UNITED STATES EN V I RONME NT AL PROTECTION AGENCY

WASHINGTON

, D.C. 20460

OFFICE OF

C H EM I C AL S AF E TY AND
POLLUTION PREVE N T I ON



### MEMORANDUM

DATE:

SUBJECT: 05-MA Y

- 20 1 5



### Prohexadione Calcium

. Section 3 Registration fo r Use o n Strawberry and

Waterc r ess. 

### Human Health Risk Asse ss ment.

PC Code: 112600 DP Barcod e: 0425888

Deci s ion No.: 489681 Ree:i s trat i on No.: 7969- 188

P e t i tion No.: 4£8264 Ree: u latorv Action: Sect i on 3

Ri s k A ssess ment T y pe: NA Case No .: 7030

TXR No .: NA CAS No.: 127277-53-6

MRID Nos.: 4933900 1

, 49339002 40 CFR: § 180 .547**~**



### FROM.

THROUGH :



### TO: 

# . 

# n/;;/f '

W1ll1am D. Wassell

, Chem i st 

# fr'V#lf**1~** A n war Y. Dunbar

, Ph

. D

., Pharmacologist '

James S. Miller, E n v ironm e n ta l

# Scienti~~l**Z** Risk Assessment Branch 1 (RAB I )

## ~ Health Effects Division (HED) (7509 P )

.**~**



### Thurston Morton, Act in g Branch Chief

# ~ 

# 1t

George F

. Kramer, Ph

. D

., Senior C h em i st

RAB 1/HED (7509P)

Barbara Madden/Laura No ll en, RM 05 Reg i stratio n Division (RD; 7505 P )

The HED of th e Office of Pesticide Programs (O PP ) i s charged with est im ati n g t h e risk to h uman
health fro m exposure to pesticides. The RD of OPP h as requested that H E D eva lu ate hazard and

exposure data and cond uct dietary, occ up at i o n al/ r es id e n t i al

, an d aggregate expos ur e assessments

,

as needed, to est i mate the risk to human health that w ill result from th e registered a nd proposed

uses of the plant-growth regulator prohexadione calci um (calcium 3

- ox id o -5- oxo-4

- propionylcyclohex-3-enecarboxylate).

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

and registered uses of prohexadione calci um are provided in th i s document. T h e ri sk assessment,

residue chem i stry data r ev i ew
, and dietary-exposure assessme nt were provided by William

Wassell (RAB I ); the hazard characterizat i on by Anwar Dunbar (RAB l ); the occupational/ r es id ent i a l exposure assessme n t by James M ill er (RAB l ); and the drinking water

assessme nt by Edom Se i fu, 

### et al

., of the Environmental F ate and Effects Division (EFED)

.

P age I of 30Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 2 of 30 

### Table of Contents 1.0 Executive Summary

................................ ................................ ................................ ................ 3

2.0 HED Recommendations

................................ ................................ ................................ ......... 6

2.1 Data Deficiencies

................................ ................................ ................................ ......... 6
2.2 Tolerance Considerations

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

2.3 Label Recommenda tions

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

3.0 Introduction

................................ ................................ ................................ ............................. 8 3.1 Identification of Active Ingredient

................................ ................................ ............ 8 3.2 Physical and Chemical Properties

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

3.3 Pesticide Use Pattern/Directions

................................ ................................ ................ 9 3.4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

................................ ................................ 10

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............... 10 4.1 Toxicology Studies Available for Analysis

................................ .............................. 10 4.2 Absorption, Dist ribution, Metabolism, & Elimination (ADME)

.......................... 10 4.3 Toxicological Effects

................................ ................................ ................................ . 11 4.4 FQPA Considerations

................................ ................................ ............................... 11

4.5 Dose

- Response Assessment

................................ ................................ ...................... 12

4.6 Cumulative Risk

................................ ................................ ................................ ....... 14 5.0 Exposure Assessment and Characterization

................................ ................................ ..... 14 5.1 Residues of Concern Summary and Rational

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

5.2. Food Residue Profile

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

5. 3 Water Residue Profile

................................ ................................ ............................... 15 5.4 Dietary Risk Assessment

................................ ................................ ......................... 16 6.0 Residential (Non

- Occupational Exposure/Risk

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

6.1 Residential Handler Exposure and Risk

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

6.2 Residential Post

- application Exposure and Risk

................................ .................. 19 6.3 Residential Bystander Post

- Application Inhalation Exposure

............................ 19 6.4 Spray Drift

................................ ................................ ................................ ................ 19 7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ...... 20 7.1 Acute Aggregate Risk

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

7. 2 Short

- Term Aggregate Risk

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

7.3 Intermediate

- Term and Chronic Aggregate Risk

................................ ................. 21

8.0 Cumulative Risk

................................ ................................ ................................ ................... 21 9.0 Occupation Exposure

................................ ................................ ................................ ........... 21 9.1 Occupational Handler

................................ ................................ ............................. 21 9.2 Occupational Post

- Application Exposure

................................ .............................. 23 Appendix A. Toxicity Profile Tables

................................ ................................ ........................ 25 Appendix B Occupational Handler Exposure Calculations

................................ ................... 29 Appendix C Protection of Human Subjects of Research

................................ ....................... 30 Appendix D. International Residue Limit (IRL) Status Form

................................ .............. 30Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 3 of 30 

### 1.0 E xecutive Summary

Prohexadione calcium is a plant

- growth regulator proposed for use o n s trawberry and watercress. The product reduces vegetative growth, shoot growth, and produces a larger stem diameter (watercress). Prohexadione calcium works by inhibiting the biosynthesis of gibberellins, resulting in a decrease in cell elongation and a slowing of cell growth. Shoot reduction may cause positive benefits such as better light penetration, better fruit coloring, and better air flow within the plants. For watercress, prohexadione calcium may suppress grow th for up to 14 days. For strawberries, vegetative growth suppression lasts for 2 to 5 weeks after application and does not affect vegetative growth the following year. The registered product, Apogee ® 

### Plant Growth Regulator (EPA Reg. No. 7969

- 188), is fo rmulated as a dry

- flowable (DF) formulation containing 27.5% prohexadione calcium

.

Tolerances are currently established under 40 CFR § 180.5 4 7(a) for residues of the plant growth regulator prohexadione calcium in/on sweet cherry, pome fruit, peanut, gr as s , and livestock

commodities at levels ranging from 0.0 5 to 3

. 5 ppm

. The proposed tolerance s for residues of the plant

- growth regulator, prohexadione calcium

, are :

Strawberry

................................ ................................ 0.3 ppm

Watercress

................................ ................................ 2 ppm

Hazard Assessment By the oral route, the most sensitive effect in the prohexadione calcium hazard database is kidney toxicity in dogs for both the subchronic and chronic durations. Minor hematological changes (decreased white blood cell counts in males), and fore

- stomach hyperplasia were seen only at very high doses in rodents. No dermal toxicity was observed up to the limit dose of 1000 mg/kg/day. There was no evidence of neurotoxicity in either of the neurotoxicity screening batteries up to or exceeding the limit dose.

In rats and rabbits, no inc reased quantitative or qualitative pre

- or postnatal susceptibility was observed. In rats, no maternal or developmental toxicity was observed up to the limit dose (1000 mg/kg/day). Three developmental studies in rabbits are available in the toxicological database for prohexadione calcium. In one study, late abortions occurred during gestational days (GD)

24

- 29 at 200 mg/kg/day, with increased mortality in maternal animals (GD 15

- 24) also noted at this dose. In another rabbit developmental study, two pre mature deliveries (on GD 24 and 26) were noted at the highest

- dose tested (350 mg/kg/day) with no developmental effects observed. No maternal or developmental effects were seen in a third rabbit developmental study up to 150 mg/kg/day. In the two

- generat ion reproductive toxicity study with rats, parental toxicity (minimal mortality) occurred at a dose well below the dose that caused decreases in offspring body weight.

