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Team recommends that the points of departure (PODs) and safety factors (SFs) along with the 

Food Quality Protection Act (FQPA) SF be re-examined and a new risk assessment be 

completed, if necessary.

The residue chemistry database is sufficient to support the current registrations. No additional 

data are required at this time. The qualitative nature of prohexadione calcium residues in the 

registered primary crops and livestock is adequately understood based on acceptable apple, 

peanut, poultry, and goat metabolism studies. The parent compound is the only residue of 

concern for the tolerance expression and dietary risk assessment. Adequate analytical 

enforcement methods are available. Additionally, adequate magnitude of the residue data 

(primary and rotational crops, livestock, and processed commodities) are available to support all 

registered uses. 

The dietary exposure database is adequate to support existing registrations; however, a revised

assessment may be required if updated estimated drinking water concentrations (EDWCs) are 

provided by the Environmental Fate and Effects Division (EFED). The dietary risk assessment

may also need to be updated if the toxicological endpoints change and to reflect most recent 

consumption database.

The residential exposure database is adequate to support the Registration Review process for 

prohexadione calcium. Updated residential handler and post-application exposure assessments 

may be required under Registration Review based upon revisions to HED’s Residential Standard 

Operating Procedures (SOPs), and body-weight assumptions. In addition, revised residential 

handler and post-application assessments may be needed if toxicological endpoints change or 

other new data are received by the Agency that impact exposure estimates.

There is sufficient information available to assess aggregate exposure. A new aggregate 

exposure risk assessment that incorporates the updated dietary and/or residential exposure 

assessments may be required during Registration Review. This assessment should also take into 

account any changes to the toxicological endpoints or any other new data received by the 

Agency that impact exposure estimates.

The occupational exposure database is adequate to support the Registration Review process for 

prohexadione calcium. Updated occupational handler exposure assessments may be required 

under Registration Review based upon revisions to the Agency’s scenario-specific surrogate 

handler-exposure data. Reviewers should incorporate new exposure monitoring data, as 

necessary, during Registration Review. In addition, chemical-specific dislodgeable foliar residue 

(DFR) data are required for Registration Review of prohexadione calcium. Updated 

occupational post-application exposure assessments may be required under Registration Review 

based upon revisions to the Agency’s post-application exposure data. Revised occupational 

handler and post-application assessments may also be needed if toxicological endpoints change 

or other new data are received by the Agency that impact exposure estimates.

Hazard Identification/Toxicology

Prohexadione calcium is a plant growth regulator that works by inhibiting the biosynthesis of 

gibberellins, resulting in a decrease in cell elongation and a slowing of cell growth. 

Prohexadione calcium is classified as having low acute toxicity by the oral, dermal, and 
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inhalation routes (Toxicity Categories III-IV). It is moderately irritating to the eyes and skin and 

is not a dermal sensitizer. 

Prohexadione calcium was rapidly absorbed in rats, with highest concentrations obtained within 

30 minutes. Blood and plasma level concentrations were saturated at both single doses (50 and 

500 mg/kg) at 30 minutes, and the compound was rapidly excreted with 60.9% recovered in the 

feces, 16% recovered in the urine, and 24.1% recovered in the cage wash for the high dose. For 

low-dose animals (50 mg/kg), 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%). The test material did not accumulate in the tissues. The primary excreta (both urine 

and feces) metabolite was identified as the free acid. 

Following subchronic dietary exposures, no treatment-related effects were seen at doses up to the 

limit dose in mice. Forestomach hyperplasia was seen only at very high doses in rats, and 

kidneys were the target organ for toxicity in dogs. Following repeated dermal exposures for 28-

days, no toxicity was seen at the limit dose. There was no evidence of neurotoxicity following 

acute or subchronic exposures to rats.

Following chronic dietary exposures, toxicity was seen only at high doses in dogs, rats, and 

mice. There was no evidence of carcinogenicity in male and female mice or male and female 

rats. 

In the rat developmental toxicity study, no treatment-related maternal or developmental toxicity 

was seen at the limit dose. Three rabbit developmental toxicity studies are also available. No 

developmental toxicity was observed in any of the three studies in rabbits. Maternal toxicity 

manifested as increased mortality, abortions, premature deliveries, and decreases in body-weight 

gain only at the highest doses tested. In the reproductive toxicity study with rats, parental 

toxicity (minimal mortality) occurred at a dose lower than the dose that caused decreases in body 

weight of the offspring. No reproductive toxicity was seen at the highest dose tested in this 

study. These results indicate no quantitative or qualitative increase in susceptibility of rats or 

rabbits to in utero and/or post-natal exposure to prohexadione calcium.

Prohexadione was non-carcinogenic in both the rat and mouse. In accordance with the EPA 

Draft Guidelines for Carcinogen Risk Assessment (July 1999), prohexadione calcium is 

classified as “not likely to be carcinogenic to humans” based upon lack of evidence of 

carcinogenicity in rats and mice. 

