Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 3 of 24 

### Team recommends that the points of departure (PODs) and safety f actors (SFs) along with the Food Quality Prote ction 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 revis ed

a ssessment 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 residentia l 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 aggregat e exposure risk assessment that incorporates the updated dietary and/or residential exposure

assessment s 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 Regist ration 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. Rev ised 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

, andProhexadione Calcium Registration Review Human

- Health Assessment Scoping Document

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### inhalation route s (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 concentr ations 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%)
fol lowed 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 exposure s 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 n o 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 studie s 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) oc curred 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 ra ts 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
cla ssified 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 thi s time (TXR# 0056433). This approach considered all of the available hazard and exposure information, including: 1) the effects observed in the
LC 50 

### study were seen only at very high concentrations (the limit c oncentration 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 purpo ses be re

- examined and a new risk assessment be completed, if necessary.Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

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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 to xicity. 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 review ed 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 Endocrin e 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 e strogen, 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
che mical 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 o f 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 relations hip 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.Prohexadione Calcium Registration Review Human

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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 0.1 0

- 3.5 ppm in 40 CFR §180. 547 (a)

. There ar e 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 su ch 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

st udies 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 devel oped 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 (LC

MS/MS) . Prohexadione is extracted using a mixture of acetonitrile and sulfuric acid. For clean

up, an ENV+ column is used. The final determination of prohexadione is performed by LC

MS/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 (L OD) was not determined.Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 7 of 24 

### 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, respectivel y (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 effe cts 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 l ivestock 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 rapesee d.

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; D P# 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, an d 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 indicate s 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 regis tered 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 anal ytical 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 requ ired.

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 as sessment was conducted using the Dietary Exposure

Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID , ver. 2.03). DEEM

-Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 8 of 24 

### 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 DEEM TM 

### (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 resul ting chronic food plus drinking water risk estimates are not of concern to HED (<100% cPAD) for all population subgroups of interest. The res ulting 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 registrat ions. The most recent chronic dietary risk assessment w as 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 b y 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 residen tial 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 dry

flowable (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 re sidential 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 re sidential 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 DF s 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 p hysical 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,Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 9 of 24 

### 4) dermal post

- application exposure for chi ldren (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

occu r 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.

Concl usions 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 th e 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 t he 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

expo sures. 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
di etary 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.

Occupatio nal 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 RegulatorProhexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 10 of 24 

### (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 previous ly
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

- applic ation 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 r isks of concern were identified (i.e., MOEs > HED’s LOC of 100).Prohexadione Calcium Registration Review Human

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Page 11 of 24 

### 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 a vailable TTR data and selected new liquid and granular default values for the fraction of the application rate available for transfer after a turf application (F AR 

### ). This default is 1% for formulations applied as liquids.
Of the available TTR studies sub mitted to the Agency, the maximum F AR 

### 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 >1,0 00 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 Re sidue (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 tha n 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 (F A R 

### ). This default value is 25%. Of the analyzed DFR studies, the maximum F AR 

### 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 th e 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 (T TR) 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 asso ciated 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 ).

R eviewers 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

- applicatio n exposure assessments

may thus 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 o r 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

- 20 12; D 404919 ). The report represents incidents occurring in the U.S. fromProhexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 12 of 24 

### 200 7 to the present.

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

A ggregate 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 assessm ent.

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 r uminant 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 ha s established MRLs for residues in milk
and ru minant 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.ene rgy.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 ens ure 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 reg arding 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 determinati ons and procedures forProhexadione Calcium Registration Review Human

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Page 13 of 24 

### 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 Agric ultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi

pesticide 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 r egulatory 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 post

application exposure data.

Risk Assessment Updates Required Under Registration Review

Risk assessment upda tes 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 ri sk

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 mos t recent consumption database

. A new aggregate exposure risk assessment that incorporates the updated dietary and/orProhexadione 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 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. Updated occupational handler exposure assessments may be required under Registration Review based upon revisions to the Agency’s scenario

- specific surrogate handler

exposure data. Revised occupational handler and post

- application asses sments 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 Dat a 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 ADDENDUMProhexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 15 of 24 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 Human

Health 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: Ex posure 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:RAB1Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 16 of 24 

### Attachment 1: Chemical Identity Table.

T able A.1. Test Compound Nomenclature.

