United States
Environmental Protection
Agency
Office of Prevention, Pesticides
and Toxic Substances
(7501C)
Pesticide
Fact Sheet
Name of Chemical: Prohexadione Calcium
Reason for Issuance: New Chemical Registration
Date Issued: April 26, 2000
DESCRIPTION OF CHEMICAL
Generic Name: calcium 3-oxido-5-oxo-4-propionylcyclohex-3-enecarboxylate
Common Name: prohexadione calcium
Trade Names: Apogee Plant Growth Regulator, Baseline Plant Regulator,
K-I Chemical Prohexadione Calcium Manufacturing Use Product
EPA Chemical Code: 112600
Chemical Abstracts Service (CAS) Number: 127277-53-6
Year of Initial Registration: 2000
Pesticide Type: Plant Growth Regulator
U.S. and Foreign Producers: K-I Chemical U.S.A., Inc.
USE PATTERNS AND FORMULATIONS
Prohexadione calcium is foliarly applied plant regulator which reduces
vegetative growth by inhibiting the synthesis of gibberellin, a naturally
occurring plant hormone. Specifically it decreases the length of shoot
internodes. Apogee in apples and pears decreases the need for pruning,
allows more light to penetrate the tree canopy increasing fruit coloration,
and, due to increased air circulation, decreases the incidence of fire
blight, a bacterial disease of apples and pears. Baseline in peanuts
decreases vegetative growth and aids mechanical harvesting. The products
are dry flowables to be mixed with water and applied with ground spray
equipment to wet leaf surfaces. Apogee is a 27.5% active ingredient (a.i.)
product applied at a maximum rate of 1.7 pounds a.i./acre/year and Baseline
is a 75% a.i. product applied at a maximum rate of 0.375 pounds
a.i./acre/year.
SUMMARY SCIENCE FINDINGS
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CHEMICAL CHARACTERISTICS
Some of the physical properties of prohexadione calcium are summarized below:
Color: pale yellow brown
Physical State: fine powder
Dissociation Constant: pKa = 5.15
pH: 6.72
Octanol/Water Partition Coefficient: K0/w = 1.25 x 10 exp.-3
Solubility: 174 mg/1 in distilled water at 20 degrees C
Hydrolysis: 4.4 to 65 days (pH 5 to 7)
Half-life: 1.4 to 20 days (laboratory and field)
TOXICOLOGY
Sub chronic and Chronic Toxicity:
The chronic reference dose (cRfD) of 0.80 mg/kg/day was selected based on both the subchronic and chronic
toxicity studies in dogs. Since a similar endpoint of equal severity (minimal and moderate dilation of basophilic
tubules) was observed in both studies, the results of the two studies can be evaluated using a single dose-response
curve. The no-observed-adverse-effect level (NOAEL) from the subchronic study was used to establish the RfD
due to the wider dose spread in the 1-year study. The NOAEL of 80 mg/kg/day was based on histopathological
changes (dilated basophilic tubules) in the kidneys and clinical chemistry changes seen at the lowest-observed-
adverse-effect level (LOAEL) of 200 mg/kg/day. No additional uncertainty factor is needed because there is no
increase in the severity of the lesions over time in the chronic study as compared to the subchronic study. The
FQPA Safety Factor Committee determined that the FQPA safety factor of Ix is applicable for chronic dietary
risk assessment. Thus, the chronic population adjusted dose (cPAD) is equivalent to the chronic RfD of 0.80
mg/kg/day.
Carcinogenicity:
In 2-year chronic toxicity/carcinogenicity studies in rats and mice, prohexadione calcium was negative for
carcinogenicity when administered at dose levels adequate for the testing of carcinogenic potential. In accordance
with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the HIARC classified prohexadione
calcium as "not likely to be carcinogenic to humans".
Teratology/Reproductive Toxicity:
No treatment-related developmental effects were noted in rats or rabbits, and no treatment-related maternal
effects were noted in rats. However, maternal effects in rabbits included increased mortality, increased abortions,
and decreased body weight gains (observed at 200 mg/kg/day), and premature deliveries (observed at 350
mg/kg/day). No reproductive toxicity was noted in rats; however treatment-related systemic toxicity was observed
in parental animals and pups. Increased mortality was observed in parental males and females at 385 mg/kg/day,
and decreased pup body weight was noted at 3850 mg/kg/day. The results of these studies indicated no
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quantitative or qualitative increase in susceptibility of rats or rabbits to in utero and/or post-natal exposure to
prohexadione calcium since no developmental effects were seen at doses up to the limit dose (1000 mg/kg/day) in
the rat developmental toxicity study or up to the highest doses tested (150, 200, and 350 mg/kg/day) in three
rabbit developmental toxicity studies. In addition, in the two-generation reproduction study in rats, the effects in
the offspring were observed only at treatment levels which resulted in evidence of parental toxicity.
