry 10.0
Coffee, bean, green 0.50 Coffee, green bean ; 2 significant figures Cotton, gin byproducts 180.0
Cotton, undelinted seed 6.0

Cucumber 0.1 Revoke
Egg 0.002

### Page 9 of 59

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No label changes are recommended at this time based on the evaluation of residue chemistry

data

.

2.3.2 Recommendations from Occupational Assessment

Labels vary with respect to requirements for work attire and personal protective equipmen t (PPE). For example, some labels do not specify any requirements for work attire, while others require respirators, chemical

- resistant gloves and coveralls over long

- sleeve shirt and long pants. Thus, label corrections/revisions should be consistently m ade to default to end

- use product Goat, fat 0.02 Goat, kidney 1.0
Goat, meat 0.02 Goat, meat byproducts, except kidney 0.20 2 significant figures Grape 2.0 Grape, raisin 12.0

Hazelnut 0.80 Filbert Hog, fat 0.02 Hog, kidney 1.0 Hog, meat 0.02 Hog, meat byproducts, except kidney 0.20 2 significant figures
Horse, fat 0.02 Horse, kidney 1.0
Horse, meat 0.02 Horse, meat byproducts, except kidney 0.20 2 significant figures

Milk 0.01
Nut, macadamia 0.50 2 significant figures
Pepper 30.0 Pineapple 2.0 Poultry, fat 0.02 Poultry, liver 0.05 Poultry, meat 0.01 Poultry, meat byproducts, except liver 0.01 Sheep, fat 0.02 Sheep, kidney 1.0 Sheep, meat 0.02 Sheep, meat byproducts, except kidney 0.20 Sugarcane, molasses 1.5

Tomato 2.0

Walnut 0.5 0
Wheat, bran 5.0 Wheat, germ 5.0 Wheat, grain 2.0 Wheat, middlings 5.0
Wheat, shorts 5.0
Wheat, straw 10.0 Sugarcane 3 0.10

### Page 10 of 59

and/or technical grade active ingredient acute (ocular, dermal, oral, and inhalation) toxicity requirements; note that the technical grade of ethephon is corrosive to the skin (Toxicity Category I).

2.3.3 Recommendations f rom Residential Assessment

No label changes are needed for the residential assessment.

3.0 In troduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula C 2 H 6 ClO 3 P

Common Name Ethephon

IUPAC name 2

- chloroethylphosphonic acid

CAS name (P)

- (2

- chloroethyl)phosphonic acid

CAS Registry Number 16672

- 87

- 0

End

- use product/EP Ethephon 2, Florel, Ethrel, Quali

- Pro

Chemical Class Plant Growth Regulator



### 3.2 Physical/Chemical Characteristics

Pure ethephon is a white waxy solid with a melting point of 74

- 75 0 

### C. Ethephon is very soluble in water, alcohol, acetone, and propylene glycol, only slightly soluble in aromatic solvents such as benzene and toluene, and insoluble in kerosene and diesel o il. The vapor pressure of ethephon is

<1 X 10

- 7 

### mm Hg at 25 0 

### C. The octanol/water partition coefficient (p) is <0.603 ±0.0006 at 25 0 

### C. The dissociation constant for ethephon is: K 1 

### = 3.16 X 10

- 3 

### and K 2 

### = 6.31 X 10

- 8 

### at 25 0 

### C.

3.3 Pesticide Use Pattern

The ethephon use pattern can be found in A ppendix C.

3.4 Anticipated Exposure Pathways

The Pesticide Re

- Evaluation Division has requested a registration review assessment of human

health risk for the registered use s of ethephon . Humans may be exposed to ethephon in food and drinking water, since ethephon may be applied directly to growing crops and application may

result in ethephon reaching surface and ground water sources of drinking water. There are

residential uses of ethephon , so there is likely to be exposure in residential or non

- occupational settings during handling and post

- application activities . In an occupational setting, applicators

### Page 11 of 59

may be exposed while handling the pesticide prior to application, as well as during application.

There is a potential for post

- application exposure for workers re

- entering treated fields.

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://www.epa.gov/compliance/environmentaljustice/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 under the National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietar y exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas

post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterizati on and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

T he toxicology database for ethephon is complete for evaluating and characterizing its toxicity and selecting endpoints for purposes of this risk assessment

. According to the revised 40 CFR Part 158 Toxicology Data Requirement s
, a subchronic inhalation toxicity study would be required. However, based on the total weight of evidence, the HED/HASPOC determined that

these data were not needed (TXR 0056295)

. A developmental neuro toxicity study was not conducted based on the unlikelihood that ethephon crosses the blood/brain barrier of offspring ( See 4.4.3 for detail, TXR 0054221)

.

The following data are available:

 Acute

- Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation rabbit, and skin sensitization guinea pig.

 Subchronic

- mouse (30 day).

 Chronic

- Oral rat, mouse and dog;

 Reproductive/developmental

- Oral developmental rabbit and rat, 2

- generation reproductive rat

### Page 12 of 59

 Other

- Oral rat and mouse cancer studies, 21

- day dermal rabbit toxicity study, acute and

subchronic neurotoxicity, acute delayed neurotoxicity, metabolism, mutagenicity screens

, immunotoxicity, 28

- day clinical oral human studies

.

4.2 Absorption, Distribution, Metabolism, & E xcretion (ADME)

No sex or dose

- related differences were seen in pharmacokinetic parameters i n an absorption, distribution, metabolism and excretion (ADME) study, where 14 

### C

- ethephon: 2

- chloro ( 14 

### C)ethyl phosphonic acid was administered to 6 groups of male and fem ale Crl:CD(SD)BR rats (5/sex/dose) in four dosing schemes: 1) a single intravenous ( iv ) dose at 50 mg/kg, or 2) single

oral doses at 50 or 3) 1000 mg/kg or 4) multiple daily oral doses (unlabeled ethephon) for 14 days at 50 mg/kg/day followed by single ora l dose (50 mg/kg/day) of the 14 

### C

- ethephon

.

Low and high oral doses, and intravenous doses (dosing schemes 1

- 3) were rapidly absorbed and excreted in the urine accounting for 48

- 71% of the administered dose (AD). The oral C
max 

### was reached in 1.3 and 1.0 h ours for the 50 mg/kg dose, 1.9 and 2.5 hours for the 1000 mg/kg dose in males and females, respectively. The half

- life of blood clearance was 7 hours (alpha

- phase) in both sexes at the low dose and 4 and 9 hours in females and males at the high dose, res pectively.

The iv dosing indicated that biliary excretion is minimal since less than 2% of the AD was

recovered in the feces. Exhaled 14 

### CO 2 

### was <1%, 14 

### C

- ethylene was 10 to 20% of the AD and less

than 7% of the AD was excreted in the feces. Residual radi oactivity in tissues was less than 0.1% of the AD. The highest tissue levels were found in the blood, liver, bone, kidney, and spleen with no differences between multiple and single dose administration. Total recovered radioactivity was 84

- 90%. Multiple dosing did not significantly alter the excretion pattern. Ethephon was not extensively metabolized. Ethephon as disodium salt accounted for 90% of the recovered radioactivity in the urine and feces with minor components of monosodium salt and

other unid entified metabolites as less than 5%. The potential decomposition products, chloroacetic acid and chloroethanol were not reported or looked for.

4.2.1 Dermal Absorption

D ermal absorption data were not required for e thephon . It is a severe skin irritant

.

4.3 Toxicological Effects

Ethephon ( 2

- chloroethyl phosphonic acid ) is a plant growth regulator used to promote fruit ripening, abscission, flower induction, breaking of apical dominance (inhibition of the growth of

lateral bu ds by the terminal bud of a shoot), by production of ethylene gas which is an important component of the plant hormone complex. Ethephon is an organophosphorus/ phosphonate compound. It is not an organo phosphate . It does not have a leaving group as in th e

organo phosphates which is required for the insecticidal mode of action.

Evidence in Laboratory Animals and In vivo and In vitro effects

Ethephon i nhibit s red blood cell and plasma cholinesterase (ChE) activities in experimental

animals and may not be accompanied by clinical signs of toxicity until a high threshold level of

### Page 13 of 59

exposure is reached. Brain ChE activity is not inhibited in vivo

. At high doses (>250 mg/kg/day) it produces clinical signs of toxicity (ataxia, prostration, reduced activity, hy pothermia, salivation, tremors and mortality).

Anemia has been reported in dogs administered doses of 52 mg/kg/day. Reduced body weight gain is noticeable in experimental animals exposed to ethephon during their gestation period or during chronic expos ure. There is no quantitative or qualitative evidence of increased susceptibility following in utero or postnatal exposure in any of the developmental or reproductive studies. Developmental and post natal toxicity occurred at doses causing maternal/parent al toxicity. Ethephon did not produce acute delayed neurotoxicity in hens after being dosed with nearly lethal doses. It produced clinical toxicity in rats following acute or subchronic neurotoxicity testing, but no neurobehavioral or neuropathological e ffects were seen.

Ethephon was mutagenic in bacteria but not in cultured mammalian cells. It was negative for cytogenic effects both in vitro and in vivo and did not cause unscheduled DNA synthesis. There was, however, evidence of mitotic gene convers ion in yeast.

Ethephon was not carcinogenic in rats or mice at doses that were considered adequate. It was initially classified in 1994 as Group D for carcinogenicity based on insufficiency of the weight of the evidence (TXR # 0011195). However, based on the lack of carcinogenicity in rats and mice and negative mutagenic effects, the HIARC in 2002, reclassified ethephon as a "Not likely to be Carcinogenic to Humans” (TXR # 0051308). In an immunotoxicity study in female mice, ethephon did not elicit sys temic toxicity or immunotoxicity at the highest dose of 7000 ppm (1373 mg/kg/day, above the limit dose) tested.

Ethephon exhibits low acute toxicity via the oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III ) routes of exposure. Ethephon is dermally corrosive. It is a skin and eye irritant (Toxicity Category I). It is not a dermal sensitizer.

Human Evidence

Humans appear to be more susceptible to the clinical toxicity of ethephon than experimental

animal s. In a human clinical study that was reviewed by the Human Studies Review Board in 2006 and found acceptable, five men and five women were given oral doses of 124 mg of ethephon (approximately 1.8 mg/kg/day) by capsule daily for 28 consecutive days. Thr ee men and three women served as placebo controls. Treated subjects complained of diarrhea and increased urgency and frequency of urination. One treated man experienced loose stools for 2 weeks and another one complained of stomach cramps or gas for the duration of the study. One control also reported increased urination. In human subjects, p lasma and RBC cholinesterase

activities were slightly elevated in treated subjects but fell within the normal range. Because humans appear to be more susceptible to ethephon toxicity than animals, HIARC relied on the human studies in selecting the toxic endpoint for risk assessments.

### Page 14 of 59

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

The FQPA safety factor for increased susceptibility to infants and children is reduced to 1x for ethephon based on the following cons iderations. T he toxicology database for e thephon contains acceptable guideline developmental and reproduction studies as well as acute and subchronic neurotoxicity studies. T here is no quantitative or qualitative evidence of increased susceptibility following in utero or postnatal exposure in any of the developmental or reproductive studies. The RfDs and toxicity endpoints established are p rotective of pre/postnatal toxicity following acute and chronic exposures.

There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessment includes anticipated residues calculated from field trial data condu cted at maximum application rates

, USDA Pesticide Data Program (PDP) monitoring data, processing factors, and available %CT information from BEAD (100%CT is assumed where BEAD data are not available). Dietary drinking water exposure is based on conservati ve modeling estimates of estimated drinking water concentrations from maximum application rates . These assessments will not underestimate the potential exposure to infants and children resulting from the use of

e thephon.

4.4.1 Completeness o f the Toxicolo gy Database

The toxicological database for ethephon is complete for the purpose of this risk assessment. Based on a WOE approach considering all the available ethephon hazard and exposure information, the HASPOC concluded that a 28

- day day inhalation to xicity study is not need ed at this time (TXR 0056295 ).