Dose

- Response Assessment Acute doses and endpoints that were attributable to a single exposure (dose) were not identified in any of the submitted studies for either the females 13

- 50 years old population subgroup or the general U.S. population (including infants and children); therefore, acute reference doses (aRfDs) were not established.

The chronic reference dose (cRfD) of 0.20 mg/kg/day was based upon the chronic toxicity study in dogs and a 100

- fold uncertainty factor (UF; 10X for interspecies extrapolation and 10X forProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 4 of 30 

### intraspecies variation). The no

- observed

- adverse

- effect level ( NOA EL ) of 20 mg/kg/day was based on histopathological changes in the kidneys (dilated basophilic tubules) and clinical chemistry changes seen at the lowest

- observed

- adverse

- effect level ( LOAEL ) of 200 mg/kg/day. The chronic population

- adjusted dose (cPAD) is equal to the cRfD divided by the Food Quality

Protection Act S afety F actor ( FQPA SF

, 1X). The incidental oral short

- and intermediate

- term endpoints were based upon the 90

- day oral toxicity study in non

- rodents (dog). The NOAEL was 80 mg/kg/day and the LOAEL was 400 mg/kg/day based upon moderate cortical areas of dilated basophilic tubu les in the kidneys and decreased potassium levels. The short

- and

intermediate

- term inhalation endpoints were selected from a developmental toxicity study in rabbits. The maternal NOAEL of 40 mg/kg/day was based on increased mortality, abortions, and

dec reased maternal body

- weight gain seen at the LOAEL of 200 mg/kg/day. Since oral NOAELs were selected, a highly conservative inhalation

- absorption factor of 100% were used

for risk assessment. Short

- and intermediate

- term dermal endpoints were not selecte d since there were no adverse dermal or systemic effects observed in the 28

- day dermal study in rats. There was also no evidence of increased quantitative or qualitative pre

- or postnatal sensitivity in the prohexadione calcium database. There is, theref ore, no concern for any duration of dermal exposure and no dermal endpoints are required.

FQPA Decision EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF w as reduced to 1X. That de cision is based on the following findings: 1) The toxicity database for prohexadione calcium is complete; 2) there is no evidence of targeted neurotoxicity in the toxicity database; 3) the toxicology database for prohexadione calcium does not show any evi dence of treatment

- related effects on the immune system; 4) t here is no quantitative or qualitative evidence of increased susceptibility of rats or rabbit fetuses to in

utero exposure in developmental studies, nor following pre

- /postnatal exposure to rats in the

two

- generation reproduction study; and 5) the dietary and residential exposure assessments are highly conservative and not expe cted to underestimate exposure

.

Dietary Risk Estimates (Food + Drinking Water) A chronic aggregate (food + drinking water) exposure and risk assessment was conducted using

the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID )

, (v er

. 3.16 ) , which uses food consumption data from the U.S. Department of Agriculture’s

National Health and Nutrition Examination Survey, What We Eat in America, ( USDA’s NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. The unrefined chronic analysis assumed DEEM (ver. 7.81) default processing factors, 100% crop treated (CT),

and tolerance

- le vel residues for all commodities. The chronic analysis also incorporated the drinking water estimates provided by EFED. The estimated drinking water concentrations (EDWCs) were Tier 1 estimates for surface water using the Rice Model for prohexadione

calc ium. The assessment is based on the maximum application rate of 0.1375 lb ai/A/application for watercress, applied using ground equipment with a second application 7 days after the initial application. An EDWC of 0.17 ppm was used in the chronic analysis

. The resulting chronic food plus drinking water risk estimates are not of concern to HED (<100% cPAD) for all population subgroups of interest

.

Occupational/Residential Exposure Estimates For this new use, the proposed label (EPA Reg. No. 7969

- 188) is for applications of a DF formulation to strawberries via groundboom equipment, and to watercress via chemigation andProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 5 of 30 

### airblast equipment. The maximum single use rate for applications to strawberries is 0.0343 lb

ai/A and 0.1375 lb ai/A for watercress.

The prohexadione calcium product labels direct mixers and loaders, and other handlers to wear long

- sleeved shirt, long pant s, chemical resistant gloves, and shoes plus socks. The restricted

entry interval (REI) is 12 hours.

No residential uses are associated with this action directly, but existing residential uses have been reassessed in this memo to reflect current toxicology findings and exposure policies as per the 2012 Residential Standard Operating Procedures (SOPs).

Short

- (1 to 30 days), and intermediate

- term (1 to 6 months) dermal and inhalation handler exposures are expected for occupational workers that are mixing, loading, and applying. While dermal exposures are anticipated for handlers, a dermal risk assessment has not been conducted since a dermal hazard was not identified for prohexadione calcium. The quantitative exposure/risk assessment developed for occupational handlers is based o n the mixing, loading, and applying of a DF formulation. Application exposures for chemigation type equipment will not be assessed because this process involves a closed system mechanical application; therefore exposure is expec ted to be minimal. Dermal post

- application exposure is also expected for occupational workers; however, a quantitative risk assessment was not conducted since no dermal points of departure (PODs) were chosen. Updates to short

- term (1 to 30 days) residential handler inhalation exposures were made for mixing, loading, applying a DF formulation, as well

as short

- term post

- application incidental oral exposures.

Margins of exposure (MOEs) for residential and occupational exposure were all greater than 100.

Short

- term post

- application inhalation risks were assessed for adults, youths, and children (3 to <6 years o ld) and did not exceed HED’s level of concern ( LOC ) for all residential post

application scenarios. Short

- term incidental oral risks were assessed for children ( 1 to < 2 years old) after applications of prohexadione calcium to lawns and did not exceed HED’ s LOC.

All risks for occupational handlers are above the target MOE of 100 with the use of gloves, and do not exceed the LOC as the proposed labels already require the use of protective gloves as personal protective equipment. There are no risks of conce rn for all occupational post

application activities associated with the proposed use on strawberries and watercress.

Aggregate

- Risk Estimates Aggregate exposure risk assessments were done for the following scenarios: short

- term (food + drinking water + residential) and chronic aggregate exposure (food + drinking water). An acute
aggregate

- risk assessment was not performed because no appropriate endpoint was available to

determine the aRf

D for the general population or any population subgroup. Intermediate

- and long

- term aggregate

- risk assessments were not performed because there are no registered or proposed uses of prohexadione calcium that result in intermediate

- or long

- term residenti al exposures. An aggregate cancer risk assessment was not performed because prohexadione calcium is classified as “not likely to be carcinogenic to humans.” All short

- term and chronic aggregate risks do not exceed HED’s LOC.

Environmental

- Justice Considerations

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 ActionsProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 6 of 30 

### to Address Environmental Justice in Minority Pop ulations 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

- establishe d 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 res idential setting. Extensive data on food consumption patterns are compiled by the USDA under 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

o n age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropria te, non

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

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

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. As indicated in Appendix C, these studies have been determi ned to require a review of their ethical conduct, and have received that review.

2.0 HED Recommendations

Pending submission of a revised Section F (see requirements under Recommended Tolerances ) and an analytical

- grade reference standard (see requireme nts under S ubmittal of Analytical

Reference Standards )

, there are no residue chemistry, toxicological, or occupational/residential exposure issues that would preclude establishme nt of a registration and the following permanent tolerance for the growth regulator, prohexadione calcium, including its metabolites and degradates, in or on the commodities listed below.

The specific tolerance recommendations are discussed in Section 2 .2. 2. There are no

recommended label modifications.

2.1 Data Deficiencies

Residue Chemistry

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the HED

- recommended tolerance

level s specified below (Section 2.2.2)

.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 7 of 30 

### 860.1650 Submittal of Analytical Reference Standards

The analytical

- grade reference standard for prohexadione calcium has expired (personal communication with Theresa Cole, Analytical Chemistry Branch (A CB), 12 / 30/2014). The registrant must either recertify the lot in the repository and send in an updated Certificate of Analysis (COA), or submit new standards (different lot #) if the previous lots will not be

recertified.