Mutagenicity:
Prohexadione calcium was not mutagenic in bacteria or mammalian cells. It did not cause structural
chromosomal aberrations in CHO cells in vitro or in rats or mice in vivo. Although there was significant increase
in polyploidy at the highest dose in vitro without S9 activation, the mouse micronucleus assay was negative up to
the limit dose suggesting the compound has intrinsic activity not expressed in vivo. In addition, there was no
evidence of carcinogen!city in rats and mice and results in the 2-generation reproduction study do not suggest a
genetic component.
Neurotoxicity:
No evidence of neurotoxicity was observed in either the acute or chronic neurotoxicity studies or in any other
toxicity studies.
Metabolism:
In a metabolism study in 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 urine and feces) metabolite was identified as the free acid.
Dietary Risk:
A chronic dietary exposure analysis for prohexadione calcium was performed using the Dietary Exposure
Evaluation Model (DEEM™). Tolerance level residues were used and 100% crop treated was assumed for all
pome fruit and peanut commodities. The chronic analysis was conducted for the U.S. population and all
population subgroups. The chronic exposure estimates (food only) for the U.S. population and all population
subgroups were <5% of the cPAD. Therefore, the results of the analysis indicate that the chronic dietary risk
estimates (food only) associated with the proposed uses of prohexadione calcium do not exceed HED's level of
concern (>100% cPAD) for the U.S. population or any population subgroups. An acute dietary exposure analysis
for prohexadione calcium was not performed because no acute dietary endpoints were selected.
OCCUPATIONAL EXPOSURE
Short- and intermediate-term exposures are expected for the commercial handler. Due to seasonal use, long-
term exposures are not expected. Since the short-term NOAEL of 100 mg/kg/day (for dermal and inhalation) is
based on the maternal effect of premature deliveries, worker exposure is assessed using 60 kg body weight,
females 13-50 years old as the most sensitive subgroup, and a 25% dermal absorption factor. Exposures from
peanut applications by ground boom equipment are expected to be lower than those from pome fruit applications
with air blast equipment. All short- and intermediate-term margins of exposure (MOE) are 1400 and above, and,
therefore, worker exposure risk estimates do not exceed HED's level of concern (MOE < 100).
Post-application exposure, although occurring for both peanut and pome fruit operations, is expected to be
greatest for harvesters of pome fruit due to higher application rates. The estimated intermediate MOE for the post
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application scenario is 130. Therefore, it is reasonable to assume that the potential risk for all workers exposed to
prohexadione calcium from the proposed uses does not exceed HED's level of concern (MOE < 100).
AGGREGATE RISK
Acute, cancer, and short- and intermediate-term aggregate exposure risk assessments were not performed
because an acute dietary endpoint was not selected, prohexadione is not carcinogenic, and there are no residential
uses proposed for prohexadione calcium, respectively. Aggregate exposure risk assessment was limited to chronic
exposure (food + water) only.
Chronic aggregate risk estimates (food + water) are below the Agency's level of concern. A Tier 1 chronic
dietary exposure analysis for prohexadione calcium was performed using tolerance level residues and assuming
100% crop treated for all pome fruit and peanut commodities. The chronic analysis was performed for the U.S.
population and all population subgroups. The chronic exposure estimates (food only) for the general U.S.
population and all population subgroups were <5% of the cPAD. Thus, the chronic dietary risk estimate
associated with the proposed uses of prohexadione calcium does not exceed the Agency's level of concern
(>100% cPAD). For ground and surface water, the EECs are less than the drinking water levels of comparison
(DWLOCs) for prohexadione calcium in drinking water as a contribution to chronic aggregate exposure.
Therefore, it is concluded with reasonable certainty that residues of prohexadione calcium in drinking water do
not contribute significantly to the chronic aggregate human health risk at the present time.
