UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEM ICAL SAFETY AND 

POLLUTION PREVENT ION 

MEMORANDUM 

DATE: 

SUBJECT: 

05-MA Y-2015 

Prohexadione Calcium. Section 3 Registration for Use on Strawberry and 

Watercress. Human Health Risk Assessment. 

PC Code: 112600 DP Barcode: 0425888 

Decision No.: 489681 Ree:istration No.: 7969- 188 

Petition No.: 4£8264 Ree:ulatorv Action: Section 3 

Risk Assessment Type: 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' 

A

W1ll1am 

nwar Y. 

D. 

Dunbar

Wassell , Ph, Chem

.D., Pharmacologist 

ist fr'V#lf 1~ ' 

James S. Miller, Environmental Scienti~~lZ Risk Assessment Branch 1 (RAB I) ~ 

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

Thurston Morton, Acting Branch Chief ~ 1t 

George F. Kramer, Ph.D., Senior Chemist 

RAB 1/HED (7509P) 

Barbara Madden/Laura Nollen, RM 05 

Registration Division (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational/residential, and aggregate exposure assessments, 

as needed, to estimate the risk to human health that will result from the registered and proposed 

uses of the plant-growth regulator prohexadione calcium (calcium 3-oxido-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 calcium are provided in this document. The risk assessment, 

residue chemistry data review, and dietary-exposure assessment were provided by William 

Wassell (RAB I); the hazard characterization by Anwar Dunbar (RAB l); the 

occupational/residential exposure assessment by James Miller (RAB l); and the drinking water 

assessment by Edom Seifu, et al., of the Environmental Fate and Effects Division (EFED). 

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

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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 Recommendations............................................................................................ 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, Distribution, 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 .............................................. 30
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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1.0 Executive Summary

Prohexadione calcium is a plant-growth regulator proposed for use on strawberry 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 growth 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 formulated as a dry-flowable (DF) formulation 

containing 27.5% prohexadione calcium. 

Tolerances are currently established under 40 CFR §180.547(a) for residues of the plant growth 

regulator prohexadione calcium in/on sweet cherry, pome fruit, peanut, grass, and livestock 

commodities at levels ranging from 0.05 to 3.5 ppm. The proposed tolerances 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 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 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 premature 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-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. 

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 for 
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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intraspecies variation). The no-observed-adverse-effect level (NOAEL) 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 Safety Factor (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 tubules 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 

decreased 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 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. 

FQPA Decision

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF was reduced to 1X. That decision 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 evidence of treatment-related effects on the immune system; 4) there 

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 expected 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), 

(ver. 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-level 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 

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. 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 and 
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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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 pants, chemical resistant gloves, and shoes plus socks. The restrictedentry 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 on 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 expected 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 old) and did not exceed HED’s level of concern (LOC) for all residential postapplication 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 concern for all occupational postapplication 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 aRfD 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 residential 

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 Actions 
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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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 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, 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 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 determined 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 requirements under Submittal of Analytical 

Reference Standards), there are no residue chemistry, toxicological, or occupational/residential 

exposure issues that would preclude establishment 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 

levels specified below (Section 2.2.2).
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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 (ACB), 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 sent 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 calcium 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 

validated 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 determination 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 0.30

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 Cooperation 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 the 
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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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 prohexadione 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 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. The chemical structure and nomenclature for 

prohexadione calcium are presented in Table 3.1. 

3.1 Identification of Active Ingredient

Table 3.1. Test Compound Nomenclature.

Compound

O

CH3

O O

O

O

Ca2+

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 products (EP) Apogee® Plant Growth Regulator (EPA Reg. No. 7969-188)
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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 10-7torr at 20 °C

Dissociation constant, pKa 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 surfactant.

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 gallons) 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 to 
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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 residential 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 extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA under the 

NHANES/WWEIA (2003-2008) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, 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 risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

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 calcium, 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 

(Tmax). Maximum plasma concentrations (Cmax) were 78.3-78.5 μg/mL for both sexes at the low-
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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 highdoses (50 and 500 mg/kg) at 30 minutes. For low-dose animals, renal 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 feces (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, no 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 toxicity 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 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 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 during 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 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-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 irritating 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.
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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 includes 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 kind for fetuses and offspring (see section 3.3). 

4.4.4 Residual Uncertainty in the Exposure Database

The dietary and residential exposure analyses 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 qualitative 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.
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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

UFA = 10X

UFH = 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

UFA = 10X

UFH = 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 

IntermediateTerm (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 

IntermediateTerm (1-6 

months)

NOAEL = 

40 

mg/kg/day

Inhalation 

assumed 

equivalent 

to oral

UFA = 10X 

UFH = 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 = lowest-observed adverse-effect level. NOAEL = no-observed adverse-effect level. LOC = 

level of concern. MOE = margin of exposure. UF = uncertainty factor. UFA = extrapolation from animal to human 

(interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). UFL

= use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population-adjusted dose (a 

= acute, c = chronic). RfD = reference dose. 
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Table 4.5.3.2. Summary of Toxicological Doses and Endpoints for Prohexadione Calcium for Use in 

Occupational Human Health Risk Assessments.

Exposure/ 

Scenario POD UFs

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 

equivalent to 

oral.

UFA = 10X 

UFH = 10X

Occupational 

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 = lowest-observed adverse-effect level. NOAEL = no-observed adverse-effect level. LOC = 

level of concern. MOE = margin of exposure. UF = uncertainty factor. UFA = extrapolation from animal to human 

(interspecies). UFH = 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 Exposure Assessment and Characterization

Summary of Analytical Chemistry and Residue Data, pending, W. Wassell, D419981

Chronic Dietary Exposure and Risk Assessment, pending, W. Wassell, D425890 

Memo, G. Kramer, 4/07/00; D263502

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 natural products from the plant carbon pool. HED concludes that this decision 

may be translated to strawberry and watercress. 
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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 concluded that 

the residues of concern in rotational crops is prohexadione calcium.