Using a WOE approach, the HASPOC concludes, that a subchronic inhalation toxicity study is 

not required for prohexadione calcium at this time (TXR# 0056433). This approach considered 

all of the available hazard and exposure information, including: 1) the effects observed in the 

LC50 study were seen only at very high concentrations (the limit concentration or at twice that 

concentration); 2) no adverse effects were seen via the oral or the dermal routes in most studies, 

and for some studies effects were only seen at higher doses; 3) the parent is largely 

unmetabolized; and 4) high inhalation MOEs for occupational (1200 for mixing/loading 

activities for aerial application) and residential (730,000 for handlers) exposure scenarios. 

Once all data have been received and reviewed, the prohexadione calcium Registration Review 

Team recommends that the PODs and SFs used for risk assessment purposes be re-examined and 

a new risk assessment be completed, if necessary.
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Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

that may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of the most recent reregistration decision, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), prohexadione 

calcium is subject to the endocrine screening part of the Endocrine Disruptor Screening Program 

(EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Prohexadione 

Calcium is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Accordingly, as part of Registration Review, EPA will issue future 

EDSP orders/data call-ins, requiring the submission of EDSP screening assays for prohexadione 

calcium. For further information on the status of the EDSP, the policies and procedures, the list 

of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website: http://www.epa.gov/endo/

Conclusions

The toxicity database for prohexadione calcium is adequate to support the current registrations. 

The following critical study is currently missing from the database:

870.7800 Immunotoxicity

When the required study is submitted, the current toxicity endpoint/dose selection may need to 

be re-evaluated along with the FQPA SF for future risk assessments.
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Residue Chemistry

Prohexadione calcium is registered for application to several agricultural crops: pome fruit, 

peanuts, cherries, and grass. Tolerances are established for residues of prohexadione calcium

in/on these crops at 0.10-3.5 ppm in 40 CFR §180.547(a). There are also tolerances established 

for secondary residues of prohexadione calcium in/on livestock commodities at 0.05-0.10 ppm in 

40 CFR §180.547(a).

Based on apple and peanut metabolism studies, the HED Metabolism Assessment Review 

Committee (MARC) concluded that for these crops the parent compound is the only residue of 

concern for the tolerance expression and dietary risk assessment (Memo, G. Kramer, 4/07/00; 

DP# 263502). 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 also concluded that this decision can be translated to 

cherry.

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. Based on these data, the HED 

MARC concluded that for livestock the parent compound is the only residue of concern for the 

tolerance expression and dietary risk assessment (Memo, G. Kramer, 4/07/00; DP# 263502).

In the confined rotational crop study (conducted at 0.343 lb ai/A), residues of prohexadione 

calcium were <0.01 ppm in/on all rotational crop commodities planted at a 31-day plantback 

interval (PBI). Based on the results of this study, HED concluded that limited rotational field 

studies are not required and a 30-day PBI is appropriate.

HED notes that if other major uses are proposed in the future, then additional plant metabolism 

studies may be required. 

To measure residues of prohexadione calcium in plants, the petitioner developed a residue 

analytical method (D9601) using gas chromatography and a mass-selective detector (GC/MSD). 

The method was designed to measure residues of prohexadione calcium as the prohexadione 

methyl ester (designated by company codes BW 125-M7 or BW9054-M7). The reported level of 

quantitation (LOQ) for prohexadione calcium is 0.05 ppm for all apple, pear, and peanut 

commodities. The method was successfully validated by the Agency Analytical Chemistry 

Laboratories (ACL) in Fort Meade.

BASF Method 564/0 was developed for determination of residues of prohexadione in different 

plant and livestock matrices using liquid chromatography with tandem mass spectroscopy (LCMS/MS). Prohexadione is extracted using a mixture of acetonitrile and sulfuric acid. For cleanup, an ENV+ column is used. The final determination of prohexadione is performed by LCMS/MS. The results show that BASF method No. 564/0 is suitable to determine residues of 

prohexadione in the plant matrices cereal forage, grain, and straw; apple and lemon fruit, and 

rapeseed; as well as in the livestock matrices bovine muscle, liver, and kidney; milk; and eggs. 

The LOQ, defined by the lowest fortification level successfully tested, was 0.01 ppm in all 

sample materials. The limit of detection (LOD) was not determined.
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The extraction solution for Method 564/0 is the same as the current enforcement methods, 

Method D9810 and Method D9608, which were previously radiovalidated using samples from 

the peanut and ruminant metabolism studies, respectively (Memo, G. Kramer, 22-NOV-1999; 

D252547).

BASF Method 564/0 was successfully validated by an independent laboratory, Dr. Specht & 

Partner Chemische Laboratorien, GMBH. However, for wheat forage, wheat straw, and 

rapeseed samples, significant matrix effects were observed resulting in signal suppression by 

about 30 to 70%. Therefore, matrix-matched external standards were used for quantitation of 

these matrices. Based on these results, Method 564/0 is considered suitable for data gathering in 

plant and livestock commodities and for enforcement purposes in cherries, apple, wheat grain, 

milk, egg, liver, and meat as defined in SOP No. ACB-019 (9/15/08). Method 564/0 is not a 

suitable enforcement method for residues in wheat forage, wheat straw, and rapeseed.