If new standards are being submitted, they should be s ent to ACB, which is located at Fort Meade, to the attention of Theresa Cole at the following address:

USEPA National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755

- 5350

(Note that the mail will be returned if the extended zip code is not used.)

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

BASF Analytical Method D9601, with minor modifications, was utilized for the determination of residues of prohexadione ca lcium in watercress samples. The method was validated prior to and in conjunction with the analysis of treated samples. BASF Method 564/0 was utilized for the determination of residues of prohexadione calcium in strawberry samples. The method was

valida ted prior to and in conjunction with the analysis of treated samples. HED has determined that BASF Analytical Method D9601 is adequate for the determination of residues of prohexadione calcium in/on watercress and Method 564/0 is adequate for the determin ation of residues of prohexadione calcium in/on strawberries.

2.2.2 Recommended Tolerances

Tolerances are currently established under 40 CFR §180.547(a) for residues of prohexadione calcium in/on pome fruit, peanut, grass, and livestock commodities at levels ranging from 0.05 to 3.5 ppm. HED concludes 40 CFR §180.547(a) should be revised to include the following

tolerances:

Table 9. Tolerance Summary for Prohexadione Calcium.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Correct Commodity Definition

Strawberry 0.3 0.3 0

Watercress 2 4 .0 * Changes from proposed tolerances are bolded.



### 2.2.3 Revisions to Petitioned

- For Tolerances

Based on the available watercress field trial data and the Organization for Economic Co

operation and Development (OECD) tolerance calculation procedure, HED concludes that the tolerance for residues in/on watercress should be established at 4.0 ppm. The revision of theProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 8 of 30 

### tolerance level for strawberries was done to conform to HED policies concerning significant figures for tolerance levels.

2.2.4 International Harmonization

An International Residue Limit (IRL) Status Form is appended to this document as Appendix D. There are currently no established Codex, Canadian, or Mexican maximum residue limits ( MRLs ) for prohexadione calcium in/on strawberries and watercress. The use on strawberry is a joint review between the U.S. EPA and Health Canada Pest Management Regulatory Agency (PMRA). The tolerance expression and level for prohexadion e calcium in/on strawberry is

harmonized with PMRA.

2.3 Label Recommendations

No revisions to the proposed label are required.

2.3.1 Recommendations from Residue Reviews

A revised Section F (proposed tolerances) is requested. Submission of an analytical

- grade reference standard is required.

3.0 Introduction

Prohexadione calcium is a plant

- growth regulator that reduces vegetative growth, shoot growth, and produces a l arger stem diameter (watercress). Prohexadione calcium works by inhibiting the biosynthesis of gibberellins, resulting in a decrease in cell elongation and a slowing of cell growth. Shoot reduction may cause positive benefits such as better light penetr ation, better fruit coloring, and better air flow within the plants. The chemical structure and nomenclature for prohexadion e calcium are presented in Table 3.1.

3 .1 Identification of Active Ingredient

T able 3 .1. Test Compound Nomenclature.

Compound

Common name Prohexadione calcium

Company experimental name BAS 125 W

IUPAC name calcium 1

- (4

- carboxy

- 2,6

- dioxocyclohexylidene)propan

- 1

- olate

CAS name calcium 3

- oxido

- 5

- oxo

- 4

- propionylcyclohex

- 3

- enecarboxylate

CAS registry number 127277

- 53

- 6

End

- use product s (EP) Apogee ® Plant Growth Regulator (EPA Reg. No. 7969

- 188)Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 9 of 30 

### 3 .2 Physical and Chemical Properties

Table 3 .2

. Physicochemical Properties of Prohexadione Calcium.

Parameter Value Reference

Water solubility (20  C for 96.6% pure sample) 174 mg/L in distilled water, 1602 mg/L in pH 5 buffer, 786 mg/L in pH 7 buffer, and 665 mg/L in pH 9 buffer Memo, H. Podall, 5/18/99, D253852

Solvent solubility (20  C for 96.6% pure sample) 0.038 mg/L in acetone 0.004 mg/L in toluene 1.11 mg/L in methanol 0.105 mg/L in isopropanol <0.003 mg/L in n

- hexane

Vapor pressure 1.00 x 10

- 7 torr at 20 °C
Dissociation constant, pK a 5.15
Octanol/water partition coefficient log P =

- 2.9 at 20 oC, pH 7 http://sitem.herts.ac.uk/aeru/footprint/en /Reports/539.htm



### 3.3 Pesticide Use Pattern/Directions

Table 3.3 provides a summary of the proposed uses of Apogee ® 

### Plant Growth Regulator

.

Table 3.3

. Summary of Proposed Directions for Use of Prohexadione Calcium.
Applic. Timing, Type, and Equipment Trade Name;

Formulation [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days)
Strawberry
Foliar application with ground equipment.

When 80 to 100% of the plants have 5 fully expanded leaves and before plants show first sign of runner

formation. Apogee ® Plant Growth Regulator

27.5% WG [7969

- 188] 0.034 3 1.02 21

Use Directions and Limitations: Do not apply with airblast equipment or by airplane. Use a minimum of 10 gallons of spray solution per acre per application. Applications may be made at intervals of 14 to 21 days. Use a standard spray adjuvant, preferably a non

- ionic sur factant.

Watercress
Foliar with ground or sprinkler irrigation systems. Apply when watercress has leafed up from the previous harvest (5 to 10 days). Apogee ® Plant Growth Regulator

27.5% WG [7969

- 188] 0.1375 2 0.275 3

Use Directions and Limitations: Apply ground applications through properly calibrated airblast equipment using a volume of 100 gallons per acre. Chemigation applications must be made as concentrated as possible. For best results, apply at 0.1 inch up to 0.15 inch (2,716 to 4,073 gall ons) of water per acre. A second application may be made 7 days after the first application. Do not tank mix with any other pesticide products, adjuvants, liquid fertilizer, nutrients, any other additives or anything other than water.



### 3.4 Anticipated Exposure Pathways

The RD has requested an assessment of human health risk to support the proposed new uses of prohexadione calcium on strawberry and watercress. Humans may be exposed to prohexadione calcium in food and drinking water since prohexadione calcium may be applied directly toProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 10 of 30 

### growing crops. Occupational exposures to prohexadione calcium are expected for short

- and

intermediate

- term durations when conducting handling and post

- application activities. Furthermore, the currently registered resi dential uses are expected to result in short

- term handler exposures for adults and short

- term post

- application exposures for adults and children.

3.5 Consideration of Environmental Justice

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

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

well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the

N HANES/WWEIA (2003

- 2008) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when

conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in d evelopment as OPP has committed resources and expertise to the development of speci alized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4 .0 Hazard Characterization and Dose

- Response Assessment

Prohexadione calcium is a plant

- growth regulator which works by inhibiting the biosynthesis of gibberellins, resulting in a decrease in cell elongation and a slowing of cell growth. The relatively low level of mammalian toxicity in the prohexadione calcium hazard database is

consistent with its highly plant

- specific herbicidal mechanism of action.

4 .1 Toxicology Studies Available for Analysis

The toxicological database for prohexadione calcium is complete for risk assessment purposes. Since the last risk assessment for prohexadione ca lcium, HED’s Hazard Science and Policy Council (HASPOC) met on August 2, 2012 and November 7, 2013 to evaluate the need for a repeated

- exposure inhalation toxicity study and a 28

- day immunotoxicity study (TXR# 0056433 and TXR# 0056827). Using a weight

- of

- evidence approach considering all available hazard and exposure data for prohexadione calcium, the HASPOC concluded that these studies are not required at this time.