Compound

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

Page 17 of 24 

### 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 UF A = 10X

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

= cPAD = 0.20 mg/kg/day Chronic toxicity

– Dog

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

Incidental Oral Short (1

- 30 days)

- and
Intermediate (1

- 6 months)

- Term NOAEL = 80

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X 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 Short

and
Intermediate

Term (1

- 30 days and 1

- 6 months) Oral Maternal

NOAEL = 40 mg/kg/day
Estimated absorption
rate 25% 1 UF A = 10X

UF H = 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
Intermediate

Term (1

- 30 days, and 1

- 6 months) Oral Maternal

NOAEL = 40 mg/kg/day (inhalation

absorption rate = 100%) UF A = 10X

UF H = 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, UF A = extrapolation from animal to human (interspecies), UF H = 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

Page 18 of 24 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 Short

and
Intermediate

Term (1

- 30 days and 1

- 6 months) Oral Maternal

NOAEL = 40 mg/kg/day
Estimated absorption
rate 25% 1 UF A = 10X

UF H = 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
Intermediate

Term (1

- 30 days, and 1

- 6 months) Oral Maternal

NOAEL = 40 mg/kg/day (inhalation

absorption rate = 100%) UF A = 10X

UF H = 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, UF A = extrapolation from animal to human (interspecies), UF H = 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

Page 19 of 24 

### 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 (95 th 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 MOE 1 Inhalation 2 Dermal MOE MOE total 2

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

1 Dietary MOE = short

- term NOAEL ÷ chronic dietary exposure.

2 MOE total = 1 ÷ ((1÷MOE dietary ) + (1÷MOE Inhalation ) + (1÷MOE dermal )); MOE >100 indicates an acceptable exposure.

Table A3.3. Short

- Term Aggregate Risk for Post

- application Exposures

. Population LOC Dietary MOE 1 Incidental Oral MOE 2 Dermal MOE MOE total 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 MOE total = 1 ÷ ((1÷MOE dietary ) + (1÷MOE incidental oral ) OR (1÷MOE deraml )); MOE >100 indicates an acceptable exposure.Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 20 of 24 

### 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 Mexico 2 

### Codex 3



### 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 belo w 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 Mexico 2 

### Codex 3


### Cattle, kidney 0.10 0.05 meat byproducts of
cattle Cattle, meat byproducts, except 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
goats Goat, meat byproducts, except kidney 0.05

Grass, forage 1 

### 0.10 Grass, hay 1 

### 0.10 Grass, seed screenings 1 

### 3.5 Grass, straw 1 

### 1.2 Hog, kidney 0.10 0.05 meat byproducts of hogs Hog, meat byproducts, except kidney 0.05

Horse, kidney 0.10 0.05 meat byproducts of
horses Horse, meat byproducts, except kidney 0.05

Peanut 1.0 Peanut, hay 0.60 Sheep, kidney 0.10 0.05 meat byproducts of sheep Sheep, meat byproducts, except 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 0.05Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 21 of 24 

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

### Codex 3



### 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. MR Ls indicated as proposed have not been finalized by the CCPR and the CAC.Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 22 of 24 

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

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

- 112, 89.8% ai).

Table 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 LD 50 >5000 mg/kg IV 870.1200 Acute dermal toxicity mouse 44457737 LD 50 >2000 mg/kg III 870.1300 Acute inhalation toxicity rat 44457738 LC 50 > 5.8 mg/L IV 870.2400 Acute eye irritation rabbit 44457739 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: m ales: 73.1 mg/kg/day; f emales: 80.4 mg/kg/day.
LOAEL: m ales: 734 mg/kg/day; f emales: 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: m ales: 10,244 mg/kg/day; f emales: 11,916 mg/kg/day (HDT).
LOAEL: m ales: >10,244 mg/kg/day; f emales: >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 NAProhexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 23 of 24 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 non

rodents (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 non

rodents (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.

De velopmental NOAEL 150 mg/kg/day;
LOAEL = not observed.

870.3700b
Prenatal developmental toxicity in non

rodents (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 = 3 5.5 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 toxic ity/ 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 mic roscopic changes in the
stomachs of males.

No evidence of carcinogenicity.Prohexadione Calcium Registration Review Human

- Health Assessment Scoping Document

Page 24 of 24 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 pol yploidy 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. Compo und 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 eryt hrocytes
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

s aturated 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 excret a (both feces and urine)
metabolite was identified as the free acid. NA = not applicable.