4.4.2 Evidence of N eurotoxicity

Ethephon did not produce acute delayed neurotoxicity in hens after being dosed with nearly lethal doses. It produced clinical toxicity ( mortality and cholinergic signs (abnormal respiratory sounds and breathing) in rats following acute or subchronic neurotoxicity testing, but no neurobehavioral or neuropathological effects were seen. No indication of abnormalities in the development of the fetal nervous system was observed in the prenatal developmental toxicity studies in either rats or rabbits, at maternally toxic oral doses up to 5 00 or 100 mg/kg/day, respectively. No neurotoxic effects were observed in the clinical observation data, brai n weights, or histopathology of the nervous system in the chronic toxicity studies with ethephon in rats, mice or dogs

.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There is no evidence of susceptibility following in utero and/or postnatal exposure in the developmental toxicity studies in rats or rabbits, and in the 2

- generation rat reproduction study. A developmental neurotoxicity study was not conducted based on the unlikelihood that ethephon

cross es the blood/brain barrier of offspring (TXR 0054221). Ethephon is highly water soluble and no brain ChE activity was inhibited in adult mice, rats or dogs at the highest doses tested. Additionally, Watanabe et al . (1990

, Placental and B lood

- B rain B arrier T ransfer F ollowing

### Page 15 of 59

P renatal and P ostnatal E xposures to N euro

- active D rugs: Relationship with P artition C oefficients

and B ehavioral T eratogenesis. Toxicol. Appl. Pharmacol. 105:66

– 77 ), using C 14



### - radiolabeled drugs demonstrated that blood brain barrier transfer of dru gs depends on their lipophilicity. Highly lipo p hilic drugs (as measured by their partition coefficients) such as propranolol, chlorpromazine, haloperidol and atropine passed easily across the B lood

- B rain B arrier ( BBB ) in adult rats (dams), their fetuses a nd their pups with a BBB transfer ratio (brain/plasma concentration ratio) ranging from 1

- 11. There was a tendency for atropine to pass at higher rate in the fetuses and the pups than in the dams. On the other hand low lipophilic drugs such as reserpine, dopamine, epinephrine, and norepinephrine passed poorly across the BBB (BBB transfer ratio less than 1) with no differences between the dams and their fetuses and their pups. Ethephon is highly water soluble with low lipophilicity (lower than the drugs de scribed in the

Watanabe et al article). Thus, the ethephon properties described above make it less likely that younger children are more susceptible to any potential inhibitory activity of the brain ChE. (TXR NO. 0054221 ).

4.4.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the exposure database.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

The point of departure for all exposure scenarios is derived from a 28

- day human study with a LOAEL of 1.8 mg/kg/day and an uncertainty factor of 30 (10x for intraspecies variation, interspecies variation reduced to 1x for use of a human study and 3x for e xtrapolating from LOAEL to a NOAEL) (TXR 0051308 )

. The 3X UF for extrapolating from a LOAEL to a

NOAEL in the selected study (MRID 0051308 ) is adequate based on:

 The duration of the effects elicited by ethephon in the 28

- day oral toxicity study in

humans is consistent with a C
max 

### reaction i.e ., compound concentration in the body quickly reaches a peak and declines very rapidly (~90% is eliminated within 24 hrs) so that every exposure appears as a single exposure).

 Mild clinical effects were observed in the 28

- day human study.

 In a 29

- day human study (MRID 00066931) at about one

- third of the dose administered

in the 28

- day human study (0.5 mg/kg/day)

, no clinical signs were reported.

The use of th e endpoint from the 28

- day human study is considered appropriate since the toxicokinetic properties of this compound indicate a C
max 

### reaction in which repeated exposures do not lead to cumulative toxicity or progression of the effects.

In a 2005 HED document by Ray Kent (TXR 0053509 ) a w eight of e vidence c omparison of

h uman and a nimal t oxicology s tudies and e ndpoints for e thephon is presented. After four different reviews by the HED HIARC (8/9/94, 4/1/98, 7/15/02 an d 11/5/02) a 28

- day human study was selected to assess all relevant exposure scenarios

.

### Page 16 of 59

The clinical signs of toxicity in th e 28

- day human study occurred at 1.8 mg/kg/day. This endpoint is conservative and is protective of any effects exhibited in experimental animals. The

28

- day human study was reviewed by the Human Studies Review Board in 20 06 and found acceptable

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential residential exposures to a pesticide, the aggregate risk assessment must consider exposures from three major sources: oral, dermal, and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated because of the common toxicity endpoint (clinical signs : diarrhea and increased ur gency and frequency of

urination

, loose stools

, stomach cra mps ) via these routes.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Ethephon was not carcinogenic in rats or mice at doses that were considered adequate. It was classified as Group D for carcinogenicity based on insufficiency of the w eight of the evidence

. An Ad Hoc Committee meeting on May 5, 1994 considered that the evidence from both rat studies and one of the mouse studies to be inadequate to support a positive carcinogenicity finding, while the evidence from one mouse study was e quivocal ( TXR # 0011195 )

. However, based on the lack of carcinogenicity in rats and mice and negative mutagenic effects, the HIARC in 2002, reclassified ethephon as a "Not likely to be Carcinogenic to Humans” (TXR # 0051308).

### Page 17 of 59

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

Assessment

Table 4.5.4 Summary of Toxicological Dose and Endpoints for Ethephon for Use in Human Risk Assessment

Exposure Scenario Dose used in Risk

Assessment

UF FQPA SF and

Endpoint for Risk

Assessment Study and Toxicological Endpoint

Acute Dietary

All population s LOAEL = 1.8 mg/kg/day

UF=30 FQPA SF = 1

a PAD = 1

. 8

30 = 0.06 mg/kg/day 28

- Day Human Clinical Study, MRID 00036510 LOAEL = 1.8 mg/kg/day based on diarrhea and increased urgency and frequency of urination, loose stools, stomach cramps or gas

Chronic Dietary

All population s LOAEL = 1.8 mg/kg/day

UF = 30 FQPA SF = 1

c PAD = 1

. 8

30 = 0.06 mg/kg/day 28

- Day Human Clinical Study, MRID 00036510

LOAEL = 1.8 mg/kg/day based on diarrhea and increased urgency and frequency of urination, loose stools, stomach cramps or gas

Short/intermediate

- Term

Incidental Oral (1day

- 1 month) LOAEL= 1.8 mg/kg/day LOC for MOE= 30 28

- Day Human Clinical Study, MRID 00036510 LOAEL = 1.8 mg/kg/day based on diarrhea and increased urgency and frequency of urination, loose stools, stomach cramps or gas

Short

- Term Dermal (1 day

- 1 month) Not Applicable

- No exposure effects expected due to dermal corrosivity of ethephon

. At dermal doses

above 150 mg/kg/day, ethephon is corrosive to the skin. In a range finding study, dermally applied ethephon was lethal above 500 mg/kg/day and was a severe irritant at 500 mg/kg/day. In the main 21

- d ay rabbit dermal toxicity study ethephon produced no systemic toxicity at 150 mg/kg/day or less, but

cause d local dermal toxicity at doses of 25 mg/kg/day and above. Since ethephon is dermally corrosive, exposures at levels high enough to cause systemic toxicity are not expected. Therefore, risk assessment of dermal exposures to ethephon would not be applicable.

Short/intermed/long

Term

Inhalation (1

- 30 days, 1

- 6 mos, > 6 mos) LOAEL= 1.8

mg/kg/day LOC for MOE= 30

Short

- Term for

Residential and Occupational 28

- Day Human Clinical Study, MRID 00036510 LOAEL = 1.8 mg/kg/day based on diarrhea and increased urgency and frequency of urination, loose stools, stomach cramps or gas

Cancer Classification Not likely to be Carcinogenic to Humans (TXR # 0051308)

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of exposure. LOC = level of concern.



### 4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, development al, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its regi stration review decision for ethephon , EPA reviewed these

data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), ethephon is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

### Page 18 of 59

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlif e similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A , or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides scheduled for registration re view and chemicals found in water. Neither of these lists should be construed as a list of known or likely endocrine disruptors. For further information on the status

of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines

and the Tier 1 screening battery, please visit our website. 2

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

2 http://www.epa.gov/en do/



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants is adequately understood based on tomato, cantaloupe, apple, fig, pineapple, tobacco, grape, walnut, filbert, cherry, tangerine, and lemon metabolism data. Ethephon degrades to ethylene, phosphate, and chlor ide. Data indicate that translocation of ethephon to fruits may occur following application to leaves. The residue of concern in plants is ethephon per se (T. Morton, D282695, 5/28/02). The qualitative nature of the residue in livestock is adequately un derstood based on goat and hen metabolism data. In ruminant tissues and milk, ethephon is incorporated into natural products (glutathione conjugates, protein, glycogen, triglycerides) and expired as 14 

### CO 2 

### and 14 

### C

- ethylene. No residues of ethephon were de tected in the goat metabolism study; however, residues of ethephon were detected in ruminant tissues and milk in a ruminant feeding study which was conducted at exaggerated rates. The metabolic pathway for ethephon in poultry as proposed by the registrant proceeds via initial cleavage of chlorine and formation of 2

- hydroxy ethyl phosphonic acid (HEPA) followed by formation of intermediates that are incorporated into the amino acid and fatty acid biosynthetic pathways. The residue of concern in plants and livestock is ethephon per

se (T. Morton, D282695, 5/28/02).

### Page 19 of 59

5.1.2 Summary of Environmental Degradation

Ethephon (2

- chloroethylphosphonic acid; CAS RN 16672

- 87

- 0) is nonvolatile, hydrophilic, and slightly

- to

- moderately mobile in soil, showing high variabi lity in adsorption values across five tested soils. The compound is an anion (pKa l 

### = 2.5) in acidic environments and a double anion in alkaline environments (pKa 2 

### = 7.2). Ethephon dissipates in the environment through both biotic and abiotic degradation an d by leaching in soils that are low in organic carbon. The compound is not expected to persist in aerobic soil (half

- life of 9.1 days) or neutral to alkaline water bodies (half

- lives of 52.4 days). Ethephon’s persistence in acidic water bodies is uncertain . Ethephon hydrolyzes with a half

- life of 74 days at pH 5; however, data are not available with which to directly estimate biodegradation rates in acidic water bodies. Susceptibility to biodegradation in acidic, aerobic soil indicates that ethephon will de grade in acidic, aerobic water bodies; however, ethephon biodegradation in acidic to alkaline anaerobic water was indiscernible when corrected for hydrolysis. Terrestrial field dissipation data indicate that the chemical dissipates by degradation

and leach ing, with dissipation half

- lives ranging from 7 to 25 days. The low end of this range is consistent with the results of the aerobic soil metabolism study, while the high end of this range is higher than expected with respect to the laboratory study results

. Major degradates of ethephon identified in environmental fate studies include ethylene, phosphoric acid, and 2

- hydroxyethylphosphonic acid (HEPA), the latter of which is less mobile than the parent compound. Minor identified degradates include methylate d phosphoric acid and carbon dioxide. Phosphoric acid, ethylene, and hydrochloric acid are expected to form in equal molar amounts during degradation; however, phosphate and chlorine were not quantified in degradation studies.

5.1.3 Comparison of Metaboli c Pathways

I n rats , parent ethephon is the major component with some formation of natural products such as

CO 2 

### and ethylene . The metabolic pathway in plants and livestock is similar with the production of natural products.

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4 Summary of Metabolites and Degradates to be included in th e Risk

Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Ethephon Ethephon

Rotational Crop Ethephon Ethephon

Livestock Ruminant Ethephon Ethephon

Poultry Ethephon Ethephon

Drinking Water Ethephon Not Applicable

### Page 20 of 59

5 .2 Food Residue Profile

All data for magnitude of the residue in plants have been evaluated and deemed adequate. Sufficient data are available to ascertain the adequacy of the established tolerances.

The Agency has concluded that currently registered use of ethephon on cucumbe rs, squash, and pumpkins for hybrid seed production is a non

- food use. T he 0.1 ppm cucumber tolerance was previously recommended for revocation but still remains in the CFR. This tolerance should be

revoked.