4 .2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Regarding its absorption, distribution, metabolism

, and excretion (ADME), prohexadione calcium was rapidly absorbed in rats, with highest concentrations obtained within 30 minutes (T max 

### ). Maximum plasma concentrations (C
max 

### ) were 78. 3

- 78. 5 μg/mL for both sexes at th e l ow

-Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 11 of 30 

### dose, and 110 and 57.6 μg /mL for males and females, respectively, at the high

- dose. Blood and plasma level concentrations were saturated following single oral doses at the low

- and high

doses (50 and 500 mg/kg) at 30 minutes. For low

- dose animals, ren al excretion was the primary route of elimination (58.3%) followed by the feces (17.2%). The remaining compound was recovered in the cage wash (24.4%). For the high

- dose animals, the proportions excreted per route were altered for the urine (16%), the fe ces (60.9%) compared to the low

- dose animals. The amount recovered in the cage wash was similar (24.1%) to the low

- dose group. Excretion of radioactivity in both the bile (  0.3% dose) and expired air (  0.1% dose) was minor for both the

low

- and high

- doses. The test material did not accumulate in the tissues. The primary excreta (both urine and feces) metabolite was identified as the free acid.

4 .2.1 Dermal Absorption

A guideline dermal absorption study is available for prohexadione calcium ; however, n o dermal toxicity was observed up to the limit dose of 1000 mg/kg/day and no dermal PODs have been

established.

4 .3 Toxicological Effects

By the oral route, the most sensitive effect in the prohexadione calcium hazard database is kidney toxic ity in dogs for both subchronic and chronic durations. Minor hematological changes (decreased white blood cell counts in males), and fore

- stomach hyperplasia were seen only at very high doses in rodents. No dermal toxicity was observed up to the limit do se of 1000 mg/kg/day. There was no evidence of neurotoxicity in either of the neurotoxicity screening batteries up to or exceeding the limit dose.

In rats and rabbits, no increased quantitative or qualitative pre

- or postnatal susceptibility was

observed . In rats, no maternal or developmental toxicity was observed up to the limit dose (1000 mg/kg/day). Three developmental studies in rabbits are available in the toxicological database for prohexadione calcium. In one study, late abortions occurred durin g GD 24

- 29 at 200 mg/kg/day, with increased mortality in maternal animals (GD 15

- 24) also noted at this dose. In another rabbit developmental study, two premature deliveries (on GD 24 and 26) were noted at the highest dose tested (350 mg/kg/day) with no d evelopmental effects observed. No maternal or developmental effects were seen in a third rabbit developmental study up to 150 mg/kg/day. In

the two

- generation reproductive toxicity study with rats, parental toxicity (minimal mortality)

occurred at a dose well below the dose that caused decreases in offspring body weight (3850 mg/kg/day).

Prohexadione calcium was categorized as having low acute lethality by the oral, dermal

, and

inhalation routes (Toxicity Categories III and IV). It is moderately irrit ating to the eyes and skin (Toxicity Category IV) and is not a dermal sensitizer.

4 .4 FQPA Considerations

The prohexadione calcium risk assessment team has determined that the FQPA SF can be reduced to 1X. The toxicology database for prohexadione calcium is adequate for characterizing toxicity and quantification of risk for food and non

- food uses. There is no evidence of neurotoxicity, no evidence of increased quantitative or qualitative susceptibility to offspring in both rats and rabbits, and no residual uncertainties in the exposure database.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 12 of 30 

### 4 .4.1 Completeness of the Toxicology Database

The existing toxicology database for prohexadione calcium is adequate for FQPA evaluation. Developmental toxicity studies in rats and rabbits, a two

- generation reproduction study in rats, and neurotoxicity studies in rats are available for FQPA consideration.

4 .4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the toxicological database for prohexadione calcium,

which include s acute and subchronic neurotoxicity studies.

4 .4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no residual uncertainties for pre

- and postnatal toxicity and there is no evidence of increased susceptibility of any k ind for fetuses and offspring (see section 3.3).

4 .4.4 Residual Uncertainty in the Exposure Database

The dietary and residential exposure analys e s are conservative and are not expected to underestimate exposure and risk. The dietary analysis assumed tolerance

- level residues, DEEM (ver. 7.81) default processing factors, 100% CT, and modeled drinking water estimates. The residential exposure analysis is conservative since it is based on the default assumptions from the

2012 Residential SOPs.

4 .5 Dose

- Response Assessment

The doses and toxicological endpoints selected for various exposure scenarios are summarized in

Tables 4 .5.3.1 and 4 .5.3.2. Since the last action, it was determined that a dermal risk assessment is not necessary due to; 1) no observed adverse dermal or systemic effects in the 28

- day dermal study in rats and; 2) there was no evidence of increased quantitative or qualita tive pre

- or postnatal sensitivity in the prohexadione calcium database.

4 .5.1 Recommendation for Combining Routes of Exposure for Risk Assessment

Based upon the different studies chosen and effects observed, incidental oral exposure cannot be

combined with inhalation exposure

.

4 .5.2 Cancer Classification and Risk Assessment Recommendations

Prohexadione calcium is classified as not likely to be carcinogenic to humans based on lack of evidence of carcinogenicity in rats and mice. A quantitative cancer risk assessment is not required.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 13 of 30 

### 4 .5.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Health Risk

Assessment

Table 4 .5.3.1 . Summary of Toxicological Doses and Endpoints for Prohexadione Calcium for Use in Dietary

and Residential Human Health Risk Assessments.

Exposure/

Scenario POD Uncertainty/FQPA Safety Factors RfD, PAD,

LOC for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (All populations) No endpoint attributable to a single dose and appropriate for the U.S. general population was seen

in the prohexadione calcium toxicological database ; therefore, an acute dietary POD for the general U.S. population was not established.

Chronic Dietary (All Populations) NOAEL =

20 mg/kg/day UF A = 10X

UF H = 10X FQPA SF= 1X Chronic RfD

= cPAD = 0.20 mg/kg/day Chronic toxicity

– dog.

LOAEL = 200 mg/kg/day based on histopathological changes in the kidneys (dilated basophilic tubules) and increased urinary volume and sodium concentration.

Incidental Oral Short (1

- 30 days)

- and

Intermediate (1

- 6 months)

- Term NOAEL =

80 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for

MOE = 100 90

- Day oral toxicity

– dog.

LOAEL = 400 mg/kg/day based on

moderate cortical areas of dilated basophilic tubules in the kidneys and decreased potassium levels.

Dermal Short

- (1

- 30 days)

and

Intermediate

Term (1

- 6 months) Short

- term and intermediate

- term dermal endpoints were not selected since there were no adverse

dermal or systemic effects observed in the 28

- day dermal study in rats . There was also no evidence of increased quantitative or qualitative pre

- or postnatal sensitivity in the prohexadione calcium database. There is therefore no concern for any duration of dermal exposure and no dermal endpoints are required.

Inhalation

Short

- (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL =

40 mg/kg/day

Inhalation

assumed equivalent

to oral UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for

MOE = 100 Prenatal Developmental Toxicity

– rabbit.

Maternal LOAEL = 200 mg/kg/day based on increased mortality, and abortions.

Cancer (oral, dermal, inhalation) “Not likely to be carcinogenic to humans” based upon lack of evidence of carcinogenicity in rats

and mice. No evidence of carcinogenic potential, therefore, cancer risk assessment is not required.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. LOAEL = lowes t

- observed adverse

- effect level. NOAEL = no

- observed adverse

- effect level. LOC =

level of concern. MOE = margin of exposure. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity am ong members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 14 of 30 Table 4 .5.3.2. Summary of Toxicological D oses and Endpoints for Prohexadione Calcium for Use in

Occupational Human Health Risk Assessments.

Exposure/

Scenario POD U F s LOC for Risk

Assessment Study and Toxicological Effects

Dermal Short

- (1

- 30 days) and

Intermediate

- Term (1

- 6 months) Short

- term and intermediate

- term dermal endpoints were not selected since there were no

adverse dermal or systemic effects observed in the 28

- day dermal study in rats. There was also no evidence of increased quantitative or qualitative pre

- or postnatal sensitivity in the prohexadione calcium database. There is therefore no concern for any duration of dermal exposure and no dermal endpoints are required.