The petitioner submitted data (MRID 44457802) concerning the recovery of residues of 

prohexadione metabolite using FDA Multiresidue Method protocols (PAM Vol. I). These data 

were forwarded to FDA for a complete evaluation (Memo, G. Kramer, 11/30/99; DP# 257930). 

The petitioner reported that residues of prohexadione are not recovered using FDA Multiresidue 

Method protocols.

The available storage stability data indicate that residues of prohexadione calcium are stable 

under frozen storage conditions in/on fortified apple fruit samples for at least 13 months and in 

peanut hay for up to 12 months. In peanut nutmeat, residues of prohexadione calcium initially 

declined (~50%) between 1- and 3-month intervals but stabilized (30-43% residue decline) at the 

6-, 9-, and 12-month intervals. 

Adequate nature and magnitude of the residue data (primary and rotational crops, livestock, and 

processed commodities) are available to support all registered uses. There are no outstanding 

issues related to the use directions and/or tolerances.

An adequate ruminant feeding study has been submitted. The estimated maximum dietary 

burden indicates a poultry feeding study is not required. 

Conclusions

The residue chemistry database is sufficient to support the current registrations. No additional 

data are required at this time. The qualitative nature of prohexadione calcium residues in the 

registered primary crops and livestock is adequately understood based on acceptable apple, 

peanut, poultry, and goat metabolism studies. The parent compound is the only residue of 

concern for the tolerance expression and dietary risk assessment. Adequate analytical 

enforcement methods are available. Additionally, adequate field trial, processing factor, and 

storage stability data are available. HED notes that if other major uses are proposed in the 

future, then additional plant metabolism studies may be required. 

Dietary Exposure

An acute dietary risk assessment has not been conducted for prohexadione calcium because an 

endpoint of concern attributable to a single dose was not identified. A chronic aggregate (food + 

dietary water) exposure and risk assessment was conducted using the Dietary Exposure 

Evaluation Model - Food Consumption Intake Database (DEEM-FCID , ver. 2.03). DEEM-
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FCID incorporates food consumption data from the United States Department of Agriculture 

(USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998). The 

unrefined chronic analysis assumed DEEMTM (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 2 estimates for surface water using the Pesticide Root Zone 

Model/Exposure Analysis Modeling System (PRZM/EXAMS) model for prohexadione calcium. 

The assessment is based on the maximum application rate of 0.75 lb ai/acre/application for turf, 

applied by ground foliar spray every 14 days (26 applications/year) to warm-season turf in CA. 

An EDWC of 0.0091 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. The resulting chronic risk estimate for children 1-2 years old (the 

subgroup with the greatest exposure) was 14% of the cPAD. A cancer dietary risk assessment 

was not performed because prohexadione calcium is classified as “not likely to be carcinogenic 

to humans.”

Conclusions

The dietary exposure database is adequate to support existing registrations. The most recent 

chronic dietary risk assessment was below HED’s level of concern (LOC) for the general U.S. 

population and all population subgroups examined. However, a revised dietary risk assessment 

may be required if updated EDWCs are provided by EFED. The dietary risk assessment may 

also need to be updated if the toxicological endpoints change and to reflect most recent 

consumption database.

Residential Exposure

Prohexadione calcium is currently registered for use on turf, including residential and 

commercial lawns, golf courses, sports fields, cemeteries, and sod farms. The product registered 

for use is GWN-6010 Plant Growth Regulator (EPA Reg. #10163-315). This product is a dryflowable (DF) formulation containing 27.5% active ai. Based on a review of the currently 

registered label, both residential handler and post-application exposures are anticipated. This 

product was assessed in 2010 (Memo, G. Kramer et al., 30-MAR-2010, D367842) and no risks 

of concern were identified for either residential handlers or for persons entering areas previously 

treated with prohexadione calcium. 

Since 2010, however, HED’s Residential SOPs have been revised, and there have been Agency 

policy changes for body-weight assumptions. Therefore, a revised residential exposure 

assessment may be needed to support Registration Review. For residential handlers, the 

following scenarios may need to be assessed:

1) mixer/loader/applicator (M/L/A) of DFs with manually-pressurized handwand, 

2) M/L/A of DF with hose-end sprayer, 

3) M/L/A of DF with backpack sprayer, and 

4) M/L/A of DF with sprinkler can. 

For residential post-application exposure, the following scenarios may need to be assessed: 

1) dermal post-application exposure for adults doing physical activities on turf, mowing,

and golfing, 

2) dermal post-application exposure for children (11 to <16 years old) golfing and mowing, 

3) dermal post-application exposure for children (6 to <11 years old) golfing, 
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4) dermal post-application exposure for children (1 to <2 years old) playing on turf, and 

5) incidental oral post-application exposure for children (1 to <2 years old) playing on turf.

Spray Drift 

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may 

occur as a result of applications of prohexadione calcium. The Agency is in the process of 

evaluating these types of exposures and will examine the need for spray drift and volatilization 

assessments for prohexadione calcium during registration review.