Adequate processing studies have been conducted on apples, barley, coffee, cottonseed, grapes, pineapple, tomato, and wheat to determine the extent to which residues of ethephon concentrate in food/feed items upon processing of the raw agricultural commodity. Data indicate that ethephon resid ues concentrate in apple juice, barley hulls, grape juice, raisins, blackstrap molasses, wheat bran, and wheat shorts and germ. Available processing data indicate that residues of ethephon do not concentrate in wet apple pomace, refined sugar of sugarcane , coffee roasted bean, freeze

- dried coffee, cottonseed meal, cottonseed oil, tomato juice, tomato puree, wheat flour, pineapple juice, or tomato paste. Therefore, separate tolerances for these processed foods are not required.

The data requirements for magnitude of the residue in livestock are fulfilled. Acceptable livestock feeding studies have been submitted and evaluated. A new maximum dietary burden (MDB) estimate was calculated based on reassessed established/proposed tol erances of feed commodities and revised Table II of OPPTS 860 Guidelines (T. Morton, 6/20/02, D280985). Holstein dairy cows were dosed daily for 28 days with ethephon at levels of 0, 43, 129 and 430 ppm in the diet (three cows per group). Milk samples wer e taken throughout the treatment period. Milk and tissue samples were analyzed with the ethylene release method. The estimated MDB in beef and dairy cows from established uses of ethephon based on a diet of cotton and wheat commodities is 46 ppm. Based on the estimated MDB, the dietary feeding levels in this study were 0.9X, 2.7X and 9X. The results of this feeding study were used to establish appropriate tolerances for meat and milk commodities. The registrant submitted data required to establish egg and poultry tissue tolerances (T. Morton, 5/7/02, D280983). Leghorn laying hens were dosed daily with ethephon at levels of 0, 2.3, 6.9 and 23 ppm in the diet. Each group had 10 hens. Egg samples were taken throughout the treatment period. Egg and tiss ue samples were analyzed with the ethylene release method. Based on the estimated MDB of 4.3 ppm, the dietary feeding levels in this study were 0.5X, 1.6X and 5.3X. The results of this feeding study were used to establish tolerances for egg and poultry c ommodities.

5.3 Water Residue Profile

The Environmental Fate and Effects Division (EFED) of the Office of Pesticide Programs (OPP) has completed a drinking water assessment for the registration review of ethephon ( D 423375

, 5/26/15 , I. Abdel

- Saheb) . The chemical is a plant growth regulator registered for use on a variety of field and specialty crops (e.g., cotton, wheat, blueberries, and cucumbers), fruit and nut orchards, vineyards, ornamentals, and turf (e.g., golf courses and residential lawns). Applic ations

### Page 21 of 59

are made by ground or aerial spray. The maximum annual application rate is 20 pounds of active ingredient per acre (lb a.i./A) (turf).

EFED recommends that the Health Effects Division use the following surface water estimated drinking water concent rations (EDWC) resulting from modeling the Florida turf scenario:

 for peak (acute) of 25.7 ppb

 for the 365

- day Avg (1

- in

- 10 yr) 0.46 ppb

 Entire Simulation Mean 0. 34 ppb

.

For groundwater, the model PRZM

- GW yielded EDWCs for acute and chronic EDWCs less than 1 ppb ( 0.102 ppb ).

Table 5.3 . Tier II Estimated Drinking Water Concentrations (EDWCs) for surface water as a result of modeling with the Surface Water Concentration Calculator (SWCC).

Surface Water Modeling Results

Recommended EDWCs from the Florida Turf Scenario are in Bold

Crop Group Model

Scenario 1

- in

- 10 year Acute

concentration (ppb) 1

- in

- 10 year

annual

average 30

- year annual

average

Berries OR berries 10.0 0.066 0.062

Cucurbits FL cucumber 8.26 0.01 0.006

Field crops & Tropical fruit MS cotton FL sugarcane

NC tobacco 23.2

6.86

12.4 0.2

0.063

0.11 0.10

0.036

0.05 Fruiting vegetables FL tomato

PA tomato 19.4

13.9 0.16

0.16 0.08

0.01

Grasses FL turf

ND wheat 25.7

2.51 0.46

0.032 0.34

0.027

Nuts OR filbert

GA Pecans 6.27

18.4 0.044

0.15 0.040

0.07

Ornamentals FL nursery NJ nursery CA nursery 25.6

23.3

6.87 0.19

0.21

0.040 0.12

0.10

0.038

Pome fruit NC apples 14.3 0.163 0.11

Stone fruit MI cherries 6.35 0.054 0.03

### Page 22 of 59

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Adequate field trial data for ethephon, reflecting maximum application rates and the appropriate

PHI , have been submitted for all registered use sites. PDP data were available and used for grape and apple commodities. Data fr om PDP and crop field trials were used for the acute dietary analysis. Processing factors from processing studies were used with the PDP monitoring

data. Anticipated residues were also used for the chronic dietary analysis.

5.4.2 Percent Crop Treated Us ed in Dietary Assessment

The following maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered for ethephon : apples: 2 5%; barley: 5%; blackberry: 51%; blueberry: 2.5%; cantaloupe: 2.5%; cherr y : 30 %; cotton : 70 %;

grapes (table) : 60 %; grape (raisin): 15%; grape (wine): 2.5%; peppers: 2.5%; tomato: 30% ; and

wheat: 2

. 5%. The following average percent crop treated estimates w ere used in the chronic dietary risk assessments for the following crops that are currently registered for ethephon : apples: 10 %; barley: 5%; blackberry: 51%; blueberry: 1%; cantaloupe: 1%; cherr y : 20 %;

cotton : 55 %; grapes (table) : 35 %; grape (raisin) : 10%; grape (wine): 1%; peppers: 2.5%;

tomato: 15% ; and wheat: 1 %.

5.4.3 Acute Dietary Risk Assessment

An ethephon acute dietary exposure assessment w as conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Datab ase DEEM

- FCIDTM, Version 3.16, which incorporates consumption data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA ). This dietary survey was

conducted from 2003 to 2008. The analys e s w as performed to support the registration review of ethephon

. Results are reported at the 99.9th percentile of exposure because the assessment incorporated field trial and PDP data to estimate residue levels and estimates of %CT. Estimated acute dietary exp osure is below HED’s level of concern for the Ge n eral U.S. population and all population subgroups except Children 1

- 2 y ea rs old . Use of PDP data, field trial data and calculated livestock anticipated residues (ARs) results in a dietary risk (food and wa ter) estimate

at the 99.9 th 

### percentile of 39 % of the acute population adjusted dose (aPAD) for the U.S. Population and 170 % for children 1

- 2 years old , the most highly exposed population subgroup.

### Page 23 of 59 Table 5.4.3 . Results of Acute Dietary (Food and Water) Exposure Analysis

Population Subgroup aPAD (mg/kg/ day) 95 th Percentile 99 th Percentile 99.9 th Percentile

Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD

General U.S. Population 0.06 0.001 345 2.2 0.00 4843 8.1 0.02 3547 39

All Infants (< 1 year old) 0.06 0.00 2242 3.7 0.01 2833 21 0.05 3926 90

Children

1

- 2 years old 0.06 0.00 5919 9.9 0.019 392 3 2 0.10 2230 170

Children 3

- 5 years old 0.06 0.00 3911 6.5 0.01 2661 21 0.04 7986 8 0

Children 6

- 12 years old 0.06 0.00 1855 3.1 0.006 242 1 0 0.03 0207 5 0

Youth 13

- 19 years old 0.06 0.00 0866 1 .4 0.00 2804 4.7 0.011 150 19

Adults 20

- 49 years old 0.06 0.001 007 1.7 0.003 332 5. 6 0.01 4792 25

Adults 50

- 99 years old 0.06 0.001 137 1.9 0.00 3841 6.4 0.018 284 3 0

Females 13

- 49 years old 0.06 0.001 020 1.7 0.003 430 5.7 0.016 453 2 7

The bolded % a PAD is the highest.



### 5.4.4 Chronic Dietary Risk Assessment

Estimated chronic dietary (food and water) exposure is below HED’s level of concern for the general population and all subpopulations. Use of tolerance level residues and %CT data results

in a maximum risk estimate of 3.5 % of the cPAD for the U.S. Population and 24 % of the cPAD

for children 1

- 2 ye ars, the most highly exposed subpopulation.

Table 5.4.4 . Results of Chronic Dietary (Food and Water) Exposure Analysis

Population Subgroup cPAD (mg/kg/day) Exposure

(mg/kg/day) % cPAD

General U.S. Population 0.06 0.002072 3.5

All Infants (< 1 year old) 0.0 6 0.006798 11

Children 1

- 2 years old 0.0 6 0.0 14585 2 4

Children 3

- 5 years old 0.0 6 0.008312 14

Children 6

- 12 years old 0.06 0.003248 5.4

Youth 13

- 19 years old 0.06 0.001244 2.1

Adults 20

- 49 years old 0.06 0.001060 1.8

Adults 50

- 9 9 years old 0.06 0.001136 1.9

Females 13

- 49 years old 0.06 0.001113 1.9

The bolded %cPAD is the highest.



### 5.4.5 Cancer Dietary Risk Assessment

Ethephon is classified as " Not likely to be Carcinogenic to Humans ’ ' based on the lack of carcinogenicity in rats and mice and mostly negative mutagenic effects data (TXR # 0051308)

.

### Page 24 of 59

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Residential handler exposure from the registered residential ornamental uses of ethephon and

r esidential post

- application exposure from the registered occupational uses of ethephon on turf in parks have been reassessed in this documents to reflect updates to HED’s 2012 Residential

S OPs 2 

### along with policy changes for body weight assump tions.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depe nding on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.

The quantitative exposure/risk assessment d eveloped for residential handlers is based on the following scenarios:

Mixing/Loading/Applying

 Manually Pressurized Handwand: Gardens/Trees (around the home and garden) and

ornamentals

.

 Hose

- end Sprayer: Gardens/Trees (around the home and garden) and or namentals

.

 Backpack Sprayer: Gardens/Trees (around the home and garden) and ornamentals

.

Residential Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential

handler risk asses sments. Each assumption and factor is detailed below.

Application Rate: The highest application rate of 0.08 lb ai/gal for ornamentals (i.e., defoliation, tall hedge buckthorn) was used as a screening

- level assessment. See Appendix C for specifics.

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for area treated or amount handled were taken from HED’s

2012 Residential SOPs 3 

### and the draft September 2013 Aquatic use SOP.

Exposure Duration:

Residential handler ex posure is expected to be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners.

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations

2 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

3 Available: http://ww w.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 25 of 59

The algorithms used to estim ate exposure and dose for residential handlers can be found in Appendix A and/or the 2012 Residential SOPs 4



### .

Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates For all residential handler exposure scenarios, there are no risk estimates of concern associated with the use of ethephon (i.e., MOEs ≥ 30). Results of this assessment are summarized in Table

6 .1.1

Table 6 .1.1. Residential Handler Non

- cancer Exposure and Risk Estimates for Ethephon.

Exposure Scenario Inhalation Unit Exposure (mg/lb ai) Max.

App.

Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

(LOC = 30)
Mixer/Loader/Applicator (Soluble Concentrate)

Manually

- pressurized

Handwand/ Handgun to Gardens /Trees 0.018

0.08 lb ai/gal 5 gal 

### 0.000090 20,000

Hose

- end Sprayer to

Gardens /Trees 0.0014 11 gal 

### 0.000015 120,000

Backpack Sprayer to

Gardens /Trees 0.14 5 gal 

### 0.00070 2,600

1. Application rate is based on the highest rate for ornamentals (i.e., defoliation, tall hedge buckthorn) from Table 4.1. 2. Based on HED’s Standard Operating Procedures for Residential Pesticide Exposure Assessment; Gardens/Trees and

Ornamentals (Feb. 2012). 3. Inhalation Dose = daily unit exposure (mg/ lb ai) x application rate (lb ai/are a treated or amount handled) x Area treated or

amount handled / body weight (80 kg). 4. Inhalation MOE = LOAEL (1.8 mg/kg/day) / daily dose (mg/ kg/ day). Level of concern = 30

.