Inhalation Short

- (1

- 30 days) and

Intermediate

- Term (1

- 6 months) NOAEL = 40

mg/kg/day

Inhalation

assumed equival ent to
oral

. UF A = 10X

UF H = 10X Occupational

LOC for MOE =

100 Prenatal d evelopmental t oxicity

– rabbit

Maternal LOAEL = 200 mg/kg/day based on increased mortality and

abortions.

Cancer (oral, dermal, inhalation) “Not likely to be carcinogenic to humans” based upon lack of evidence of carcinogenicity in

rats and mice. No evidence of carcinogenic potential, therefore, cancer risk assessment is not required. Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. LOAEL = lowest

- observed adverse

- effect level. NOAEL = no

- observed adverse

- effect level. LOC =

level of concern. MOE = margin of exposure. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies).



### 4

. 6 Cumulative Risk

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for prohexadione calcium and any other substances; and prohexadione calcium does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has assumed that prohexadione calcium does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

5 .0 E xposure Assessment and Characterization
Summary of Analytical Chemistry and Residue Data, pending, W. Wassell, D 419981 Chronic Dietary Exposure and Risk Assessment, pending, W. Wassell, D 425890 Memo, G. Kramer, 4/07/00; D 263502



### 5

. 1 Residues of Concern Summary and Rational

Based on apple and peanut metabolism studies, the HED MARC concluded that for these crops
parent compound (prohexadione calcium) is the only residue of concern for the tolerance expression and dietary risk assessment. Prohexadione calcium is rapidly metabolized to prohexadione and parent

- like oxidative intermediates and ultimately to tricarballylic acid, citric acid, and other natu ral products from the plant carbon pool. HED concludes that this decision may be translated to strawberry and watercress.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 15 of 30 

### A confined rotation crop study was submitted. No residues of prohexadione calcium or related metabolites were identified. Based on the results of this study, the HED MARC conclude d that the residues of concern in rotational crops is prohexadione calcium.

The qualitative nature of the residue in livestock is adequately understo od. In ruminants, prohexadione is metabolized to de spropionyl prohexadione metabolites or precursors and then to despropionyl prohexadione. The subsequent metabolism of despropionyl prohexadione then yields low molecular weight carboxylic acid and finall y incorporation into naturally occurring products such as sugars, lipids

, and proteins. In poultry, prohexadione is metabolized to tricarballylic acid and then to natural products such as proteins

. The HED MARC concluded that only the parent compound (pr ohexadione calcium) needs to be included in the tolerance expression for livestock and is the only compound to be included in the dietary assessments

.

The HED MARC concluded that only the parent compound needs to be included in the drinking

water risk assessments.

5 .2 Food Residue Profile

Prohexadione calcium is a plant growth regulato r proposed for use on strawberry and watercress. The product red uces vegetative growth, shoot growth, and produces a larger stem diameter (watercress). Prohexadione calcium works by inhibiting the biosynthesis of gibberellins, resulting in a decrease in cell elongation and a slowing of cell growth. Shoot reduction ma y cause positive benefits such as better light penetration, better fruit coloring, and better air flow within the plants. For watercress, prohexadione calcium may suppress growth for up to 14 days. For strawberries, vegetative growth suppression lasts fo r 2 to 5 weeks after application and does not affect vegetative growth the following year. The registered product, Apogee ® 

### Plant Growth Regulator (EPA Reg. No. 7969

- 188), is formulated as a DF containing 27.5% prohexadione

calcium

.

Tolerances are currently established under 40 CFR §180.547(a) for residues of prohexadione

calcium in/on sweet cherries, pome fruit, peanut, grass, and livestock commodities at levels ranging from 0.05 to 3.5 ppm.

The HED

- recommended tolerance s for res idues of the plant

- growth regulator, prohexadione

calcium are :

Strawberry

................................ ................................ 0.30 ppm

Watercress

................................ ................................ 4.0 ppm

Adequate crop field trial data are available for prohexadione calcium on strawberry and watercress. Based on the results of these trials, the appropri ate tolerance for residues of prohexadione calcium in/on strawberry is 0.3 0 ppm and in/on watercress is 4.0 ppm. A revised Section F is required.

5.3 Water Residue Profile

Memo, 1/30/2015, E. Seifu, et al . D419983



### Environmental fate and transport data indicate that prohexadione calcium is not persistent (laboratory and field half

- lives ranged from 1.4 to 23 days), but is moderately mobile in the soilProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 16 of 30 

### environment. Once prohexadione calcium has entered surface water, it is not likely to persist, degrading by chemical and biological processes including hydrolysis in acidic (half

- life 4.4 days at pH 5) and neutral (half

- life 65 days at pH 7) waters and photolysis (half

- life 9.9 days at pH 5, and 23.2 days in pH 9) in or near clear surface waters. The drinking water assessment was completed by EFED (Memo, 1/30/2015, E. Seifu, et al . D419983). The dietary

- exposure assessment was completed by HED (Memo, pending, W. Wassell, D 425890 ).

Drinking water residues were incorporated directly into the chronic dietary analysis (“water, direct, all sources” and “water, indirect, all sources”) and were provided by EFED . The EDWCs

were Tier 1 estimates for surface water using the Rice Model for prohexadi one calcium. The assessment is based on the maximum application rate of 0.1375 lb ai/A/application for watercress, applied using ground equipment with a second application 7 days after the initial application.

Table 5.3. Tier 1 EDWCs Resulting From Gr ound Applications of Prohexadione Calcium.

Drinking W ater
S ource (model) Use (modeled rate) Acute EDWC (ppb) Chronic EDWC

(ppb) 30

- year A verage

(ppb)

Surface water (Tier 1 Rice Model) Watercress (0.275 lb ai/A/year) 170 170 NR 1

Groundwater (SCIGROW) Turf (19.5 lbs ai/A/year) 0.137 0.137 NR

1 NR = not reported.



### An EDWC of 0.17 ppm was used in the chronic analysis.

5

. 4 Dietary Risk Assessment
Memo, pending, W. Wassell, D 425890



### There is no study with a single dose and endpoint appropriate for the acute scenario and there is no evidence of carcinogenic potential. Therefore, these risk assessments were not performed for prohexadione calcium.

A n unrefined prohexadione calcium chronic exposure and risk assessment was conducted using

DEEM

- FCID (ver. 3 .16) which incorporates food consumption data from USDA’s NHANES/WWEIA (2003

- 2008). The chronic analysis assumed DEEM (ver. 7.81) default processing factors, 100% CT, tolerance

- level residues for all commodities , and modeled drinking

water estimates

. The resulting chronic risk estimates are not of concern to HED. The most highly exposed population subgroup was children 1

- 2 years old utilizing 1 9 % of the cPAD. See

Table 5

. 4.1 for a summary of the results of the dietary assessment.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 17 of 30 Table 5

. 4.1. Summary of Dietary (Food and Drinking Water) Exposure Risk for Prohexadione Calcium

. 1

Population Subgroup cPAD (mg/kg/day) Chronic Dietary

Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population

0.20 0.007637 3.8 All Infants (<1 year old) 0.029740 15

Children 1

- 2 years old * 0.038201 19

Children 3

- 5 years old 0.022459 11

Children 6

- 12 years old 0.010120 5.1

Youth 13

- 19 years old 0.005035 2.5

Adults 20

- 49 years old 0.005172 2.6 Adults 50+ years old 0.005198 2.6

Females 13

- 49 years old 0.005329 2.7

* The population with the greatest risk estimate is bolded.