Conclusions

The residential exposure database is adequate to support the Registration Review process for 

prohexadione calcium. Updated residential handler and post-application exposure assessments 

may be required under Registration Review based upon revisions to HED’s Residential SOPs, 

and body weight assumptions. In addition, revised residential handler and post-application 

assessments may be needed if toxicological endpoints change or other new data are received by 

the Agency that impact exposure estimates.

Aggregate Risk Assessment

The most recent aggregate assessment was completed in 2011 (Memo, G. Kramer et al., 13-

OCT-2011, D384103) in conjunction with a registration request for use on cherries. Aggregate 

exposure risk assessments were assessed 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.”

The total short-term food and residential aggregate MOEs are ≥340. As this MOE is greater than 

100, the short-term aggregate risks do not exceed HED’s LOC. Since there are no 

registered/proposed uses that result in chronic residential exposure, the chronic aggregate 

exposure assessment consists of exposure from food and drinking water only. The chronic 

dietary exposure estimates were ≤14% the cPAD and, therefore, do not exceed HED’s LOC.

Conclusions

There is sufficient information available to assess aggregate exposure. A new aggregate 

exposure risk assessment that incorporates the updated dietary and/or residential exposure 

assessments may be required during Registration Review. This assessment should also take into 

account any changes to the toxicological endpoints or any other new data received by the 

Agency that impact exposure estimates.

Occupational Exposure

Prohexadione-calcium is registered for several agricultural uses including uses on peanuts, 

apples, grass grown for seed, pears, sweet cherries, and sod farms. The registered products 

include: Baseline Plant Regulator (EPA Reg. #7969-189), Apogee®Plant Growth Regulator 
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(EPA Reg. #7969-188), and GWN-6010 Plant Growth Regulator (EPA Reg. #10163-315). All 

registered products are DF formulations. It is also registered for use on turf, including residential 

and commercial lawns, golf courses, sports fields, cemeteries, and sod farms. The product 

registered for use is GWN-6010 Plant Growth Regulator (EPA Reg. #10163-315). This product 

is a DF formulation containing 27.5% ai. Based on a review of the currently registered labels, 

occupational handler and post-application exposures are anticipated. These products were 

assessed previously, and no risks of concern were identified. Since the previous reviews, 

however, there have been several updates to HED’s exposure policies, including:

Updated exposure data for occupational handler assessments; 

Updates to body-weight assumptions; and

Updated exposure data for occupational post-application assessments.

Occupational Handlers: The major exposure scenarios identified and assessed previously 

include:

Mixer/Loaders

Mixing/loading DFs for aerial application; 

Mixing/loading DFs to support groundboom applications,

Mixing/loading DFs to support airblast applications,

Mixing/loading DFs to support lawn-care operator (LCO) handgun applications,

Applicators

Applying sprays with aerial equipment 

Applying sprays with groundboom sprayer,

Applying sprays with airblast sprayer,

Applying sprays with handgun sprayer,

Flaggers

Flaggers for aerial applications,

Mixer/Loader/Applicators

Mixing/loading/applying liquids with low-pressure handwand sprayer (surrogate for 

DFs),

Mixing/loading/applying liquids with backpack sprayer (surrogate for DFs), 

Mixing/loading/applying DFs with handgun sprayer, and

Mixing/loading/applying liquids with a sprinkling can (surrogate for DFs).

These scenarios were assessed using the maximum application rate from the proposed label, 

exposure data from Pesticide Handlers Exposure Database (PHED) Ver. 1.1, and assumptions for 

area treated from Science Advisory Council for Exposure (ExpoSAC) Policy #9. Provided 

handlers wore gloves as recommended on the labels, all occupational exposure scenarios 

assessed previously resulted in MOEs above HED’s LOC (i.e., 100). 

Occupational Post-application: All post-application activities associated with the registered 

crops (peanuts, apples, grass grown for seed, pears, sweet cherries, and sod farms) as identified 

in ExpoSAC Policy #3 were assessed previously using the maximum application rate proposed 

on the labels. No risks of concern were identified (i.e., MOEs > HED’s LOC of 100).
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In accordance with the updated Part 158 data requirements (2007), a turf-transferrable residue 

(TTR) study is required for all occupational (e.g., sod farms) or residential turf uses. As part of 

the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for 

Residential Pesticide Exposure Assessment, HED analyzed all of the available TTR data and 

selected new liquid and granular default values for the fraction of the application rate available 

for transfer after a turf application (FAR). This default is 1% for formulations applied as liquids. 

Of the available TTR studies submitted to the Agency, the maximum FAR value seen using a 

liquid product was 6.1% or 6.1 times higher than the default residue transfer value. Therefore, 

HED has decided that a calculated MOE of approximately 10 times higher than the LOC (e.g., an 

MOE >1,000 if the LOC = 100) using the default residue transfer values would provide an 

adequate margin of safety for any potentially higher residues seen in a chemical-specific TTR 

study (ExpoSAC Memo, 6/7/12, “Guidance for Requiring/Waiving Turf Transferrable Residue 

(TTR) and Dislodgeable Foliar Residue (DFR) Studies”). For the current uses of prohexadione 

calcium, a TTR study will not be required for Registration Review since estimated dermal MOEs 

for occupational workers exposed to treated sod are greater than 1000. If the use pattern and/or 

toxicological points of departure change in the future, this requirement may be revisited.