### 6.2 Residential Post

- Application Exposure

In the absence of a point of departure for dermal toxicity, dermal post

- application exposure assessments were not conducted. However, incidental oral exposure and risk was estimated for children (1 to < 2 year old) playing on treated turf (i.e., parks). The quantitative e xposure/risk assessment for residential post

- application exposures is based on the following scenarios:

Recreational Turf (parks):

 Incidental Oral: Hand to mouth (HtM), Object to Mouth (OtM), and Soil Ingestion (SI)

Application Rate:

The maximum application rate of 0.09 lb ai/1,000 ft 2 

### (3.9 lb ai/A) for commercial turf (including parks) was used. See Appendix C

.

Exposure Duration: Residential post

- application exposure is expected to be short

- term in duration.

Residential Post

- application Non

- Cancer Exposure and Risk Equations

4 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 26 of 59

The algorithms used to estimate residential post

- application exposure and dose can be found in the ORE exposure assessment as Appendix A and/or the 2012 Residential SOPs.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates The residential post

- application incidental oral exposure and risk estimates for children (1 to < 2 year old) are summarized in Table 6 .2.1. All incidental oral MOEs are ≥ 30.

Table 6 .2.1. Residential Post

- applicat ion Non

- cancer Exposure and Risk Estimates for Ethephon.

Lifestage Post

- application Exposure Scenario Application

Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Use Site Route of Exposure/Activity

Children
(1 < 2) Turf (parks) Incidental oral / hand to mouth

3.9 lb ai/A 0.060 30

Incidental oral / Object to

mouth 0.0018 990

Incidental oral / soil ingestion 0.00013 14,000

1 Application rate is based maximum rate of 0.09 lb ai/1,000 ft2 (3.9 lb ai/A) for commercial turf (including parks) was used. See Table 4.1.

2 Dose (mg/kg/day) equations provided in Appendix [ A ].

3 MOE = POD (1.8 mg/kg/day) ÷ Dose (mg/kg/day).



### Turf Tran sferable Residue (TTR): In accordance with 40 CFR 158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. In the absen ce of chemical

- specific TTR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular default values for the fraction of the application rate available for transfer after a turf application (FAR). These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liqu ids, 11 studies using wettable powders/water dispersible granules, and 12 studies using granules). The liquid results (N=131) indicate a range of FAR values from 0.0005% to 6.1 % and the granular results (N=37) indicate a range of 0.00064% to 0.69%. In b oth the liquid and granular data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity) ; or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in FAR values is not expected when considering TTR data for a single chemical.

HED selected 1% and 0.2% as high

- end FAR default values for liquid a nd granular products, respectively. Because ethephon

- specific TTR data are not available, EPA is using the default

value of 1% . Although there may be a small degree of uncertainty in the use of the default TTR

value for ethephon (i.e., there is a small c hance that the FAR value may exceed the applicable default value), it is likely that the health

- protective aspects of EPA’s residential post

- application turf assessment methodology will more than compensate for this potential uncertainty (i.e., the

method ology is likely to overestimate exposure by a factor greater than the factor than the highest measured FAR values exceed the defaults ). For example, when assessing residential

post

- application turf exposure, EPA assumes the following: exposures occur t o zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, the grass is not mowed, etc); individuals

### Page 27 of 59

perform the same post

- application activiti es performed in the turf transfer coefficient study day after day (e.g., tumbling, playing on turf with toys, etc.); and individuals engage in these post

application activities for a high

- end amount of time every day that is represented by data reflecting time children spend outdoors and not specifically engaged in activities on turf, when in actuality children do not spend all of their outdoor time on turf and high

- end levels of activity will not occur every day. Given the conservatisms discussed above an d the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

In the case of ethephon; default assumptions were used in all calculations. Since the estimated residential turf post

- application exposure for residential turf (i.e., parks) using default TTR values for ethephon is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern, MOE = 30 compared to the LOC of 30), future refinements of this post

- application exposure for ethephon may be necessary due to increased use of ethephon or ad vances in EPA risk assessments. Therefore, EPA is requiring the 40CFR ethephon

- specific TTR data to facilitate any necessary exposure assessment refinements and to further EPA’s general understanding of the availability of turf transferable pesticide resi dues.

6. 3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6 .3.1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for ethephon. The incidental oral scenarios for children 1 to < 2 years old (i.e.,

hand

- to

- mouth, object

- to

- mouth

, and soil ingestion) are considered inter

- related and it is likely that they occur interspersed amongst each other across time. C ombining exposures from the

three incidental oral scenarios would compound the conservatism associated with each individual

scenario , so only the most protective one was selected

. The target MOE for these exposures is

30.

Table 6 .3.1 Recommendations for the Residential Exposures for the ethephon Aggregate Assessment.

Lifestage Ex posure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Backpack

Sprayer Treating

Gardens/Trees N/A 0.00070 N/A N/A N/A 2,600 N/A N/A

Child

(1 to 2

years old) Hand to mouth

activities on

treated turf N/A N/A 0.060 N/A N/A N/A 30 N/A

1. Dose = the highest dose for each applicable life stage and activity of all residential scenarios assessed.

2. MOE = LOAEL (1.8 mg/kg/day) / dose. LOC = 30



### 6. 4 Residential 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

### Page 28 of 59

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 stu dies, route

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

6. 5 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposures ( e.g. , children playin g on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf produc ts.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 5 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, su ch as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indir ect exposure are the focus of this analysis analogous to how exposures to turf products are

considered in risk assessment.

Several ethephon products have existing labels for use on turf, thus it was considered whether the

risk assessment for that use ma y be considered protective of any type of exposure that would be associated with spray drift. It should be noted that the registered residential uses on turf result in exposure greater than potential exposure from spray drift; therefore, no new residentia l assessment needs to be completed. If the maximum application rate on crops, adjusted by the amount of drift expected, is less than or equal to existing turf application rates, the existing turf assessment is considered protective of spray drift exposure . The currently registered maximum single application rate of ethephon for crops is 2 lb ai/A . The highest degree of spray drift noted for any application method immediately adjacent to a treated field (Tier 1 output from the aerial application using fin e to medium spray quality) results in a deposition fraction of 0.26 of the application rate. A quantitative spray drift assessment for ethephon is not required because the maximum application rate to a crop/target site, multiplied by the adjustment factor for drift of 0.26, is less than the maximum direct spray residential turf application rate of 3.9 lb ai/A 6 

### for any ethephon products. The turf post

- application MOEs are based on the revised SOPs for Residential Exposure Assessment (i.e., see above in Sec tion 5.2).

5 This approach is consistent wi th the requirements of the EPA’s Worker Protection Standard.

6 2 lb ai/A x 0.26 ≤ 3.9 lb ai/A

### Page 29 of 59

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, when there are potential residential exposures to a pesticide, the Agency must aggregate risk s based on exposures from three major routes: oral, dermal, and

inhalation if the exposures share a toxicity endpoint . There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exposures

from rele vant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exp osure.

7.1 Acute Aggregate Risk

T he acute exposure estimates provided in the Dietary Exposure Section represent acute aggregate

exposure.

7.2 Short

- Term Aggregate Risk

Short

- term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level).

Table 7.2.1aggregates the short

- term risk for toddlers from incidental oral and food an d water (as a background). The short

- term aggregate risk MOE of 24 for children 1 < 2 years old exceeds HED’s level of concern (LOC= 30 ). This assessment is considered conservative in that the chronic dietary exposure estimate is based on tolerance level residues and average percent crop treated.

Table 7.2.1. Short

- term Aggregate Risk Estimates to Ethephon for Children 1

- 2 years old

Exposure Scenario Target

MOE Route of Exposure Exposure LOAEL (mg/kg/day) MOE at Day 0 Combined

MOE 4

Average Food and Water N/A Oral 0.014585

1.8 120 2

24 Hand to mouth activities on

treated turf 30 1 Oral 0.060 30 3

1 Target MOE= 3 0, L OAEL= 1.8 mkd

2 MOE food = [(short

- term oral L OAEL)/(chronic dietary exposure)]

3 MOE oral = [(short

- term oral L OAEL)/(hand

- to

- mouth residential exposure)]

4 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE incidental oral)].



### Table 7.2.2 aggregates the short

- term risk for adults from residential handler exposure , and average food and water (as a background). The short

- term aggregate risk MOE of 99 0 for adults does not exceed HED’s level of concern (LOC = 30)

.

### Page 30 of 59

Table 7.2.2: Short

- term Aggregate Risk Estimates to E thephon for Adults from Post

- Application Acti vities

Exposure Scenario Target

MOE Route of Exposure Exposure or

Daily dose L OAEL

(mg/kg/day) MOE at Day 0 Combined MOE 4

Average Food and Water

(As background) N/A Food and

water 0.001136

1.8 16 00 2

99 0
Residential Handler ( Backpack
Sprayer Treating Gardens/Trees ) 3 0 1 Inhalation 0.00070 260 0 3

1 Target MOE= 3 0, L OAEL = 1.8 mkd

2 MOE food and water = [(short

- term oral NOAEL)/(chronic dietary exposure)]

3 MOE inhalation = [(short

- term inhalation NOAEL)/(high

- end inhalation residential exposure)]

4 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE handler inhalation )].



### 7.3 Intermediate

- Term Aggregate Risk

No intermediate exposure scenarios were identified for ethephon, therefore, no intermediate

aggregate risk was calculated.

7.4 Chronic Aggregate Risk

The chronic exposure estimates provided in the Dietary Exposure Section represent chronic

aggregate exposure.

7.5 Cancer Aggregate Risk

Ethephon is classified as "Not likely to be Carcinogenic to Humans ’ ' based on the lack of carcinogenicity in rats and mice and negative mutagenic effects (TXR # 0051308)

. No

assessment was needed or conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cu mulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to ethephon and any other substances and ethephon does not appear to produce a toxic metabolite produced by other substances. For the purposes of registration review , therefore, EPA has not

assumed that ethephon 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 evaluat e the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on

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

### Page 31 of 59

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- and Intermediate

- term Handler 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 (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the registered u ses. The quantitative exposure and risk assessment developed for occupational handlers is based on

the scenarios listed in Table s 9 .1.1 and 9.1.2

.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational

handler risk assessment s. Each assumption and factor is detailed below on an individual basis.

Application Rate : The maximum single application rates are listed in Appendix C . As a screening

- level assessment, the maximum application rate for a given scenario was used, and is protective of all other crops with lower application rates.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, 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 us e in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 7 

### ”, which, along with additional information on HED policy on use of su rrogate data, including descriptions of the various sources, can be found at the Agency website 8



### .

Area Treated or Amount Handled: The area treated or amount handled is based on HED ExpoSAC Policy 9.1. The amount/area treated for each scenario is listed in the Occupational Handler Exposure Table (Table s 9 .1.1 and 9.1.2 ).

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for

7 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

8 Avail able: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

### Page 32 of 59

more than a one

- month time frame; however, there may be a la rge agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).

For ethephon, based on the registered use pattern, short

- and intermediate

- term exposures are expected. However, since the short

- and intermediate

- term inhalation POD is the same for both durations, the assessment is protective of both durations.

Mitigation/Personal Protective Equipment: Estimated inhalation risks were calculated for the “baseline” level of PPE, defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as engineering

controls

, where applicable. According to the currentl y registered ethephon labels, o ccupational

handlers must wear baseline attire and chemical

- resistant gloves.

Occupational Handler Non

- Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Appendix A of the ORE memorandum ( D428505)

.

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates

There are no occupational handler risk estimates of concern for the registered uses of ethephon at

th e baseline level of PPE. The level of concern (LOC) for occupational handler inhalation risk estimates is an MOE of 30. The occupational inhalation MOEs ranged from 150 to 42,000. A summary of risk estimates is provided in Table s 9 .1.1 and 9.1.2

.

### Page 33 of 59

Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethephon.