ECOLOGICAL CHARACTERISTICS
Avian Acute Toxicity:
Bobwhite Quail: LD50 = >5250 mg/kg (practically nontoxic)
Mallard Duck: LD50 = >5250 mg/kg (practically nontoxic)
Avian Dietary Toxicity:
Bobwhite Quail: LC50= >2000 ppm (practically nontoxic)
Mallard Duck: LC50 = >2000 ppm (practically nontoxic)
Reproductive Toxicity:
Bobwhite Quail NOEC = 1000 ppm
LOEC = > 1000 ppm
Mammalian Acute and Chronic Toxicity:
Laboratory rat - acute oral LD50= > 5000 mg/kg (practically nontoxic)
- chronic LD50 for reproduction = > 2000 mg/kg
Insect Toxicity:
Honey bee LD50 = > 100 mg/a.i./bee (practically nontoxic)
Freshwater Fish Acute Toxicity:
Bluegill Sunfish LC50 = 95.6 ppm (practically nontoxic)
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Rainbow Trout LC50 = 94.6 ppm (practically nontoxic)
Freshwater Invertebrate Acute Toxicity:
Daphnia magna EC50 = 90 ppm (practically nontoxic)
Aquatic Invertebrate Life Cycle: Chronic Toxicity
Daphnia magna NOAEC = 12.5 ppm
LOAEC = 25 ppm
Estuarine and Marine Organisms Toxicity:
Sheepshead Minnow LC50 =122 ppm (practically nontoxic)
NOAEC = 122 ppm
Eastern Oyster EC50 =117 ppm (practically nontoxic)
Mysid Shrimp NOAEC = 125 ppm (practically nontoxic)
Seedling Emergence:
Ten crop plant species including corn, oat, wheat, onion, ryegrass, cucumber, radish, soybean, sunflower,
tomato and cabbage were tested. None exceeded the >25% adverse growth level required to trigger the tier two
tests, but a 24% reduction in lettuce emergence was recorded.
Vegetative Vigor:
Ten crop plant species (same as above) were tested. None exceeded the >25% adverse growth level required to
trigger the tier two tests, but a 23% reduction in rye grass vigor was recorded.
Growth and Reproduction of Aquatic Plants - Acute Toxicity:
Vascular Plant:
Lemma gibba EC50 = 1200 ppb
Nonvascular Plants:
Prohexadione calcium is not phytotoxic to any of the following micro-algae at the maximum label dosage.
Diatoms:
Navicula pelliculosa (freshwater) EC50 = 1200 ppb
NOAEC/NOAEL = 120 ppb
Skeletonema costatum (marine) NOAEC/NOAEL = 1100 ppb
Algae:
Anabaenaflos-aquae (blue-green) NOAEC/NOAEL = 1200 ppb
Selanestrum capricornutum (green) NOAEC/NOAEL = 1100 ppb
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Prohexadione calcium has very low toxicity to avian species, mammals, freshwater and estuarine/marine fish
and invertebrates, aquatic and terrestrial plants, and honey bees. Acute and chronic risk quotients (RQ) with
ranges combining apple/pear and peanut uses are indicated below:
Acute Chronic
Avian 0.0 to 0.08 0.004 to 0.4
Mammalian 0.00002 to 0.1 0.004 to 0.2
Aquatic (freshwater) <0.0004 0.0 to 0.0004
Marine 0.0 to <0.0003 0.0 to 0.0003
Nontarget plants (aquatic) 0.03
ENVIRONMENTAL CHARACTERISTICS
Prohexadione calcium is not expected to persist in the environment based on laboratory studies submitted. Its
low octanol/water partition coefficient and low persistence suggest little or no potential to bioaccumulate. The
major route of dissipation is oxidative mineralization to carbon dioxide in the soil. Prohexadione calcium is likely
to be mobile in some soils but its rapid degradation suggests little potential to contaminate most ground water.
Estimated drinking water concentrations from surface water sources are not likely to exceed 35.61 ug/L The 56-
day average chronic concentrations are not likely to exceed 7.73 ug/L. Groundwater monitoring data are
unavailable so the SCI-GROW screening model was used to estimate ground water concentrations. Estimated
concentrations of prohexadione calcium in drinking water from shallow ground water sources are not expected to
exceed 0.001 ppb for application on apples and 0.0003 ppb for peanuts. These concentrations can be considered
as both acute and chronic values.