Also in accordance with the updated Part 158 data requirements (2007), one or more DFR 

studies are required when a pesticide has residential or occupational uses that could result in 

post-application dermal exposure. HED analyzed a number of DFR studies and selected a new 

default value for the fraction of the application rate available to be dislodged after a foliar 

application (FAR). This default value is 25%. Of the analyzed DFR studies, the maximum FAR

value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, a 

calculated MOE of approximately 4 times higher than the LOC (i.e., an MOE >400 if the LOC = 

100) using the default dislodged residue value would provide an adequate margin of safety for 

any potentially higher residues seen in a chemical-specific DFR study (ExpoSAC Memo, 6/7/12, 

“Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar 

Residue (DFR) Studies”). A DFR study (875.2100) for prohexadione calcium will be required 

for Registration Review since estimated dermal MOEs for occupational workers exposed to 

treated foliage (specifically for activities associated with apple and pear trees) are less than 400.

Conclusions

The occupational exposure database is adequate to support the Registration Review process for 

prohexadione calcium. Updated occupational handler exposure assessments may be required 

under Registration Review based upon revisions to the Agency’s scenario-specific surrogate 

handler exposure data (http://www.epa.gov/pesticides/science/handler-exposure-table.pdf). 

Reviewers should incorporate new exposure monitoring data, as necessary, during Registration 

Review. In addition, as noted above, chemical-specific DFR data are required for Registration 

Review of prohexadione calcium. Updated occupational post-application exposure assessments 

may thus be required under Registration Review based upon revisions to the Agency’s postapplication exposure data. Revised occupational handler and post-application assessments may 

also be needed if toxicological endpoints change or other new data are received by the Agency 

that impact exposure estimates.

Public Health and Pesticide Epidemiology Data

A summary report listing incidents for prohexadione calcium reported to the Office of Pesticide 

Programs (OPP) Incident Data System (IDS) has been provided for the docket (Memo, S. 

Recore, 30-AUG-2012; D404919). The report represents incidents occurring in the U.S. from 
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2007 to the present.

Because there are no incident cases reported for prohexadione calcium in either the Main or 

Aggregate IDS, there does not appear to be a concern at this time that would warrant further 

investigation. The Agency will continue to monitor the incident information and if a concern is 

triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §180.547) and maximum residue limits (MRLs) are 

summarized in Attachment 3. 

Conclusions

Residue definitions and MRLs for prohexadione calcium have not been established by Codex. 

The U.S. and Canadian residue definitions are harmonized. Tolerance/MRL levels for residues 

in apples and ruminant meat byproducts, except kidney are harmonized with Canada. The U.S. 

tolerance level for residues in ruminant kidney is not harmonized with the Canadian MRL level 

for residues in ruminant meat byproducts. There are several U.S. tolerances for which there are 

no Canadian MRLs (cherry, peanut, grass). Canada has established MRLs for residues in milk

and ruminant meat and fat; however, U.S. tolerances are not established for residues in these 

livestock commodities. Mexico adopts U.S. tolerances and/or Codex MRLs for export purposes. 

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

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

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

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

Cumulative 

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 
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cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

Human Studies

Past prohexadione calcium risk assessments rely in part on data from studies in which adult 

human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as PHED and the Agricultural Reentry 

Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multipesticide generic exposure databases, and has found no clear and convincing evidence that the 

conduct of any of them was either fundamentally unethical or significantly deficient relative to 

the ethical standards prevailing at the time the research was conducted. All applicable 

requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 

26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

Data Requirements Required Under Registration Review

Data needs required under Registration Review for prohexadione calcium are as follows:

Toxicology:

Immunotoxicity (870.7800).

Occupational/Residential Exposure:

Chemical-specific DFR data are required for Registration Review of prohexadione 

calcium (875.2100). Updated occupational post-application exposure assessments may 

be required under Registration Review based upon revisions to the Agency’s postapplication exposure data. 

Risk Assessment Updates Required Under Registration Review

Risk assessment updates required under Registration Review for prohexadione calcium are as 

follows:

Toxicology:

When the required immunotoxicity study is submitted, the current toxicity endpoint/dose 

selection may need to be re-evaluated along with the FQPA SF for future risk 

assessments.

Residue Chemistry/Dietary Exposure:

A revised dietary risk assessment may be required if updated EDWCs are provided by 

EFED. The dietary risk assessment may also need to be updated if the toxicological 

endpoints change and to reflect most recent consumption database.

A new aggregate exposure risk assessment that incorporates the updated dietary and/or 
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

Page 14 of 24

residential exposure assessments may be required during Registration Review. This 

assessment should also take into account any changes to the toxicological endpoints or 

any other new data received by the Agency that impact exposure estimates.