Exposure Scenario Representative
Crop or Target 1 Inhalation Unit Exposure ( μ g/lb ai) 2 Maximum
Application

Rate 3 Area Treated or

Amount Handled Daily 4 Inhalation Risk Estimates 4

(LOC = 30)

Baseline Baseline Dose
(mg/kg/day) 5 Baseliene

MOE 6

Mixer/Loader

Mixer/Loader Liquids for Aerial

Application Pineapple

0.219 2 350 0.00191 940

Cotton 2 1200 0.00658 270

Mixer/Loader Liquids for Airblast

Application Nursery 8 20 0.000438 4,100

Apple 2 40 0.000219 8,200

Mixer/Loader Liquids for Chemigation Application Pineapple 2 350 0.00191 940

Mixer/Loader Liquids for Groundboom Application Nursery 8 60 0.00131 1,400

Pineapple 2 80 0.000438 4,100

Cotton 2 200 0.0011 1,600

Applicator

Applicator for Sprays via Aerial

Application Pineapple 0.0049
(engineering control; enclosed cockpit) 2 350 0.0000429 42,000

Cotton 2 1200 0.000148 12,000

Applicator for Sprays via Airblast

Application Nursery 4.71 8 20 0.00943 190

Apple 2 40 0.00471 380

Applicator for Sprays via Groundboom Application Nursery

0.34 8 60 0.00204 880

Pineapple 2 80 0.00068 2,600

Cotton 2 200 0.0017 1,100

Flagger

Liquid Applications Nursery 0.35 8 60 0.0021 860

Cotton 2 350 0.00306 590

### Page 34 of 59

Table 9 .1. 2 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethephon.

Exposure Scenario Representative
Crop or Target 1 Inhalation Unit Exposure ( μ g/lb ai) 2 Maximum
Application

Rate 3 Area Treated or

Amount Handled Daily 4 Inhalation Risk Estimates 4

(LOC = 30)

Baseline Baseline Dose
(mg/kg/day) 5 Baseliene

MOE 6

Mixer/Loader/Applicator

Liquid for Backpack Applications Nursery 140 0.08
lbs ai/gallon 40

gallons 0.0056 320

Liquids for Manually

- Pressurized

Handwand Nursery 30 0.08
lbs ai/gallon 0.0012 1,500

Liquids for Mechanically

Pressurized Handgun Greenhouse 120 0.008
lbs ai/gallon 1000

gallons 0.012 150

Nursery 3.9 0.08
lbs ai/gallon 0.0039 460

Landscaping 1.9 3.9 lb ai/A 5 acres 0.000464 3,900

1 Representative crop with highest application rate and area treated for each scenario

– for screening

- level assessment.

2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( Feb 2015 ); Level of mitigation: Baseline and Eng. Controls (for aerial applicators only).

3 Based on registered labels (See Table 4.1). Th e rate for “Nursery” was based on 0.08 lb ai/gal for ornamentals (i.e., defoliation, tallhedge buckthorn), assuming 100 gallo ns of treatment solution per acre (i.e., 8 lb ai/A).

4 Exposure Science Advisory Council Policy #9.1 and assumptions in the Occupational Exposure Handler Spreadsheet (February 2015).

5 Inhalation Dose = Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW (80 kg).

6 Inhalation MOE = Inhalation LOAEL (1.8 mg/kg/d ay) ÷ Inhalation Dose (mg/kg/day).

### Page 35 of 59

9.2 Short

- /Intermediate

- Term Post

- Application 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

- appli cation exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post

- application inhalation expos ure to individuals performing post

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

- HQ

OPP

- 2014

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

- specific inhalation toxicological studies) or further analysis is

req uired for ethephon.

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.

9

. 2 .2 Occupational Post

- application Dermal Exposure/Risk Estimates

Occupational Post

- application Dermal Exposure Data and Assumptions

No dermal toxicity point of departure was identified for ethephon, therefore a dermal post

application risk assessment was not completed.

Restricted Entry Interval The REI specified on the registered labels is 48 hours. Ethephon is classified as Toxicity Category III via the dermal route and Category I for dermal and eye irritation (it is corrosive to the skin), but is not a skin sensitizer. Based on the acute toxicity of ethephon

, a 48 hour REI is adequate.

### Page 36 of 59

10.0 Refere nces

Ethephon. Occupational and Residential Exposure Assessment for Registration Review. D 428505

, 9 / 1 5 / 15

, K.
O’Rourke

.

Ethephon: Acute Probabilistic and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment Registration Review Risk Assessment. D 428504

, 10 / 1 /1 5

, T. Morton.

Ethephon: Drinking Water Assessment for Registration Review . D 423375

, 5/26/15

, I. Abdel

- Saheb

.

PP#4E6835. Ethephon (099801): Ethephon in/on Filberts. D313792. 3/9/06. T. Morton.

PP#0E6205. Ethephon (099801): Ethephon in/on Coffee. D283033. 6/20/01. T. Morton

Tolerance Reassessment Eligibility Document (TRED) of Ethephon (PC Code 099801) : Product and Residue Chemistry Considerations . D280985. 6/20/01. T. Morton.

### Page 37 of 59

A ppendix A . Toxicology Profil e and Executive Summaries

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.340) for Registration Review for Ethephon are in Table A.1.

Study Technical

Required Satisfied

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

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... no

yes

yes

no waived* - yes

yes

-

-

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

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

ye s

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 Develop. Neurotoxicity

................................ ................. yes

no

yes

yes waived** yes

- yes

yes

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

-

yes

Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no -

-

- * TXR 0056295

** TXR 0054221

### Page 38 of 59

A.2 Toxicity Profiles

Table A.2

. 1 Acute Toxicity Data on Ethephon

Guideline

No. Study Type MRID #(S). Results Toxicity Category

870.1100 Acute Oral 41154501 (1989) LD 50 = 3030 mg/kg III

870.1200 Acute Dermal 41154502 (1989) LD 50 = 1560 mg/kg III

870.1300 Acute Inhalation 41154504 (1989) LC 50 = 4.53 mg/L IV

870.2400 Primary Eye Irritation Not required Assumed Corrosive I

870.2500 Primary Skin Irritation 00029514 (1979) Corrosive I

870.2600 Dermal Sensitization 41154503 (1989) Non

- sensitizer Non

- sensitizer

Table A.2.2 : Ethephon: Toxicity Profile

- Toxicological Studies Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day oral toxicity rats 00029516 (1979) Unacceptable/Guideline

75% a.i. 0, 50, 100 or 200 mg/kg/day LOAEL = 200 mg/kg/day for systemic toxicity based on decreased ovary weight, ovarian/body weight ratio and liver/body weight ratio

in females with a NOAEL of 100 mg/kg/day.

The ChE inhibition activity findings were inconsistent and not in agreement with other ethephon studies. Plasma ChE activity was inhibited at all dose levels, RBC ChE activity was not affected at any dose. This is also the only study that reports brain ChE

inhibition follo wing treatment with ethephon.

Non

- guideline

30

- day oral feeding study

Mice 00087920 (1978) Acceptable/Non

Guideline Purity not reported
0, 225, 450, 900 or 3600 ppm (0, 34, 68, 135, or 540 mg/kg/day) LOAEL for systemic toxicity is 3600 ppm (540 mg/kg/day) based on a significant depressed male relative liver weight and the

NOAEL is 900 ppm (135 mg/kg/day).

870.3150

90

- Day oral toxicity dog See one and two year dog studies

870.3200

21

- Day dermal toxicity

rabbit

Range

- finding study

- rabbit 41295901 (1989) Acceptable/Guideline

72.2% a.i.
0, 25, 75, or 150 mg/kg/day, 5 days/week

for 3 weeks LOAEL = 25 mg/kg/day for dermal effects based on the incidence and severity of erythema of the treated skin and the NOAEL is <25 mg/kg/day.

LOAEL = >150 mg/kg/day for systemic effects based on the lack of

toxic effects and the NOAEL is 150 mg/kg/day. Doses were based on a range finding study at 0, 125, 250, 500, 750, or 1000 mg/kg/day applied to shaved skin of one rabbit/sex/group; two highest doses caused mortality or moribundity within 2

- 6 days; animals exhibited low food consumption, hypothermia, prostration, ataxia, salivation tremors and dyspnea. Mild irritation was exhibited

at 125 and 250 mg/kg/day and severe dermal irritation at higher

doses.

870.3465

90

- Day inhalation toxicity Waived, HASPOC TXR 0056295

870.3700a Prenatal developmental in

rodents

- rats 00063745 (1980) Acceptable/guideline 0, 200, 600 or 1800 mg/kg/day Maternal Toxicity

LOAEL = 1800 mg/kg/day based on excessive maternal mortality (56%), gastroenteritis, respiratory disease, and necrotic hepatitis an

the NOAEL is 600 mg/kg/day. Developmental Toxicity

LOAEL = 1800 mg/kg/day based on slightly reduced pup weight

and the NO AEL is 600 mg/kg/day.

### Page 39 of 59

Table A.2.2 : Ethephon: Toxicity Profile

- Toxicological Studies Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal developmental in

rodents

- rat 41103001 (1989) Acceptable/guideline

71.7% 0, 125, 250 or 500 mg/kg/day Range Finding I. 0, 450,
900, 1350, or 1800 mg/kg/day Range Finding II. 0, 300, 600 and 1200 mg/kg/day Maternal Toxicity

LOAEL = 600 mg/kg/day based on the maternal mortality noted in the range finding study and the NOAEL is 500 mg a.i./kg/day. Developmental Toxicity

LOAEL = >500 mg/kg/day (the highest dose tested; the NOAEL is 500 mg/kg/day

870.3700b Prenatal developmental in

rodents

- rabbit 00085755 (1981) Acceptable/guideline 0, 50, 100 or 250 mg/kg/day Maternal Toxicity

LOAEL = 100 mg/kg/day, based on mortality.

NOAEL = 50 mg/kg/day. Developmental Toxicity

LOAEL = 100 mg/kg/day based on decreased fetal viability.

NOAEL = 50 mg/kg/day

870.3700b Prenatal developmental in

nonrodents

- rabbit 41557201 (1990) Acceptable/guideline

71.9

- 72.2% purity
0, 62.5, 125, or 250 mg/kg/day Maternal Toxicity

LOAEL = 250 mg/kg/day, based on mortality, clinical toxicity (ataxia, prostration, reduced activity) and significant body weight gain decrease during the dosing period.

NOAEL = 125 mg/kg/day. Developmental Toxicity

LOAEL = 250 mg/kg/day based on decreased live fetuses/doe and increased early resorptions and post implantation loss.

NOAEL = 125 mg/kg/day.

870.3800 Reproduction and fertility

effects

2

- generation, rat 41508701 (1990) Acceptable/guideline

71.14

- 72.14% purity dietary dose levels of 0,
300, 3,000 or 30,000 ppm Parental Toxicity

LOAEL = 3000 ppm (245 mg a.i./kg/day) based on decrements in adult female pre

- mating body weight, reduced food consumption

and relative food utilization.

NOAEL = 300 ppm (24 mg a.i. mg/kg/day) Offspring Toxicity

LOAEL = 3000 ppm (245 mg a.i./kg/day) based on body weight

decrement.

NOAEL = 300 ppm ((24 mg a.i. mg/kg/day).

870.4100b

2

- Year Chronic toxicity

– dogs 00060359 (1977) Acceptable/guideline 75.6% purity 0, 30, 300 or 3000 ppm (0, 0.75, 7.5, 75 mg/kg/day) LOAEL for systemic toxicity is >1500 ppm (>37.5 mg/kg/day) based on lack of toxicity at this dose. The NOAEL = 1500 ppm (37.5 mg/kg/day).

870.4100b

1

- Year Chronic toxicity dogs 41135001 (1989) Acceptab le/guideline 71.14% a.i. (Adjusted to 100% a.i.) Main Study : 0, 100, 300, 1000 or 2000 ppm (0, 2.7, 8.2, 28.5 and 52.1 mg/kg/day) Main Study

LOAEL = 2000 ppm (52.1 mg/kg/day) for systemic toxicity (decreased body weight, decreased spleen weight and anemia in males). ChE not measured in Main Study.