### 6.0 Residential (Non

- Occupational Exposure/Risk

Prohexadione calcium is currently registered for use on residential lawns, ornamentals, athletic fields, parks, and golf courses. There are no additional proposed residential uses at this time; however, the existing residential handler and post

- applicatio n uses that have been reassessed in this document to reflect current toxicology updates, as well as revisions to HED’s 2012

Residential SOPs 1 

### along with policy changes for body weight assumptions. The revision of residential exposures will impact the huma n health aggregate risk assessment for prohexadione

calcium. The algorithms used to estimate exposure and dose for residential handlers can be

found in the 2012 Residential SOPs 3



### .

Table 6.0 provides a summary of the existing residential uses for prohexad ione calcium.

Table 6.0. Summary of Use Directions for E xisting Residential uses of Prohexadione Calcium.

Crop Product,

Formulation Target of

Application Application

Equipment Maximum

Application

Rate Maximum

Application Rate per Year (Maximum

Number of Applications) Application timing

and Re

Treatment Interval (RTI)

Residential Uses

Turf grass GWN

- 6010

EPA Reg No.

10163

- 315

(Gowan Company

27.5% ai Dry flowable) Residential

lawns Manually

pressurized

handwand sprayer and hose

end sprayer 0.03 lb ai/A 19.5 lb ai/A (not provided) RTI: 3

- 4 week

intervals during

active Poa annua growth

Ornamentals Bedding plants and bedding plugs Manually

pressurized

handwand sprayer, hose

- end sprayer, and sprinkling can 0.008 lb

ai/gallon 1.8 lb ai/A

(2 per year) RTI: 1

- 2 weeks after

transplanting or 2

- 3 weeks after pinching

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

- exposure

- sop.htmlProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 18 of 30 

### 6

. 1 Residential Handler Exposure and Risk

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task as was described above for occupational handlers. 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 developed for residential handlers is based on the following scenarios: mixing/loading/applying DF formulations outdoors to turf and bedding plants via (1) manually pressurized handwand and (2) hose

- end sprayer.

There are no registered products that would lead to any residential handler risk estimates of

concern. Short

- term inhalation residential handler MOEs range from 63,000 to 8,400,000 (see Table 6.1).

Table 6.1 provides a summary of the existing residential uses for prohexadione calcium.

Table 6.1. Short

- Term Residential Handler Inhalation Exposure and Risk for Prohexadione Calcium.

Exposure Scenario Crop or Target Maximum

App Rate 1
(lb ai/A) Acres

Treated Daily 2 Baseline

Unit Exposure Baseline

Dose (mg/kg/day) Baseline

MOEs

Inhalation mg/lb ai Inhalation 3 Inhalation 4

Mixer/Loader/Applicator

M/L/A dry flowable formulation via Manually

pressurized handwand Turf grass 0.03 lb ai/A 1 acre 0.018 0.00048 84,000

Bedding plants 0.008

lb ai/gal 5 gallons 1.1 0.00064 63,000

M/L/A dry flowable

formulation via Hose

- end

sprayer Turf grass 0.03

lb ai/A 0.5 acres 0.022 0.0000048 8,400,000

Bedding plants 0.008

lb ai/gal 11 gallons 0.0014 0.0000018 22,000,000

1. Based on rates provided in previous assessment for a proposed label (EPA Reg. No. 10163

- GRL). 2. Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). The assumption for manually

- pressurized handwand applications to turfgrass is 5 gallons per the SOPs, h owever, a rate in terms of volume was not available for this reassessment. Therefore, an assumption of 1 acre treated per day was used. 3. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ BW (kg). 4. Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 19 of 30 

### 6.2 Residential Post

- application Exposure and Risk

Prohexadione calcium can be used in many areas that are frequented by t he general population including residential areas (e.g., home lawns and gardens). As a result, individuals can be exposed by entering these areas if they have been previously treated. Table 6.2 presents the post

application MOE values calculated for todd lers after turf applications of prohexadione calcium.

Post

- application non

- cancer risks do not exceed HED’s LOC for any of the scenarios assessed.

Table 6.2. Short

- Term Residential Post

- application Exposure and Risk for Prohexadione Calcium

Exposure Scenario Route of Exposure Application

Rate (lb ai/acre) MOE at Day 0 (L O C = 100)

Children (1 to <2 years old)
Hand to Mouth Activity on Turf

Incidental Oral 0.03 180,000

Object to Mouth Activity on Turf 5,800,000

Incidental Soil Ingestion 79,000,000



### 6.3 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to

individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meeti ngs/200 9/120109meeting.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 Registr ation Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

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

6.4 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) em ployed for prohexadione calcium. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result

of a Data Call

- In issued by EPA), EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 2 

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

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quanti fication of indirect non

- occupational exposure to drift.

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 20 of 30 

### 7 .0 A ggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and drinking water) and residential (dermal, inhalation, and incidental oral) sources. When aggregating exposures and risks from these sources, HED considers the route and duration of exposure as well as the toxicological effects for each route. Based on this and the proposed/registered uses, aggregate short

- term and chronic assessments were conducted.

7.1 Acute Aggregate Risk

An acute aggregate

- risk assessment was not performed because no appropriate endpoint was available to determine the aRfD for the general p opulation or any population subgroup.

7 .2 Short

- Term Aggregate Risk

The short

- term aggregate risk assessment estimates risks likely to result from exposure to prohexadione calcium residues from food, drinking water, and residential pesticide uses. Hi gh

end estimates of residential exposure are used, while average values are used for food and drinking water exposure. For the purpose of this human health risk assessment, a summary of

the worst

- case residential exposure estimates are provided in Table 7 .2.1.

Table 7.2.1. Recommendations for the Residential Exposures for the Prohexadione Calcium

Aggregate Assessment.

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

Inhalation Oral Total Inhalation Oral Total

Adult Manually

- pressurized

handwand applications to bedding plants 0.00064 N/A 0.00064 63,000 N/A 63,000

Child Hand

- to

- mouth

(exposure from applications to turf N/A 0.0005 0.0005 N/A 180,000 180,000

1 Dose = the highest dose for each applicable l ifestage of all residential scenarios assessed. Total = (Inhalation + Incidental Oral) where applicable.

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Inhalation MOE) + (1/Incidental Oral MOE) where applicable.



### Sh ort

- term aggregate risk is calculated in Table 7.2.2 below. All short

- term aggregate exposure estimates resulted in MOEs greater than 100, and were not of concernProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 21 of 30 Table 7.2.2 Short

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adults 50+ years

old 80 100 0.80 0.005198 0.00064 0.005838 14,000

Children 1 to < 2 years old 80 100 0.80 0.038201 0.0005 0.038701 2,100

1 The LOC includes the standard inter

- and intra

- species UF s (UF A and UF H , respectively) totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC.

3 Residential Exposure from Table 7.2.1.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure).

5 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential Exposure)].



### 7 .3 Intermediate

- Term and Chronic Aggregate Risk

Intermediate

- and long

- term aggregate risk assessments were not performed because there are no registered or proposed uses of prohexadione calcium that result in intermediate

- or long

- term residential exposures. T he chronic aggregate exposure assessment consists of exp osure from

food and water only . The chronic dietary exposure estimates were ≤ 1 9 % the cPAD and, therefore, do not exceed HED’s LOC (see Section 5.4 ).

8 .0 C umulative Risk

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for prohexadione calcium and any other substances; and prohexadione calcium does not appear to produce a toxic metabolite produced by other substances. For th e purposes of this tolerance action, therefore, EPA has assumed that prohexadione calcium does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to

determine which chemicals have a common mechanism of t oxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a comm on mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 .0 O ccupation Exposure

The proposed use s are for agricultural crop s ; therefore, there is potential for occupational handler and post

- application exposure. Application methods , maximum application rates, and use sites

are summarized in Table 3.3 . Occupational handler and post

- application exposure is expected and based on the use pattern and information provided on the labels, is expected to be short

- or intermediate

- term based on the use pattern and information provided on the labels

.