Occupational/Residential Exposure:

Updated residential handler and post-application exposure assessments may be required 

under Registration Review based upon revisions to HED’s Residential SOPs, and bodyweight assumptions. In addition, revised residential handler and post-application 

assessments may be needed if toxicological endpoints change or other new data are 

received by the Agency that impact exposure estimates.

Updated occupational handler exposure assessments may be required under Registration 

Review based upon revisions to the Agency’s scenario-specific surrogate handlerexposure data.

Revised occupational handler and post-application assessments may also be needed if 

toxicological endpoints change or other new data are received by the Agency that impact 

exposure estimates.

References

Table 1. Memoranda Relevant to Registration Review.

Author Barcode Date Title

G. Kramer 252547 & 

253640 22-NOV-1999

PP# 8F04941. New Chemical- Prohexadione calcium, in/on 

Peanuts, Pome Fruits, and Cattle Meat Byproducts (Kidney). 

Evaluation of Residue Data and Analytical Methods.

G. Kramer 257931 30-NOV-1999 Multiresidue Method Testing of Prohexadione calcium.

G. Kramer 262930 14-FEB-2000 Prohexadione calcium. Issues to be Presented to the HED 

Metabolism Assessment Review Committee Meeting on 2/22/00.

G. Kramer 264488 & 

264533 07-APR-2000

PP# 8F04941. Prohexadione calcium, in/on Peanuts, Pome Fruits, 

and Cattle Meat Byproducts (Kidney). Review of Amendments 

Dated 2/18/00 & 3/16/00 Submitted in Response to HED’s 

Memo of 11/22/99.

D. Vogel 264281 12-APR-2000 Occupational and Residential Exposure and Risk 

Assessment/Characterization for Prohexadione.

J. Kidwell, et al.

246724, 

263660, 

264539

19-APR-2000 PP#8F4941. PROHEXADIONE CALCIUM IN/ON PEANUTS 

AND POME FRUITS. HED Risk Assessment.

J. Smith 267887 12-MAR-2001

PP# 0F6127. New Use of Prohexidione [sic] Calcium on Grass 

Grown for Seed (MRID# 451262-01) - Residue Chemistry 

Review.

G. Kramer 273292 13-MAR-2001

PP# 8F04941. Prohexadione calcium in/on Peanuts, Pome Fruits, 

and Meat Byproducts. Results of Petition Method Validation 

(PMV).

G. Kramer 273510 10-APR-2001

ID# 007969-00208. PP# 8F04941. Prohexadione calcium in/on 

Peanuts, Pome Fruits, and Livestock Commodities. Review of 

Amendment Dated 8/15/00 Submitted in Response to HED’s 

Memo of 4/7/00. Request for Reconsideration of Additional Data 

Requirements.

M. Dow 264281 02-MAY-2001 Occupational Exposure/Risk Assessment for the Use of 

Prohexadione calcium on Grass Grown for Seed.

J. Smith 275867 05-MAY-2001 PP# 0F6127. New Use of Prohexadione Calcium on Grass Grown 

for Seed- Human Health Risk Assessment ADDENDUM
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Table 1. Memoranda Relevant to Registration Review.

Author Barcode Date Title

G. Kramer, et al. 367842 30-MAR-2010

Prohexadione Calcium. Proposed Use on Commercial and 

Residential Turf, Golf Courses, Sod Farms, and Ornamental 

Bedding Plants and Bedding Plant Plugs. Preliminary HumanHealth Risk Assessment.

K. Lowe 368151 01-APR-2010

Prohexadione Calcium; Occupational and Residential Risk 

Assessment for Proposed Use of Prohexadione Calcium on 

Commercial and Residential Turf, Golf Courses, Sod Farms, and 

Ornamental Bedding Plants and Bedding Plant Plugs.

A. Nowotarski 384708 25-APR-2011

Prohexadione Calcium: Occupational and Residential 

Exposure/Risk Assessment for Proposed New Use on Sweet 

Cherries.

G. Kramer 384707 17-MAY-2011 Prohexadione Calcium. Section 3 Registration for Use on Sweet 

Cherries. Chronic Dietary Exposure and Risk Assessment. 

G. Kramer 384706 02-JUN-2011 Prohexadione Calcium. Section 3 Registration for Use on Sweet 

Cherries. Summary of Analytical Chemistry and Residue Data.

G. Kramer, et al. 384103 13-OCT-2011 Prohexadione Calcium. Section 3 Registration for Use on Sweet 

Cherries. Human-Health Risk Assessment.

J. Van Alstine TXR# 

0056433 14-SEP-2012

Prohexadione Calcium: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of August 2, 2012: 

Recommendations on the Requirement of a Subchronic Inhalation 

Study for Prohexadione Calcium.

S. Recore 404919 30-AUG-2012 Prohexadione calcium: Review of Human Incidents

Attachments

Attachment 1: Chemical Identity Table.

Attachment 2: Prohexadione Calcium Endpoint Selection Tables.

Attachment 3: Exposure Potential for Adult and Child Aggregate Risk Estimates.