NOAEL = 1000 ppm (28.5 mg/kg/day). Range Finding Study No mortalities or clinical signs were obs erved. The females receiving the 3000 and 10000 ppm and the male receiving the 10000

### Page 40 of 59

Table A.2.2 : Ethephon: Toxicity Profile

- Toxicological Studies Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

2

- week Range Finding Study : 30, 100, 30, 1000, 3000, or 10000 ppm (0.8, 2.7, 8.2, 28.5, 85.5, 285 mg/kg/day) ppm had weight losses. Plasma ChE activity was inhibited at all dose levels (36

- 93% at one week and 41

- 94% at two weeks in males

and 27

- 94% at one week and 33

- 95% at two w eeks in females). RBC ChE activity was inhibited at levels of 1000 ppm and above (47

- 90% at one week and 56

- 95% at two weeks) in males and 300 ppm and above in females (22

- 93% at one week and 27

- 98% at two weeks).

870.4200

18

- Month Carcinogenicity

Mouse 00081634 (1981) Unacceptable 75% a.i.: 0, 30, 300, or 1000 ppm (0, 4.5, 45, 150 mg/kg/day) The study was inconclusive in establishing a LOAEL and NOAEL for ethephon toxicity. Not definitive for oncogenicity findings

870.4200

18

- Month Carcinogenicity

Mouse 41050801 (1988) Acceptable/guideline

70.6

- 72.1% a.i.
0, 100, 1000, 10,000 or 50,000 ppm (0, 15.5, 156, 1630, 7750 mg/kg/day LOAEL = 10000 ppm (1630 mg/kg/day) based on body weight and body weight gain depression in females. NOAEL = 1000 ppm (156 mg/kg/day). The 50,000 ppm group was terminated at 12 days due to excessive mortality and moribundity and clinical signs of tremors and dehydration. Negative for carcinogenicity

870.4300

24

- Month Carcinogenicity

Rats 00060358 (1978)

Acc eptable/guideline 75.6% purity 0, 30, 300, or 3,000 ppm (0, 1.5, 15, 150 mg/kg/day) LOAEL = > 3,000 ppm (150 mg/kg/day) for systemic toxicity, the highest dose tested, based on the lack of clinical toxicity and treatment related histopathological findings.

NOAEL = 3000 ppm (150 mg/kg/day). There was a significant increase in pancreatic islet cell tumors at the 3000 ppm dose level that were within the historical range.

870.4300

24

- Month Carcinogenicity

Rats 41139001 (1989) Acceptable/guideline

70.6

- 72.1% a.i.
0, 300, 3000, 10000, or 30000 ppm ( Males: 0, 13, 131, 446,

1465 mg/kg/day

, Females 0, 16, 161, 543, or 1794 mg/kg/day) LOAEL = 10,000 ppm (446 mg/kg/day) for systemic toxicity based on reduction in mean body weight and mean body weight gain in

males and the NOAEL is 3000 ppm (131 mg/kg/day). The test material was not carcinogenic at the doses tested.

Gene Mutation

870.5100

Bacterial reverse mutation 00077065 (1980) Acceptable/guideline

21.6% formulation 50 to 5000 μg/plate tested up to cytotoxic dose Positive: Increased the number of revertant colonies (0.4

- 0.7 over the number of the spontaneous reversion rate) in strain TA1535 at concentrations of 50, 166, 500 and 1666 μg/plate but not at 5000 μg/plate.

Gene Mutation

870.5100

Bacterial reverse mutation 40412401 (1987) Acceptable/guideline 72.3% purity 0.1 to 50 μl/plate tested up to cytotoxic dose. Positive: 40% or greater reduction in histidine+ colonies of strains TA1537, TA 1538, and TA98 exposed to 50 μl/plate ± activation. In TA1535 strain, a dose related increase in reversion ranging from 1.5 at 5.0 μl/plate to 4

- fold at 50 μl/plate in the absence of S9

activation and 2

- fold at 10 and 25 μl/plate and 3.5 fold at 50 μl/plate + activation. A repeat test confirmed that the test material is mutagenic in the TA1535 st rain.

Other Effects

870.5300

870.5300 40498101 (1988) Acceptable/guideline

40555301 (1988) Acceptable/guideline Negative: Ethephon did not induce forward mutations in CHO cells. The 5.0 mg/ml dose was 100% cytotoxic

### Page 41 of 59

Table A.2.2 : Ethephon: Toxicity Profile

- Toxicological Studies Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.5395

870.5500

870.5500

870.5575 00077061 (1981) Acceptable/guideline

40555201 (1988) Acceptable/guideline

41255601 (1984) Acceptable/guideline

00077066 (1980) Acceptable/guideline Negative: Ethephon did not induce chromosomal aberrations in CHO cells in the pre sence or absence of microsomal metabolic activation at doses reaching subtoxic levels of 2000 μg/mL.

Negative: Ethephon did not produce a statistical significant increase in the number of micronuclei per 1000 polychromatic erythrocytes

in the treated anim als when compared to the control group. Ethephon is not mutagenic in this micronucleus test.

Negative: Concentrations of the test material below the cytotoxic dose of 2000 μg/mL did not induce unscheduled DNA synthesis.

Negative: for inducing Unschedule d DNA Synthesis at concentrations up to and including 1000 μg/well. Doses above 1000 μg/well were cytotoxic

Positive: Increased mitotic gene conversion in strain D7 at doses of 42 and 45 mg/ml without metabolic activation. Was not tested with

metabolic activation.

870

- 5575 00077063 (1980) Mitotic gene conversion assay ( Saccharomyces

cerevisiae ), July 15, 1980

21.6% formulation 1/3, 1/10, 1/30, 1/100 dilution of a high dose that

caused 50% survival of the yeast cells. Ethrel formulation 21.6% did not induce mutation in Saccharomyces

cerevisiae cells under the conditions of the test. Unacceptable/Non

- guideline : actual concentrati ons not given.

Ethrel was not tested with metabolic activation. The test was not performed on levels beyond the 50% survival rate

870.5450 00029494 (1979) Dominant lethal assay in

rats: oral gavage at 0, 250, 500 or 1000 mg/kg/day for 5 days Inconclusive. The study protocol is not consistent with the current guidelines. Purity not given. unacceptable

870.6200a Acute neurotoxicity 44000802 (1996) Acceptable/guideline

72.4% a.i. Single doses at 0, 500, 1000 or 2000 mg/kg sacrificed on Day 15 LOAEL = 500 mg/kg bw (the lowest dose tested) based on pinpoint pupils in all ethephon treated groups which lasted throughout the observation period. A NOAEL was not established. Pupillary constriction, increased urination (males only), reduced food

con sumption and body weight, decreased body temperature (females only), and reduced motor activity and mortality at the mid

- and the high

- dose level. No neuropathological lesions were seen that were

attribute to treatment. ChE inhibition was not evaluated.

870.6100 Acute Delayed Neurotoxicity

- Hen 00144559 (1983) Acceptable/guideline

70.75% single oral gavage 3160 or 3850 mg/kg, administered

another dose of 2370 mg/kg on day 21, sacrificed on day 42. Mortality 28/30 & 10/30 birds at 3850 & 3160 mg/kg, re spectively during the first 21 day period. Body weight & food consumption reduced. Lethargy and anorexia 3

- 5 hours after dosing and lasted for up to 72 hours. No signs of ataxia in any of the birds. A low

incidence of lesions in the nerves in controls and ethephon treated groups, but none appeared to be treatment related, except in the positive control (TOCP) where various lesions were noted.

### Page 42 of 59

Table A.2.2 : Ethephon: Toxicity Profile

- Toxicological Studies Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Ethephon did not produce acute delayed neurotoxicity in hens after being dosed with nearly lethal doses.

Non

- guideline

2

- week range finding neurotoxicity study

rats 44283001 (1997) Acceptable/non

- guideline

72.5% a.i.
0, 100, 300, 600, or

1000 mg/kg/day, gavage. LOAEL = 600 mg/kg/day based on mortality and cholinergic signs (abnormal respiratory sounds and breathing) and body weight loss.

The NOAEL for systemic toxicity is 300 mg/kg/day. Plasma ChE activity was inhibited at all dose levels but not RBC ChE activity. Brain ChE activity was not evaluated. Mortality at 1000 mg/kg/day (6/6 males, 5/6 females died between Days 3 and 10), and 600 mg/kg/day (2/6 males, 4/7 females died between Days 2 and 9). Rats in the 1000 and 600 mg/kg/day treatment groups had mean bod y weights 27

- 34 and 13

- 19% lower, respectively, than the controls (days 8

- 12), and a mean food consumption 23

- 48% lower than the controls during the first week of the study.

870.6200b Subchronic neurotoxicity screening battery

Rats 44283002 (1997) Accep table/non

- guideline

72.5% a.i.
0, 75, 150 or 400/300 mg/kg/day for 13 weeks. LOAEL for neurotoxic effects (abnormal respiratory sounds, vocalization in males, cold to touch in males and mortality) is 400/300 mg/kg/day, the highest dose tested. The NOAEL for neurotoxic effects is 150 mg/kg/day. Inhibition of plasma and/or

RBC ChE activ ity at the lower dose levels was not accompanied by cholinergic and/or clinical signs and is not considered relevant to the human response to ethephon. Brain ChE activity was not inhibited at any of the dose levels.

870.6300 Developmental neurotoxicity r ats A developmental neurotoxicity study was not conducted based on the unlikelihood that ethephon crosses the blood/brain barrier of offspring (TXR 0054221).

870.7800 Immunotoxicity Study

– Mice 49037903 (2012) Ethephon 70.8% a.i.
0, 1000, 3000 or 7000 ppm (0, 187, 575, 1373 mg/kg/day for 28 days LOAEL for systemic and immunotoxicity is > 7000 ppm (>1373 mg/kg/day).

NOAEL for systemic and immunotoxicity = 7000 ppm (1373 mg/kg/day).

870.7485

Metabolism and pharmacokinetics

Rats 41906101 (1990) Acceptable/guideline single intravenous doses at 50 mg/kg, or single oral doses at 50 or 1000 mg/kg or in multiple daily oral doses (unlabeled ethephon) for 14 days at 50 mg/kg/day followed by single oral dose of the 14 C

ethephon to groups of male

and fema le Crl:CD(SD)BR rats (5/sex/dose) Oral and IV doses were rapidly absorbed and excreted in the urine accounting for 48

- 71% of the administered dose (AD). The iv dosing indicated that biliary excretion is minimal since less than 2%

of the AD was recovered in the feces. Exhaled 14 CO 2 was <1%, 14 C

ethylene was 10 to 20% of the AD. Less than 7% of the AD was excreted in the feces. Residual radioactivity in tissues was less than 0.1% of the AD. Total recovered radioactivity was 84

- 90%. There were no signi ficant differences in the pharmacokinetics between the sexes. Multiple dosing did not significantly alter the excretion

pattern. Ethephon was not extensively metabolized. Ethephon as disodium salt accounted for 90% of the recovered radioactivity in the u rine

and feces with less than 5% as mon o sodium salt and other unidentified metabolites. The potential decomposition products, chloroacetic acid & chloroethanol were not reported or analyzed for.

870.7600 Dermal penetration NA, Not required. Ethephon is a severe skin irritant

Special studies Human Oral Study 00036510 (1972) Acceptable/nonguideline 0 (3/sex) or 1.8 mg/kg/day (5/sex) for 28 days LOAEL = 1.8 mg/kg/day based on diarrhea and increased urgency and frequency of urination, loose stools, stomac h cramps or gas.