The qualitative nature of the residue in livestock is adequately understood. In ruminants, 

prohexadione is metabolized to despropionyl prohexadione metabolites or precursors and then to 

despropionyl prohexadione. The subsequent metabolism of despropionyl prohexadione then 

yields low molecular weight carboxylic acid and finally 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 (prohexadione 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 regulator proposed for use on strawberry 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 growth 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 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 tolerances for residues 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 appropriate tolerance for residues of 

prohexadione calcium in/on strawberry is 0.30 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 soil 
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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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, D425890).

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 prohexadione 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 Ground Applications of Prohexadione Calcium.

Drinking Water 

Source (model)

Use

(modeled rate)

Acute EDWC

(ppb)

Chronic EDWC

(ppb)

30-year Average 

(ppb)

Surface water (Tier 1 

Rice Model)

Watercress

(0.275 lb ai/A/year)

170 170 NR1

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, D425890

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.

An 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 19% of the cPAD. See 

Table 5.4.1 for a summary of the results of the dietary assessment.
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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-application uses that have been reassessed in 

this document to reflect current toxicology updates, as well as revisions to HED’s 2012 

Residential SOPs1along with policy changes for body weight assumptions. The revision of 

residential exposures will impact the human 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 SOPs3.

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

Table 6.0. Summary of Use Directions for Existing 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 ReTreatment 

Interval (RTI)

Residential Uses

Turf grass GWN-6010

EPA Reg No. 

10163-315

(Gowan 

Company 

27.5% ai 

Dry flowable)

Residential 

lawns

Manuallypressurized 

handwand 

sprayer and hoseend 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

Manuallypressurized 

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.html
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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 Rate1

(lb ai/A)

Acres 

Treated 

Daily2

Baseline 

Unit 

Exposure

Baseline 

Dose

(mg/kg/day)

Baseline

MOEs

Inhalation

mg/lb ai Inhalation3

Inhalation4

Mixer/Loader/Applicator

M/L/A dry flowable 

formulation via Manuallypressurized 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, however, 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).
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6.2 Residential Post-application Exposure and Risk

Prohexadione calcium can be used in many areas that are frequented by the 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 postapplication MOE values calculated for toddlers 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

(LOC = 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 nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act

(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/meetings/2009/120109meeting.html). The 

Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological 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) employed 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 source of exposure in risk assessments 

for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide 

during the Registration Review process which ensures that all uses for that pesticide will be 

considered concurrently. The approach is outlined in the revised (2012) Standard Operating 

Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment 

Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document

outlines the quantification of indirect non-occupational exposure to drift.

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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7.0 Aggregate 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 population 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. Highend 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 MOE2

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 lifestage 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.

Short-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 concern
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Table 7.2.2 Short-Term Aggregate Risk Calculations

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

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 UFs (UFA and UFH, 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. The chronic aggregate exposure assessment consists of exposure from 

food and water only. The chronic dietary exposure estimates were ≤19% the cPAD and, 

therefore, do not exceed HED’s LOC (see Section 5.4). 

8.0 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 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 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/.

9.0 Occupation Exposure 

The proposed uses are for agricultural crops; 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 requirements 
Prohexadione Calcium Human Health Risk Assessment DP# 425888

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(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 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 scenarios, 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 DF 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. Each 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.

Summary 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-prescribed 

personal-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 ≥ 100).

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.

Rate2

(lbs ai/Acre)

Area Treated or 

Amount Handled Daily3

(Acres)

Inhalation

(LOC = 100)

Dose4

(mg/kg/day) MOE5

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 (DF)

Groundboom Strawberries 0.34

(No Resp.)

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

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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.

Rate2

(lbs ai/Acre)

Area Treated or 

Amount Handled Daily3

(Acres)

Inhalation

(LOC = 100)

Dose4

(mg/kg/day) MOE5

Airblast Watercress 4.71 0.1375 40 0.000375 110,000

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; level of mitigation: baseline (no respirator).

2. PPE and maximum 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-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its 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 

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-OPP2014-0219). 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 assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is 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 primary 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

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cc: W. Wassell, (RAB1), A. Dunbar (RAB1), J. Miller (RAB1)

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

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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

No1

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

No2

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

No1

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 870.4300
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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 LD50 >5000 mg/kg IV

870.1200 Acute dermal toxicity mouse 44457743 LD50 >2000 mg/kg III

870.1300 Acute inhalation toxicity rat 44457744 LC50 >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 LD50 >5000 mg/kg IV

870.1200 Acute dermal toxicity mouse 44457737 LD50 >2000 mg/kg III

870.1300 Acute inhalation toxicity rat 44457738 LC50 >5.8 mg/L IV

870.2400 Acute eye irritation rabbit 44457739 Moderate III

870.2500 Acute dermal irritation rabbit 44457740 Moderate III

870.2600 Skin sensitization guinea pig 44457741 Negative 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.
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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 4457762

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/day.

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.
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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 without 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 micronucleated 

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 

animals, 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

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Appendix B Occupational Handler 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 MOE, 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

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Appendix C Protection of Human Subjects of Research

Many such studies, involving exposure to many different pesticides, comprise generic pesticide 

exposure databases such as Pesticide 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-pesticide 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 regulatory 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 Mexico2 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

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 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.