Attachment 4: Prohexadione Calcium International Residue Limit Status. 

Attachment 5: Toxicity Profile Tables

cc: K. Lowe (RAB1), G. Kramer (RAB1), A. Dunbar (RAB1)

RDI: RAB1 (8/15/12), D. Vogel (8/13/12), J. Rowland (9/10/12)

G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

Page 16 of 24

Attachment 1: Chemical Identity Table.

Table A.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 3-oxido-5-oxo-4-propionylcyclohex-3-enecarboxylate

CAS name calcium 3-oxido-5-oxo-4-propionylcyclohexa-3-enecarboxylate

CAS registry number 127277-53-6

End-use products (EP) Apogee®Plant Growth Regulator (EPA Reg. No. 7969-188)
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Attachment 2: Prohexadione Calcium Endpoint Selection Tables.

(From Memo, G. Kramer et al., 13-OCT-2011, D384103)

Table A2.1a. Summary of Toxicological Doses and Endpoints for Prohexadione Calcium.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA SFs

RfD, PAD, 

LOC for Risk 

Assessment Study and Toxicological Effects

Acute Dietary 

(All 

Populations)

NA NA NA There is no study with a single dose and 

endpoint appropriate for this scenario. 

Therefore, this risk assessment was not 

performed.

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 Na+ion 

concentrations.

Incidental Oral 

Short (1-30 

days)- and 

Intermediate 

(1-6 months)-

Term 

NOAEL = 80 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for 

MOE = 100

(Residential)

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 Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

Oral Maternal 

NOAEL = 40 

mg/kg/day

Estimated 

absorption 

rate 25%1

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Prenatal Developmental Toxicity –

Rabbit

LOAEL = 200 mg/kg/day based on 

increased mortality, abortions, and 

decreased maternal body-weight gain.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days, and 1-6 

months)

Oral Maternal 

NOAEL = 40 

mg/kg/day

(inhalationabsorption 

rate = 100%)

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Prenatal Developmental Toxicity –

Rabbit

LOAEL = 200 mg/kg/day based on 

increased mortality, abortions, and 

decreased maternal body-weight gain.

Cancer (oral, 

dermal, 

inhalation)

No evidence of carcinogenic potential; therefore, a cancer risk assessment is not required.

UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), FQPA SF = FQPA Safety 

Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, 

PAD = population-adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of 

exposure, LOC = level of concern, NA = not applicable.

1

25% Dermal-absorption factor – Derived from HIARC report 112600HA.002.
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Table A2.1b. Summary of Toxicological Doses and Endpoints for Prohexadione Calcium for Use in 

Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA SFs

RfD, PAD, 

LOC for Risk 

Assessment Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

Oral Maternal 

NOAEL = 40 

mg/kg/day

Estimated 

absorption 

rate 25%1

UFA = 10X

UFH = 10X

FQPA SF = 1X

Occupational 

LOC for 

MOE = 100

Prenatal Developmental Toxicity –

Rabbit

LOAEL = 200 mg/kg/day based on 

increased mortality, abortions, and 

decreased maternal body-weight gain.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days, and 1-6 

months)

Oral Maternal 

NOAEL = 40 

mg/kg/day

(inhalationabsorption 

rate = 100%)

UFA = 10X

UFH = 10X

FQPA SF = 1X

Occupational 

LOC for 

MOE = 100

Prenatal Developmental Toxicity –

Rabbit

LOAEL = 200 mg/kg/day based on 

increased mortality, abortions, and 

decreased maternal body-weight gain.

Cancer (oral, 

dermal, 

inhalation)

No evidence of carcinogenic potential; therefore, a cancer risk assessment is not required.

UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), FQPA SF = FQPA Safety 

Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, 

PAD = population-adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of 

exposure, LOC = level of concern, NA = not applicable.

1

25% Dermal-absorption factor – Derived from HIARC report 112600HA.002.
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Attachment 3: Exposure Potential for Adult and Child Aggregate Risk Estimates.

(From Memo, G. Kramer et al., 13-OCT-2011, D384103)

Table A3.1. Summary of Dietary (Food and Drinking Water) Exposure Risk for Prohexadione Calcium.

1

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population

NA NA

0.004064 2.0

NA NA

All Infants (<1 year old) 0.022988 12

Children 1-2 years old 0.028369 14

Children 3-5 years old 0.017364 8.7

Children 6-12 years old 0.006133 3.1

Youth 13-19 years old 0.002154 1.1

Adults 20-49 years old 0.001551 <1.0

Adults 50+ years old 0.001860 <1.0

Females 13-49 years old 0.001772 <1.0

1

 The values for the highest exposed population subgroup are bolded.

NA = not applicable.

Table A3.2. Short-Term Aggregate Risk for Residential Handlers. 

Population LOC Dietary MOE1Inhalation2 Dermal MOE MOEtotal

2

General U.S. Population MOE <100 9844 3,700,000 350 340

1

 Dietary MOE = short-term NOAEL ÷ chronic dietary exposure.