NOAEL = <1.8 mg/kg/day

### Page 43 of 59

Table A.2.2 : Ethephon: Toxicity Profile

- Toxicological Studies Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Special studies Human Oral Study 00066931 (1977)

Unclassifiable 0 (6 males and 4 females) or 0.5 mg/kg/day (10/sex) for 16 days with 29 day recovery period. No clinical symptoms were reported. Hematological, clinical chemistry values and urinalysis parameters were comparable to the placebo controls. Plasma and RBC ChE activities were significantly inhibited in both placebo and test groups. Therefore, this f inding makes any conclusions regarding the effects attributable to ethephon administration impossible. This is in contradiction to the study authors overall conclusion that a daily ethephon oral dosage of 0.5 mg/kg/day produces significant plasma ChE inhi bition which is reversible in 15 days.

### Page 44 of 59

A.3 Hazard Identification and Endpoint Selection

A.3.2 Acute Reference Dose

The HIARC selected an acute RfD of 0.06 mg/kg from a 28 day human clinical study based upon cholinergic signs in humans of both sexes following daily bolus dosing (capsule) at the Lowest Observed Adverse Effect Level (LOAEL) of 1.8 mg/kg/day. Plasma and R BC cholinesterase were slightly elevated in treated subjects but fell within the normal range. The study is considered appropriate for selection of an acute endpoint because clinical signs were generally seen between days 1 and 4. A UF of 10 for intraspe cies variation is adequate for this risk assessment. The conventional UF of 10x for interspecies extrapolation was not applied because of the use of a human study. An additional traditional 3X factor is applied for the lack of a

NOAEL in the selected stu dy (MRID 0051308 )

. The 3X UF for extrapolating from a LOAEL to a NOAEL is adequate based on:

 The duration of the effects elicited by ethephon in the 28

- day oral toxicity study in

humans are consistent with a C
max 

### reaction (i.e., compound concentration in the body quickly reaches a peak and declines very rapidly (~ 9 0% is eliminated within 24 hrs) so that every exposure appears as a single exposure).

 Mild clinical effects seen in the 28

- day human study. Another 29

- day human study (MRID 00066931 )at one thir d of the dose (0.5 mg/kg/day) no clinical signs were reported.

 The use of this endpoint/study is considered appropriate since the toxicokinetic properties of this compound indicate a C
max 

### reaction in which repeated exposures do not lead to

cumulative toxi city or progression of the effects. The HIARC recommended a (UF) of 30x for the general population and all population subgroups except infants <1 year old and children 1

- 6 years. The HIARC recommended that an additional 3X factor be applied to dietary exp osure assessments for infants <1 year old and children 1

- 6 years old for lack of data indicating that ethephon does not cross the blood brain barrier in the young. As previously noted, the 3X UF has been removed based HED’s reevaluation of the FQPA factor in light of additional data. The Acute RfD is:

aRfD for general population = 1

. 8 mg / kg ( LOAEL )

10 ( UF ) 3 ( SF ) = 0

. 06 mg / kg

A.3.3 Chronic Reference Dose

The HIARC selected a chronic RfD of 0.06 mg/kg from a 28 day human clinical study based upon cholinergic signs in humans of both sexes following daily bolus dosing (capsule) at the Lowest Observed Adverse Effect Level (LOAEL) of 1.8 mg/kg/day. The same s tudy is considered appropriate for selection of a chronic endpoint because metabolism studies (MRID 41906101) in rats have shown that ethephon is rapidly excreted in urine (48

- 71% of the administered dose) as disodium salt of the parent, and exhalation (10

- 20% of the AD) as ethylene and is not retained in the body. Therefore chronic exposures would not lead to accumulative effects and the short term study selected would be appropriate for the chronic exposure. The

### Page 45 of 59

same uncertainty factors recommended for the acute RfD are considered appropriate for the

chronic RfD for the same reasons. The ChronicRfD is:

cRfD for general population = 1

. 8 mg / kg ( LOAEL )

10 ( UF ) 3 ( SF ) = 0

. 06 mg / kg

A.3.4 Incidental Oral Exposure

- All Durations

The HIARC selected a chronic RfD of 0.06 mg/kg from a 28 day human clinical study based upon cholinergic signs in humans of both sexes following daily bolus dosing (capsule) at the Lowest Observed Adverse Effect Level (LOAEL) of 1 .8 mg/kg/day. However, exposure via incidental ingestion was not assessed because the current limited residential use pattern of ethephon is unlikely to result in exposure via this route.

A.3.5.1 Dermal Exposure

- All Durations

At dermal doses above 1 50 mg/kg/day, ethephon is corrosive to the skin. In a range finding study, dermally applied ethephon was lethal above 500 mg/kg/day and was a severe irritant at 500 mg/kg/day. In the main 21

- Day rabbit dermal toxicity study ethephon produced no systemic toxicity at 150 mg/kg/day or less, but cause local dermal toxicity at doses of 25 mg/kg/day and above. Since ethephon is dermally corrosive, exposures at levels high enough to cause systemic toxicity are not expected. Therefore, risk assessment of derm al exposures to ethephon would not be applicable.

A.3.5.2 Dermal Absorption

Dermal absorption data are not available and also not applicable for risk assessment purposes.

A.3.6 Inhalation Exposure

- All Durations

The HIARC selected a dose for inhalation risk assessment of 0.06 mg/kg from a 28 day human clinical study based upon cholinergic signs in humans of both sexes following daily bolus dosing (capsule) at the Lowest Observed Adverse Effect Level (LOAEL) of 1.8 mg/kg/day. Absorption

via th e inhalation route is considered to be equivalent to the oral route.

### Page 46 of 59

Appendix B . Physical/Chemical Properties

Table C1. Physico

- Chemical Properties

Parameter Value Reference

Molecular Weight 144.5

R. Daiss, D327932, 5/10/2006 pH

Water solubility (20°C) readily soluble in water

Solvent solubility (20°C to 25°C) very soluble in water, alcohol, acetone, and propylene glycol, only slightly soluble in

aromatic solvents such as benzene and toluene,

and insoluble in

kerosene and diesel oil
Vapor pressure (25°C) <1 x 10

- 7 mmHg at 25 C

Dissociation constant, pKa K 1 = 3.16 X 10

- 3 and K 2 = 6.31 X 10

- 8 at 25 C Octanol/water partition coefficient, log K OW (25°C) <0.603 ±0.0006 at 25 C

### Page 47 of 59

Appendix C . Ethephon Use Pattern

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

Crop Uses

Apple

Foliar Ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 2 2 7 48 A 30

- day plant

- back interval is specified. Do not apply through irrigation system.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 2 2 7 48 A 30

- day plant

- back interval is specified. Do not apply through irrigation system.

Barley

Foliar, broadcast

Ground and aerial equipment 2 lb/gal SC/L (228

- 660) (66330

- 262) (85678

- 9) 0.5 0.5 40 48 Apply ground and aerial applications in a minimum of 7 and 3 gal/A, respectively. Grazing or foraging by livestock or cutting for hay or silage are prohibited. Mature straw at normal harvest may be consumed by

animals. A 30

- day plant

- back interval is specified.

Foliar, broadcast Early to late boot stage prior to awn emergence

Ground and aerial equipment 4 lb/gal SC/L (264

- 377) 0.5 0.5 40 24 Apply ground and aerial applications in a minimum of 7 and 3 gal/A, respectively. Grazing or foraging by livestock or cutting for hay or silage are prohibited. 3 Mature straw at normal harvest may be consumed by

animals. A 30

- day plant

- back interval is specified.

Foliar, broadcast

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 0.5 0.5 40 48 Not for use in CA. Grazing or foraging by livestock or cutting for hay or silage are

### Page 48 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

prohibited. A 30

- day plant

- back interval is specified.

Blackberry

Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660)
(264

- 267)
(66330

- 262)
(85678

- 9) 2 2 3 48 For use on blackberries in OR and WA only.

A 30

- day plant

- back interval is specified.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 2 2 3 48 For use on blackberries in OR and WA only.

A 30

- day plant

- back interval is specified.

Blueberry
Foliar, broadcast

Ground and aerial equipment 2 lb/gal SC/L (228

- 660)
(264

- 267)
(66330

- 262)
(85678

- 9) 2 2 NS 48 Apply ground and aerial applications in a

minimum of 100

- 200 gal/A and 10 gal/A, respectively. A 30

- day plant

- back interval is specified.

Foliar, broadcast

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 2 2 NS 48 Not registered for use in CA.

Cantaloupe

Foliar Aerial or ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 0.75 0.75 2 48 AZ, CA, and TX only. Ground and aerial applications can be made in a minimum of 40 and 10 gal/A, respectively. Ground equipment may be used for application in CA and AZ. Aerial or ground applications are allowed in TX only. A 30

- day plant

- back interval is specified.

Foliar 3 lb/gal EC (5905

- 595) 0.75 0.75 2 48 AZ, CA, and TX only. Ground and aerial applications can be made in a minimum of 40

### Page 49 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

Ground and aerial equipment and 10 gal/A, respectively. Ground equipment may be used for application in CA

and AZ. Aerial or ground applications are allowed in TX only. A 30

- day plant

- back interval is specified.

Cherry (sweet and tart)

Foliar Ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 1 (sweet)

0.25 (tart) 1 7 48 This use is not permitted in CA. Apply in a minimum of 50 gal/A. A 30

- day plant

- back interval is specified.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 1 (sweet)

0.25 (tart) 1 7 48 This use is not permitted in CA.

Cotton

Foliar, Broadcast Ground equipment Aerial equipment also* 2 lb/gal SC/L (66330

- 262)

2.28 lb/gal SC (228

- 607) (34704

- 911)*

6 lb/gal EC (228

- 659)* (228

- 709)* (228

- 727)* (264

- 418)* (264

- 703)* (9779

- 349)* (34704

- 856)* (55467

- 16)* (66222

- 136)* 2 2 7 48 A 30

- day plant

- back interval is specified. EPA Reg. No. 264

- 703 specifies 3 gal/A by air and 10 gal/A by ground. A 30 day plant

back interval is specified for all crops. Do not apply through irrigation equipment. Apply in a minimum of 2 gal/A by air. In AZ and CA, aerial spray volume must be at least 5 gal/A.

### Page 50 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

(66330

- 250)* (66330

- 273)* (83222

- 33)* (83520

- 35)* (84009

- 16)* (84930

- 31)* (85678

- 5)* (89167

- 8)*

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 2 2 7 48 Apply in a minimum of 3 gal/A by air. In AZ and CA, aerial spray volume must be at least 5 gal/A. A 30

- day plant

- back interval is specified.

Grape

Foliar Ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 0.5 0.5 14 48 For use on table grapes in AZ and CA only. Also for use on Thompson seedless for raisin production. A 30

- day plant

- back interval is specified.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 0.5 0.5 14 48 For use on table grapes in AZ and CA only. Also for use on Thompson seedless for raisin production. A 30

- day plant

- back interval is specified.

Macadamia Nut

Foliar

Prior to harvest Ground equipment 4 lb/gal SC/L (HI100005) 0.7 lb ai/100 gal 1 5 24 SLN No. HI100005 permits one application to leaves and nuts in HI only at 100

- 200 gal/A. Grazing and foraging of cover crops is not permitted.

Pepper

### Page 51 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

Foliar

Ground and aerial equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 1 1 5 48 A 30

- day plant

- back interval is specified.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 1 1 5 48 Not for use in CA. A 30

- day plant

- back interval is specified.

Pineapple

Foliar broadcast Ground equipment 2 lb/gal SC/L (264

- 267)
(66330

- 262)
(85678

- 9) 2 3 2 48 Apply in a minimum of 100 gal/A. Grazing of pineapple forage is not permitted.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 2 3 2 48 Not for use in CA. A 30

- day plant

- back interval is specified.

Sugarcane

Foliar, broadcast

Aerial equipment 2 lb/gal SC/L (264

- 267)
(66330

- 262) 0.5 0.5 2

months 48 Application permitted in HI only. Grazing of

sugarcane forage is not permitted.

Foliar

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 0.5 0.5 2

months 48 Not for use in CA. A 30

- day plant

- back

interval is specified.

Tobacco (Flue

- cured only) 1

Foliar, directed Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (264

- 292) (66330

- 262) 2 2 2 48 A 30

- day plant

- back interval is specified.