9 .1 Occupational Handler

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirementsProhexadione Calcium Human Health Risk Assessment DP# 425888

Page 22 of 30 

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

Based on the anticipated use pattern and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed agricultural use. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenario s
, which include mixing, loading, and applying a DF formulation of prohexadione calcium.

Occupational handler Exposure Scenarios

 Mixing/Loading a DF to support groundboom, airblast and chemigation applications ;

 Applying a D F with groundboom (strawberries only) and airblast (watercress only).

Note: Chemigation uses automated application methods ; therefore

, an application exposure scenario will not be assessed for that equipment.

Occupational Handler Exposure Data and Assumptions: A series of assumptions and exposure factors served as the basis for completing the occupational

handler risk assessments. Eac h assumption and factor is detailed below on an individual basis.

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 B.

Summ ary of Occupational Handler Non

- Cancer Exposure and Risk Estimates It is noted that no hazard was identified for dermal exposure (all durations); therefore a dermal assessment is unnecessary. A summary of the risk estimates, representative of label

- prescr ibed

p ersonal

- protective equipment ( PPE ) for mixers/loaders and applicators (i.e., baseline; no respirator) are provided in Table 9.1. The non

- cancer inhalation risk estimates for commercial mixer/loader and applicators are not of concern (i.e., MOEs ≥ 10 0).

Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Prohexadione

Calcium.

Exposure Scenario Crop or Target Inhalation

Unit Exposure (μg/lb ai) 1 Max. App.

Rate 2 (lbs ai/Acre) Area Treated or

Amount Handled Daily 3
(Acres) Inhalation

(LOC = 100)

Dose 4 (mg/kg/day) MOE 5

Mixer/Loader (

DF )

Groundboom Strawberries

8.96 (No Resp.) 0.0343 80 0.000357 110,000

Chemigation

Watercress 0.1375 350 0.00625 6,400

Airblast 40 0.000714 56,000

Applicator (D F

)

Groundboom Strawberries 0.34 (No Resp

. ) 0.0343 80 0.0000135 3,000,000Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 2 3 of 30 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Prohexadione

Calcium.

Exposure Scenario Crop or Target Inhalation

Unit Exposure (μg/lb ai) 1 Max. App.

Rate 2 (lbs ai/Acre) Area Treated or

Amount Handled Daily 3
(Acres) Inhalation

(LOC = 100)

Dose 4 (mg/kg/day) MOE 5

Airblast Watercress 4.71 0.1375 40 0.000375 110,000

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; l evel of mitigation: b aseline (no respirator).

2. PPE and m aximum application rates are based on proposed label (Reg. No. 7969

- 188). 3. Exposure Science Advisory Council Policy #9.1. 4. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (69 kg). 5. Inhalation MOE = Inhalation POD (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).



### 9 .2 Occupational Post

- Application Exposure

There are multiple potential sources of post

- applicati on inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency soug ht expert advice and input on issues related to volatilization of pesticides from its FIFRA 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

evalua ted the SAP report and has developed a volatilization

- s creening t ool and a subsequent

v olatilization s creening a nalysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

2014

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

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

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

- application inhalation exposure data generated by the Agricultural Reentry Task Force (ARTF). 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 assessme nts.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

In the case of this registration action, a dermal assessment was not performed since a dermal

hazard was not identified.

Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of prohexadione calcium.

Prohexadione calcium is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR § 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and p rimary skin irritation are assigned a 12

- hour REI. Therefore, the [ 40 CFR § 156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from
post

- application exposures to prohexadione

.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 24 of 30 cc: W. Wasse ll, (RAB1), A. Dunbar (RAB1) , J. Miller (RAB1)

RDI: Branch ( 03 / 05 / 2015 )Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 25 of 30 

### Appendix A. Toxicity Profile Tables

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for a food use and non

- food use for prohexadione calcium are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

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 (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

................................ .......................... Yes

Yes

Yes

Yes

NA

No 1 Yes

Yes

Yes

Yes

NA

- 870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . Yes

Yes

Yes Yes

Yes

Yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... Yes

No 2

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

Yes

Yes

Yes 870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. No

No

Yes

Yes

No -

-

Yes

Yes

No

870.7485 General Metabolism

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

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

................................ ............................. Yes

No

No 1 Yes

No

-

1 Studies are not required at this time based upon weight of evidence decisions by the HASPOC. Decisions

are discussed in detail in TXR#s 0056433 and 0056827.

2 Requirement fulfilled by 870.4300Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 26 of 30 Table A1. Acute Toxicity Data on Prohexadione Calcium Technical *.

Guideline No./ Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity rat 44457742 LD 50 >5000 mg/kg IV 870.1200 Acute dermal toxicity mouse 44457743 LD 50 >2000 mg/kg III 870.1300 Acute inhalation toxicity rat 44457744 LC 50 >4.21 mg/L IV 870.2400 Acute eye irritation rabbit 44457745 mild IV

870.2500 Acute dermal irritation rabbit 44457746 negative IV 870.2600 Skin sensitization guinea pig 44457747 negative NA *Prohexadione calcium technical (BX

- 112, 89.8% ai).

Table A2. Acute Toxicity Data on Prohexadione Calcium Formulation*.

Guideline No./Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity rat 44457736 LD 50 >5000 mg/kg IV

870.1200 Acute dermal toxicity mouse 44457737 LD 50 >2000 mg/kg III 870.1300 Acute inhalation toxicity rat 44457738 LC 50 >5.8 mg/L IV 870.2400 Acute eye irritation rabbit 44457739 M oderate III

870.2500 Acute dermal irritation rabbit 44457740 M oderate III 870.2600 Skin sensitization guinea pig 44457741 N egative NA *Prohexadione calcium formulation, BAS 125 08 W (74.9% ai).

Table A.2.2

. Subchronic, Chronic

, and Other Toxicity Profile

. Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 44457749, 44499902

(1991) Acceptable/guideline M: 0, 73.1, 734, 2270, 3924 mg/kg/day; F: 0, 80.4, 815, 2478, 4221 mg/kg/day. NOAEL: Males: 73.1 mg/kg/day; Females: 80.4 mg/kg/day.

LOAEL: Males: 734 mg/kg/day; Females: 815 mg/kg/day based on squamous cell hyperplasia

of the forestomach.

870.3100 90

- Day oral

toxicity (mouse) 44457750 (1991)

Acceptable/non

- guideline 0, 400, 2,000, 10,000, 50,000 ppm. (M: 0, 80, 389, 1986, 10,244 mg/kg/day; F: 0, 93, 454, 2256, 11,916 mg/kg/day.) NOAEL: Males:  10,244 mg/kg/day; Females:

 11,916 mg/kg/day (HDT). LOAEL: Males: >10,244 mg/kg/day; Females: >11,916 mg/kg/day.

870.3150 90

- Day oral

toxicity (dog) 44457752 (1997)

Acceptable/guideline M & F: 0, 80, 400, 2000 mg/kg/day. NOAEL = 80 mg/kg/day. LOAEL = 400 mg/kg/day based on moderate cortical areas of dilated basophilic tubules in the kidneys and decreased potassium levels.

870.3200 28

- Day dermal

toxicity (rat) 45430301 (2001)

Acceptable/ guideline

M & F: 0, 60, 300, 1000 mg/kg/day. NOAEL  1000 mg/kg/day.

LOAEL = not observed.

870.3700a Prenatal

developmental in (rat) 44457758, 44457757

(1990) Acceptable/guideline F: 0,100, 300, 1000 mg/kg/day. Maternal NOAEL  1000 mg/kg/day (limit dose);

LOAEL = not observed. Developmental NOAEL  1000 mg/kg/day (limit dose);

LOAEL = not observed.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 27 of 30 Table A.2.2

. Subchronic, Chronic

, and Other Toxicity Profile

. Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700b Prenatal

developmental in (rabbit) 44457760, 44457759

(1990) Acceptable/guideline F: 0, 40, 200, 750 mg/kg/day. Maternal NOAEL = 40 mg/kg/day;

LOAEL = 200 mg/kg/day based on increased mortality and abortions. Developmental NOAEL  200 mg/kg/day;

LOAEL = not observed.