2

 MOEtotal = 1 ÷ ((1÷MOEdietary) + (1÷MOEInhalation) + (1÷MOEdermal )); MOE >100 indicates an acceptable exposure. 

Table A3.3. Short-Term Aggregate Risk for Post-application Exposures. 

Population LOC Dietary MOE1Incidental Oral MOE2 Dermal MOE MOEtotal

2

General U.S. Population

MOE 

<100

9844 -- 11,000 5200

Children 1-2 yrs. old 

(Dermal Activities) 1410 -- 14,000 1300

Children 1-2 yrs. old (Hand 

to Mouth Activities) 2820 180,000 -- 2820

Youth 13-19 yrs old 18,578 -- 7400 5300

1

 Dietary MOE = short-term NOAEL (incidental oral = 80 mg/kg/day, oral = 40 mg/kg/day) ÷ chronic dietary exposure.

2

 MOEtotal = 1 ÷ ((1÷MOEdietary) + (1÷MOEincidental oral) OR (1÷MOEderaml )); MOE >100 indicates an acceptable exposure. 
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Attachment 4: International Residue Limits. 

Prohexadione Calcium (112600; 7/16/12)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.547

Plants/Livestock: (a) General. Tolerances 

are established for residues of the growth 

regulator, prohexadione calcium, including 

its metabolites and degradates, in or on the 

commodities in the table below. 

Compliance with the tolerance levels 

specified below is to be determined by 

measuring only prohexadione calcium 

(calcium 3-oxido-5-oxo-4-

propionylcyclohex-3-enecarboxylate) in or 

on the following commodities.

calcium 3,5-dioxo-4-(1-

oxopropyl)

cyclohexanecarboxylate

None

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

US Canada Mexico2 Codex3

Cattle, kidney 0.10 0.05 meat byproducts of 

Cattle, meat byproducts, except cattle

kidney

0.05

Cherry, sweet 0.40

Fruit, pome, group 11 3.0 3.0 apples

Goat, kidney 0.10 0.05 meat byproducts of 

Goat, meat byproducts, except goats

kidney

0.05

Grass, forage10.10

Grass, hay10.10

Grass, seed screenings13.5

Grass, straw11.2

Hog, kidney 0.10 0.05 meat byproducts of 

Hog, meat byproducts, except hogs

kidney

0.05

Horse, kidney 0.10 0.05 meat byproducts of 

Horse, meat byproducts, except horses

kidney

0.05

Peanut 1.0

Peanut, hay 0.60

Sheep, kidney 0.10 0.05 meat byproducts of 

Sheep, meat byproducts, except sheep

kidney

0.05

MRLs with NO US Equivalent

Fat of cattle 0.05

Fat of goats 0.05

Fat of hogs 0.05

Fat of horses 0.05

Fat of sheep 0.05

Meat of cattle 0.05

Meat of goats 0.05

Meat of hogs 0.05
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Meat of horses 0.05

Meat of sheep 0.05

Milk 0.01

Completed by: M. Negussie; 07/18/2012 

1 Registration is limited to grass grown for seed. 

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

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Attachment 5: Toxicity Profile Tables

Table A5.1. 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 A5.2. 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 A5.3. Toxicity Profile of Prohexadione Calcium.

Guideline No./ Study 

Type

MRID No./ (year)/ 

Classification /Doses Results

870.3100

90-Day oral toxicity 

rodents (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 

rodents (mouse)

44457750 (1991)

Acceptable/non-guideline

Concentrations: 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 

in non-rodents (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 rodents (rat)

45430301 (2001)

Acceptable/ guideline

M & F: 0, 60, 300, 1000 

mg/kg/day.

NOAEL 1000 mg/kg/day.

LOAEL = not observed.

870.3250

90-Day dermal 

toxicity

NA NA

870.3465

90-Day inhalation 

toxicity

NA NA
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Table A5.3. Toxicity Profile of Prohexadione Calcium.

Guideline No./ Study 

Type

MRID No./ (year)/ 

Classification /Doses Results

870.3700a

Prenatal 

developmental 

toxicity in rodents 

(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.

870.3700b

Prenatal 

developmental 

toxicity in nonrodents (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, 

abortions, and decreased maternal body-weight gain.

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 

toxicity in nonrodents (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 

toxicity in nonrodents (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

2-Generation 

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 and increased urinary volume and 

sodium concentrations.

870.4300

Chronic toxicity/

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.

870.4200

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 body-weight 

gain and food utilization and microscopic changes in the 

stomachs of males.

No evidence of carcinogenicity.
Prohexadione Calcium Registration Review Human-Health Assessment Scoping Document

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Table A5.3. Toxicity Profile of Prohexadione Calcium.

Guideline No./ Study 

Type

MRID No./ (year)/ 

Classification /Doses Results

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.

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.

870.5385

In vivo mammalian 

chromosome 

aberration (rat bone 

marrow cells)

44457769 (1997)

Acceptable/guideline

5000 mg/kg body weight.

Negative at 6-, 24-, and 48-hour sacrifices. Compound 

tested to the limit dose.

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). 

870.5500

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

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. 

NA = not applicable.