### Page 52 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

(85678

- 9)

Foliar, directed Foliar, broadcast Ground equipment 6 lb/gal EC (228

- 659)
(228

- 709)
(264

- 418)
(34704

- 856)
(55467

- 16)
(66222

- 136)
(66330

- 250)
(66330

- 273)
(83222

- 33)
(83520

- 35)
(84009

- 16)
(84930

- 31)
(85678

- 5)
(89167

- 8) 2 2 2 48 A 30

- day plant

- back interval is specified.

Foliar, broadcast

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 2 2 2 48 Not for use in CA.

Tomato (fresh market)

Foliar, broadcast Aerial and ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 1.25 1.25 3 48 This use is permitted only in CA. A 30

- day plant

- back interval is specified.

Foliar, broadcast Aerial and ground equipment 3 lb/gal EC (5905

- 595) 1.24 1.63 3 48 Do not use on greenhouse tomatoes.

Tomato (for processing)

Foliar, broadcast 2 lb/gal SC/L 1.63 1.63 3 48

### Page 53 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

Aerial and ground equipment (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) Apply in a minimum of 20 (ground) and 10 (air) gal/A. A 30

- day plant

- back interval is specified. Do not use on greenhouse

tomatoes. Foliar, broadcast Aerial and ground equipment 3 lb/gal EC (5905

- 595) 1.63 1.63 3 48 Do not use on greenhouse tomatoes.

Tomato (Greenhouse)

Foliar, broadcast Ground equipment 2 lb/gal SC/L (264

- 267) 1.25 1.25 2 48 Do not apply through irrigation system.

Tomato (Home Garden)
Foliar, broadcast Ground equipment 0.33 lb/gal SC/L (264

- 543) (66330

- 284) 0.018 lb ai/gal NS 14 NS Thoroughly wet leaves and fruit.

Walnut

Foliar Ground Equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (66330

- 262) (85678

- 9) 1.25 1.25 5 48 A 30

- day plant

- back interval is specified. For use in CA only.

Foliar, broadcast Aerial and ground equipment 3 lb/gal EC (5905

- 595) 1.25 1.25 5 48 A 30

- day plant

- back interval is specified. For use in CA only.

Wheat

Foliar, broadcast

Ground and aerial equipment 2 lb/gal SC/L (228

- 660) (66330

- 262) (85678

- 9) 0.5 0.5 40 48 Apply ground and aerial applications in a minimum of 7 and 3 gal/A, respectively. Grazing or foraging by livestock or cutting for hay or silage are prohibited. 3 Mature straw at normal harvest may be consumed by

### Page 54 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

animals. A 30

- day plant

- back interval is specified.

Foliar, broadcast

Ground and aerial equipment 3 lb/gal EC (5905

- 595) 0.5 0.5 40 48 Not for use in CA. Grazing or foraging by livestock or cutting for hay or silage are prohibited. A 30

- day plant

- back i nterval is specified.

Foliar, broadcast Early to late boot stage prior to awn emergence

Ground and aerial equipment 4 lb/gal SC/L (264

- 377) 0.5 0.5 40 24 Apply ground and aerial applications in a minimum of 7 and 3 gal/A, respectively. Grazing or foraging by livestock or cutting for hay or silage are prohibited. 4 Mature straw at normal harvest may be consumed by

animals. A 30

- day plant

- back interval is specified.

Ornamental Fruit Trees (Apple, carob, crabapple, cottonwood, elm, flowering pear, horse chestnut, maple, oak, olive, pine, sour orange, sweetgum, sycamore)

for Fruit Elimination 2

Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (53883

- 314) (66222

- 151) (66330

- 262) (70506

- 288) (85678

- 9)

0.33 lb/gal SC/L (264

- 263) (264

- 543) (54705

- 8) (66330

- 284) 0.009 lb ai/gal NS NA 48 Apply as a foliar spray but not to runoff. No REI on the residential product 264

- 543.

Foliar, broadcast Ground equipment 3 lb/gal EC (5905

- 595) 0.1875 NS NA 48

Ornamentals (ornamental conifers, Douglas fir ornamentals, and ornamental deciduous trees) for Mistletoe Removal

### Page 55 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (264

- 267) (53883

- 314) (66222

- 151) (66330

- 262) (70506

- 288) (85678

- 9)

0.33 lb/gal SC/L (264

- 543) (54705

- 8) (66330

- 284) 0.05 lb ai/gal NS NA 48 0.05 lb ai/ gal rate is for deciduous trees. 0.025 lb ai/gal rate is for ornamental conifers. 0.0125 lb ai/gal rate is for ornamental douglas

fir.

Foliar, broadcast Ground equipment 3 lb/gal EC (5905

- 595) 0.05 lb ai/gal 0.5 40 48 0.05 lb ai/gal rate is for deciduous trees. 0.025 lb ai/gal rate is for ornamental conifers. 0.0125 lb ai/gal rate is for ornamental douglas

fir.

Ornamental Bromeliads for Flower Induction
Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (85678

- 9)

0.33 lb/gal SC/L (264

- 263) (54705

- 8) (66330

- 283) 0.02 lb ai/gal

0.125 lb ai/10 ft 2 NS NA 48 Avoid overspraying to runoff. The 0.125 lb

ai/10 ft 2 is for greenhouse bench or outdoor

bed area.

Ornamental Defoliation (roses, tallhedge buckthorn, and apple nursery stock in WA)
Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (85678

- 9)

0.33 lb/gal SC/L (264

- 263) 0.008 lb ai/gal roses

0.08 lb ai/gal tallhedge buckthorn 0.0017 lb ai/gal apple nursery stock 0.0033 lb ai/gal for apple nursery

stock NA 48 Apply to thoroughly wet foliage.

### Page 56 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

(54705

- 8) (66330

- 283) Increased Lateral Branching on Ornamentals (see label for species)
Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (85678

- 9)

0.33 lb/gal SC/L (264

- 263) (54705

- 8) (66330

- 283) 0.004 lb ai/gal

except azalea 0.04 lb ai/gal for

azalea NS NA 48 Apply to thoroughly wet foliage but not to

runoff.

Reduction of Hyacinth Stem Topple and Daffodil Plant Height
Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660) (85678

- 9)

0.33 lb/gal SC/L (264

- 263) (54705

- 8) (66330

- 283) 0.033 lb ai/gal NS NA 48

Hybrid Seed Production (cucumber, squash, and pumpkins)
Foliar, broadcast Ground equipment 2 lb/gal SC/L (228

- 660)

0.33 lb/gal SC/L (264

- 263) (66330

- 283) (85678

- 9) 0.08 lb ai/A

cucumber and squash

0.25 lb ai/A pumpkins (IL only)

0.25 lb ai/A pumpkins, squash, cucumbers (CA only) 16

1.5

1.5 NS

42

60 48 Do not harvest any treated cucumbers,

squash, or pumpkins for human or livestock consumption. Seed production only.

### Page 57 of 59

Table 4 .1. Summary of Directions for Use of Ethephon.

Site Application Type Application Timing Application Equipment Formulation (EPA Reg No.) Maximum Single

Application Rate (lb ai/A) Maximum

Seasonal Rate (lb ai/A) PHI

(days) Reentry

Interval (Hours) Use Limitations

Foliar, broadcast Ground equipment 0.33 lb/gal SC/L (54705

- 8) 0.25 lb ai/A

cantaloupe, pumpkin, squash, cucumber (CA only)

0.08 lb ai/A cantaloupe, cucumber, and squash

0.25 lb ai/A pumpkins 1.5 60

42 48

Commercial Turf (golf course, parks and sports turf)
Foliar, broadcast Ground equipment 2 lb/gal SC/L (264

- 267) (228

- 660) (432

- 1230) (53883

- 314) (66222

- 151) (66330

- 262) (70506

- 288) (85678

- 9) 0.09 lb ai/1000 ft 2 0.47 lb

ai/1000 ft 2 NA 48 No REI specified on 432

- 1230.

Foliar, broadcast Ground equipment 3 lb/gal EC (5905

- 595) 0.08 lb ai/1000 ft 2 0.47 lb

ai/1000 ft 2 NA 48

1 Non

- food use.

2 Label directions for apples, crabapples, carob, and olives that are for ornamental use only must be clearly designated as such on a ll pertinent labels.

3 These label restrictions are no longer appropriate since the Agency has determined that barley and wheat forage and hay are not under grower/farmer control (OPPTS 860 Guidelines), therefore, are not practical or enforceable.

### Ethephon Human Health Risk Assessment DP No. D423165

Page 58 of 59 Appendix D. Ethephon (PC Code 099801 ; 0 8 / 10 /1 5 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2

40 CFR 180.300:

Plant/Livestock: Compliance with the tolerance levels specified below is to be determined by measuring only ethephon [(2

- chloroethyl) phosphonic acid] (P)

- (2

- chloroethyl)phosphon

ic acid Ethephon

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2
Apple 5.0 3 5 Apple, juice 10.0 6 Barley, bran 5.0 Barley, grain 2.0 0.5 1

Barley, straw 10.0 5 barley straw and fodder, dry Blackberry 30.0 20 Blueberry 20.0 10 20 Cantaloupe 2.0 2 1
Cattle, fat 0.02 Cattle, kidney 1.0 0.2 (*)
Cattle, meat 0.02 0.1 (*) Cattle, meat byproducts, except kidney 0.2 0.2 (*)

Cherry 10.0 8 sweet cherries

2 tart cherries 10

Coffee, bean, green 0.5 1 Cotton, gin byproducts 180.0
Cotton, undelinted seed 6.0 7 2

Cucumber 0.1 Egg 0.002 0.2 (*) chicken eggs
Goat, fat 0.02 Goat, kidney 1.0 0.2 (*) edible offal
Goat, meat 0.02 0.1 (*) Goat, meat byproducts, except kidney 0.2 0.2 (*) edible offal

Grape 2.0 2 1

Grape, raisin 12.0 5 5 dried grapes (=currants, raisins and sultanas)

Hazelnut 0.80 0.2 Hog, fat 0.02 Hog, kidney 1.0 0.2 (*) edible offal
Hog, meat 0.02 0.1 (*) Hog, meat byproducts, except kidney 0.2 0.2 (*) edible offal

Horse, fat 0.02 Horse, kidney 1.0 0.2 (*) edible offal

Horse, meat 0.02 0.1 (*) Horse, meat byproducts, except kidney 0.2 0.2 (*) edible offal

Milk 0.01 0.05 (*) milk of cattle, goats, sheep
Nut, macadamia 0.5 0.01

### Ethephon Human Health Risk Assessment DP No. D423165

Page 59 of 59 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2

Pepper 30.0 5 bell peppers, non

bell peppers 5 peppers

50 peppers chili, dried Pineapple 2.0 2 2 Poultry, fat 0.02

Poultry, liver 0.05 0.2 (*) poultry edible

offal of Poultry, meat 0.01 0.1 Poultry, meat byproducts, except

liver 0.01 0.2 (*) poultry edible

offal of Sheep, fat 0.02 Sheep, kidney 1.0 0.2 (*) edible offal Sheep, meat 0.02 0.1 (*) Sheep, meat byproducts, except kidney 0.2 0.2 (*) edible offal

Sugarcane, molasses 1.5 1.5

Tomato 2.0 2 2

Walnut 0.5 0.3 black walnuts, English walnuts 0.5

Wheat, bran 5.0 2.2 Wheat, germ 5.0 Wheat, grain 2.0 2 1 Wheat, middlings 5.0
Wheat, shorts 5.0

Wheat, straw 10.0 5 wheat straw and fodder, dry MRLs with NO US Equivalents Figs, dried or dried and candied 3 figs 10 Rye 1 Rye straw and fodder, dry 5 Barley milling fractions, excluding flour 2

Citrus fruits 1

Cranberries 2 Completed: M. Negussie; 08/24/2015

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portio n of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

(c) Tolerances with regional registrations. A tolerance with regional registration, as defined in §180.1(m), of 0.1 part per million is established for residues o f the plant regulator ethephon [(2

- chloroethyl)phosphonic acid] in or on the food commodity sugarcane.