TOLERANCE ASSESSMENT
Tolerances Established:
Peanut 1.0 ppm
Peanut, hay 0.60 ppm
Fruit, pome, group 3.0 ppm
Cattle, goats, hogs, horses, and sheep, kidney 0.10 ppm
Cattle, goats, hogs, horses, and sheep, meat byproducts, except kidney 0.05 ppm
Aggregate Risk Exposure:
Acute, cancer, and short- and intermediate-term aggregate exposure risk assessments were not performed
because an acute dietary endpoint was not selected, prohexadione is not carcinogenic, and there are no residential
uses proposed for prohexadione calcium, respectively. Aggregate exposure risk assessment was limited to chronic
exposure (food + water) only.
Chronic aggregate risk estimates (food + water) are below the Agency's level of concern. A Tier 1 chronic
dietary exposure analysis for prohexadione calcium was performed using tolerance level residues and assuming
100% crop treated for all pome fruit and peanut commodities. The chronic analysis was performed for the U.S.
population and all population subgroups. The chronic exposure estimates (food only) for the general U.S.
population and all population subgroups were <5% of the cPAD. Thus, the chronic dietary risk estimate
associated with the proposed uses of prohexadione calcium does not exceed the Agency's level of concern
(>100% cPAD). For ground and surface water, the estimated environmental concentrations (EECs) are less than
the drinking water levels of comparison (DWLOCs) for prohexadione calcium in drinking water as a contribution
to chronic aggregate exposure. Therefore, it is concluded with reasonable certainty that residues of prohexadione
calcium in drinking water do not contribute significantly to the chronic aggregate human health risk at the present
time.
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Cumulative Toxicity and Metabolism:
In a rat metabolism study, prohexadione calcium is rapidly absorbed with highest tissue/carcass concentrations
obtained within 30 minutes; however, absorption became saturated at the highest dose. Test material did not
accumulate in the tissues. For low dose animals, renal excretion is the primary route of elimination. The primary
excreta (both urine and feces) metabolite is identified as the free acid.
Determination of Safety for Infants and Children:
The Health Effects Division's Hazard Identification Assessment Review Committee (HIARC) concluded the
following. The pre- and post-natal toxicology database for prohexadione calcium is adequate for FQPA
considerations. The results of these studies indicated no quantitative or qualitative increase in susceptibility of rats
or rabbits to in utero and/or post-natal exposure to prohexadione calcium. No developmental effects were seen at
doses up to the limit dose (1000 mg/kg/day) in the rat developmental toxicity study or up to the highest doses
tested (150, 200, and 350 mg/kg/day) in three rabbit developmental toxicity studies. In the two-generation
reproduction study in rats, the effects in the offspring were observed only at treatment levels which resulted in
evidence of parental toxicity. A developmental neurotoxicity (DNT) study is not required. No neuropathology or
central nervous system (CNS) malformations were seen in the developmental toxicity studies. In the two-
generation study in rats, there were no findings in pups that were suggestive of changes in neurological
development, although no functional assessment was performed. Additionally, there was no evidence of
neurotoxicity in either the acute or subchronic neurotoxicty studies in rats and no evidence of neurotoxicity in
other studies.
The FQPA Safety Factor Committee determined that the FQPA safety factor of Ix is applicable for chronic
dietary risk assessment. The Safety Factor was removed because the pre- and post-natal toxicology database is
complete, there is no indication of increased susceptibility, and a developmental neurotoxicity study is not
required. The dietary (food and drinking water) exposure assessments will not underestimate the potential
exposures for infants and children from the use of prohexadione calcium (currently there are no proposed
residential uses and, therefore, non-occupational exposure is not expected).
SUMMARY OF DATA GAPS
Registration is conditional depending on the following: submission of storage stability data on the processed
commodities of peanuts within 12 months, submission of a 21-day dermal toxicity study in rabbits within 6
months, and Agency validation of analytical enforcement method for plants.
CONTACT PERSON AT EPA
Cynthia Giles-Parker
Product Manager (22)
Fungicide Branch
Registration Division (7505C)
E-Mail Address:
Giles-Parker.Cynthia@epamail.epa.gov
Mailing Address:
Ms. Cynthia Giles-Parker
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Office of Pesticide Programs (7505C)
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, N.W.
Washington, DC 20460
Office Location and Telephone Number
Room 249, Crystal Mall Building #2
1921 Jefferson Davis Highway
Arlington, VA 22202
(703)305-7740
DISCLAIMER: The information presented in this Pesticide Fact Sheet is for informational purposes only and
may not be used to fill data requirements for pesticide registration and reregi strati on.
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