(Due to severe mortality at 750 mg/kg/day, 200 mg/kg/day was deemed the high dose for evaluation.)

870.3700b Prenatal

developmental in (rabbit) 44457761 (1991)

Acceptable/guideline in conjunction with MRID

4457760 and 445776 2 F: 0, 30, 75, 150 mg/kg/day. Maternal NOAEL =  150 mg/kg/day;

LOAEL = not observed. Developmental NOAEL  150 mg/kg/day;

LOAEL = not observed.

870.3700b Prenatal

developmental in (rabbit) 44457762 (1992)

Acceptable/guideline F: 0, 30, 100, 350 mg/kg/da y. Maternal NOAEL = 100 mg/kg/day; LOAEL = 350 mg/kg/day based on premature

deliveries. Developmental NOAEL  350 mg/kg/day.

LOAEL = not observed.

870.3800 Reproduction and

fertility effects (rat) 44457764, 44457763

(1992) Acceptable/guideline M & F: 0, 35.5, 385, 3850 mg/kg/day. Parental/Systemic NOAEL = 35.5 mg/kg/day; LOAEL = 385 mg/kg/day based on increased mortality. Reproductive NOAEL  3850 mg/kg/day; LOAEL >3850 mg/kg/day. Offspring NOAEL = 385 mg/kg/day; LOAEL = 3850 mg/kg/day based on decreased pup body weight.

870.4100 Chronic toxicity

(dog) 44457755, 44457751

(1997) Acceptable/guideline M & F: 0, 20, 200, 1000 mg/kg/day. NOAEL = 20 mg/kg/day. LOAEL = 200 mg/kg/day based on histopathological changes in the kidneys (dilated basophilic tubules) and increased urinary volume and sodium concentrations.

870.4200 Carcinogenicity

(rat) 44457754 (1993)

Acceptable/guideline M: 0, 18.5, 93.9, 469, 968 mg/kg/day; F: 0, 22.3, 114, 572, 1180 mg/kg/day. NOAEL = 93.9 mg/kg/day. LOAEL = 469 mg/kg/day based on decreased

WBC in males.

No evidence of carcinogenicity.

870.4300 Carcinogenicity

(mouse) 44457756 (1992)

Acceptable/guideline M: 0, 55, 279, 2847, 5911 mg/kg/day; F: 0, 68, 351, 3489, 7334 mg/kg/day. NOAEL = 279 mg/kg/day. LOAEL = 2847 mg/kg/day based on decreased food utilization and microscopic changes in the

stomachs of males.

No evidence of carcinogenicity.

870.5100 Bacterial reverse

mutation assay (Ames test) 44457765 (1997)

Acceptable/guideline 312.5, 625, 1250, 2500, 5000 μg/plate. Negative with and without S

- 9 activation up to the HDT (5000 μg/plate).

870.5300 In vitro

mammalian gene mutation assay 44499903 (1992)

Acceptable/guideline 50 to 500 μg/mL (

- S9), 50 to 475 μg/mL (+S9) Negative with S

- 9 activation up to 475 μg/mL. Negative without S

- 9 activation up to 500 μg/mL. Compound tested to concentrations limited by solubility.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 28 of 30 Table A.2.2

. Subchronic, Chronic

, and Other Toxicity Profile

. Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5375 In vitro

mammalian

chromosome aberration (CHO cells) 44457768 (1997)

Acceptable/guideline 62.5 to 500 μg/mL (

- S9 and +S9). Increase in polyploidy in the absence of S9 activation at 500 μg/mL for 6 hours at the 24

- hour cell harvest time; effect not observed after

treatments of 24

- or 48

- hours. No increase in aberration frequency at any concentration or

harvest time with or wit hout S9. Compound was tested up to concentrations limited by solubility.

870.5395 Mammalian

erythrocyte

micronucleus test 44457767 (1997)

Acceptable/guideline 1250, 2500, 5000 mg/kg (oral gavage). Negative at 24

- , 48

- , and 72

- hour sacrifices.

No increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow.

870.5395 Mammalian

erythrocyte

micronucleus test 44457767 (1997)

Acceptable/guideline 1250, 2500, 5000 mg/kg (oral gavage). Negative at 24

- , 48

- , and 72

- hour sacrifices. No increase in the frequency of micronu cleated polychromatic erythrocytes in bone marrow.

870.5550 UDS in primary

rat hepatocytes 44499904 (1992)

Acceptable/guideline 5.0 to 500 μg/mL. Negative up to cytotoxic concentration (500 μg/mL).

870.5550 Rec assay with

Bacillus subtilis 44457766 (1997)

Acceptable/guideline 50 to 5000 μg/mL. Negative for DNA damage when tested up to the limit dose (5000 μg/mL) both with and

without S9.

870.6200a Acute

neurotoxicity screening battery 44457748 (1996)

Acceptable/guideline 0, 500, 1000, 2000 mg/kg. NOAEL  2000 mg/kg.

LOAEL = not observed.

870.6200b Subchronic

neurotoxicity screening battery 44457753 (1996)

Acceptable/guideline M: 0, 70, 285, 1148; mg/kg/day; F: 0, 85, 330, 1348 mg/kg/day. NOAEL  1148 (M) or 1348 (F) mg/kg/day.

LOAEL = not observed.

870.7485 Metabolism and

pharmacokinetics (rat) 44457770

- 44457773

(1993

- 95) Acceptable/guideline 50, 500 mg/kg. Following oral treatment of rats, prohexadione calcium was rapidly absorbed with highest

tissue/carcass concentrations obtained within 30 minutes; however, absorption became saturated at the highest dose. The test material

did not accumulate in the tissues. For low dose

ani mals, renal excretion was the primary route

of elimination. At the high dose, fecal excretion became the primary route of elimination. The primary excreta (both feces and urine) metabolite was identified as the free

acid.Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 29 of 30 

### Appendix B Occupational Ha ndler Exposure Calculations

1.0 Occupational Handlers

1.1 Occupational Handler Exposure Calculations

Occupational Non

- cancer Handler Algorithms

Potential daily exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug

where:

E = exposure (mg ai/day),

UE = unit exposure (μg ai/lb ai),

AR = maximum application rate according to proposed label (lb ai A or lb ai/gal), and

A = area treated or amount handled (e.g., A/day, gal/day).

The daily doses are calculated using the following formula:

ADD= E * AF

BW where :

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day),

E = exposure (mg ai/day),

AF = absorption factor (dermal and/or inhalation), and

BW = body weight (kg).

Margin of Exposure: Non

- cancer risk estimates for each application handler scenario are calculated using a M OE, which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers are compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers for each exposure route. All MOE values are calculated using the following formula:

MOE= PODADD

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),

POD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).Prohexadione Calcium Human Health Risk Assessment DP# 425888

Page 30 of 30 

### Appendix C Protection of Human Subjects of Research

Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as P esticide Handlers Exposure Database (PHED), Outdoor Residential Exposure Task Force (ORETF), Agricultural Handlers Exposure Task Force (AHETF), and the Agricultural Reentry Task Force (ARTF) databases. EPA has reviewed all the studies in these

multi

- pesti cide generic exposure databases, and based on available evidence has found them to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no reg ulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR §26) have been satisfied.

Appendix D. International Residue Limit (IRL) Status Form

Prohexadione Calcium (112600; 12/29/2014)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 2 Codex

40 CFR §180.547

Plant/Livestock:

calcium 3

- oxido

- 5

- oxo

- 4

- propionylcyclohex

- 3

- enecarboxylate calcium 3,5

- dioxo

- 4

- (1

- oxopropyl)cyclohexanecarboxyla

te None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex Strawberry 0.3

Watercress 4.0 Completed: M. Negussie; 12/30/14

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.