EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Andrew Ertman, (703) 308-9367

 

Interregional Research Project Number 4 (IR-4) 

PP #1E7855

EPA has received a pesticide petition (PP #1E7855) from Interregional Research Project 

Number 4 (IR-4), 500 College Road East, Suite 201W, Princeton, NJ 08540 proposing, 

pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 

346a(d), to amend 40 CFR part 180.434 by establishing tolerance for residue of

propiconazole, 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl] 

methyl]-1H-1,2,4-triazole and its metabolites determined as 2,4,-dichlorobenzoic acid and 

expressed as parent compound in or on the raw agricultural commodity Bean, snap at 0.8 

parts per million (ppm); bean, succulent shelled at 0.15 ppm; bean, dry seed at 0.3 ppm; 

legume, foliage at 25 ppm; tomato at 2.5 ppm; fruit, citrus, group 10-10 at 8.0 ppm; fruit, 

stone, group 12, except plum, at 7.0 ppm; plum at 1.0 ppm and by removing the established 

tolerance on fruit, stone, group 12 at 1.0 ppm.

EPA has determined that the petition contains data or information regarding the elements set 

forth in section 408 (d)(2) of the FDDCA; however, EPA has not fully evaluated the sufficiency 

of the submitted data at this time or whether the data supports granting of the petition. Additional 

data may be needed before EPA rules on the petition.

A. Residue Chemistry. 

 

1. Plant metabolism. The metabolism of propiconazole as well as the nature of the residues is 

adequately understood for purposes of the tolerances. Plant metabolism has been evaluated in 

five diverse crops, wheat, grapes, celery, peanuts and carrots which should serve to define the 

similar metabolism of propiconazole in a wide range of crops. The plant metabolism pathway 

for propiconazole is well understood. Parent metabolite CGA-64250 is the major compound 

found in crops. Comparison of the metabolism of propiconazole in different plant species 

shows that the differences between the respective metabolic pathways to be quantitative in 

nature.

2. Analytical method. The metabolism data in plants and animals suggest that analytical methods 

to detect either the phenyl or the triazole ring would be appropriate for the measurement of 

residues. However, because of the natural occurrence of compounds that interfere with the 

measurement of triazoles, methods designed to detect this moiety have been proven unreliable 

and unacceptable. Conversely, conversion of phenyl moiety to 2,4-dichlorobenzoic acid 

(DCBA) has proven to be satisfactory for all agricultural products analyzed to date. Analytical 

methods AG-626 and AG-454A were developed for the determination of residues of 

propiconazole and its metabolites containing the DCBA moiety. Analytical method AG-626 

has been accepted and published by EPA as the tolerance enforcement method for crops. The 
limit of quantitation (LOQ) for the method is 0.05 ppm. 

3. Magnitude of residues. . IR-4 conducted magnitude of residue trials on several crops under 

OPPTS 860.1500 to support the requested uses of propiconazole . These residue trials satisfy the 

proposed tolerances for these crops.

B. Toxicological Profile

1. Acute toxicity. Propiconazole exhibits low toxicity. Data indicated the following: a rat acute 

oral LD50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a 

rat inhalation LC50 >5.8 mg/liter air; minimal skin and slight eye irritation; and nonsensitization.

2. Genotoxicty. Propiconazole exhibits low toxicity. Data indicated the following: a rat acute 

oral LD50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a 

rat inhalation LC50 >5.8 mg/liter air; minimal skin and slight eye irritation; and nonsensitization. 

3. Reproductive and developmental toxicity. In an oral teratology study in the rabbit, a maternal 

no observed adverse effect level (NOAEL) of 30 mg/kg was based on reduced food intake but 

without any fetotoxicity even at the top dose of 180 mg/kg. In an oral teratology study in the 

rabbit, a maternal NOAEL of 100 mg/kg was based on reductions in body weight gain and food 

consumption and a fetal NOAEL of 250 mg/kg was based on increased skeletal variations at 400 

mg/kg. In an oral teratology study in the rat, a maternal and fetal NOAEL of 100 mg/kg was 

based on decreased survival, body weight gain, and food consumption in the dams and delayed 

ossification in the fetuses at 300 mg/kg. In a second teratology study in the rat, a maternal and 

fetal NOAEL of 30 mg/kg was based on reductions in body weight gain and food consumption 

in the dams and delayed development in the fetuses at 90 and 360/300 mg/kg. A supplemental 

teratology study in the rat involving eight times as many animals per group as usually required 

showed no teratogenic potential for the compound. A 2-generation reproduction study in the rat 

showed excessive toxicity at 5,000 ppm without any teratogenic effects. A 2-generation 

reproduction study in the rat showed no effects on reproductive or fetal parameters at any dose 

level. Postnatal growth and survival were affected at the top dose of 2,500 ppm, and parental 

toxicity was also evident. The NOAEL for development toxicity is 500 ppm.

4. Subchronic toxicity. In a 21-day dermal study in the rabbit, a NOAEL of 200 mg/kg was based 

on clinical signs of systemic toxicity. In a 28-day oral toxicity study in the rat, a NOAEL of 50 

mg/kg was based on increased liver weight. In a subchronic feeding study in the mouse, a 

NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a 13 week feeding study 

in the male mouse, a NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a 

90 day feeding study in rats, the NOAEL was 240 ppm (24 mg/kg) based on a reduction in body 

weight gain. In a 90 day feeding study in dogs, the NOAEL was 250 ppm (6.25 mg/kg) based on 

reduced food intake and stomach histologic changes.

5. Chronic toxicity. In a 12-month feeding study in the dog, a NOAEL of 50 ppm (1.25 mg/kg) 

was based on stomach histologic changes. In a 24 month oncogenicity feeding study in the 

mouse, the NOAEL was 100 ppm (15 mg/kg). The MTD was exceeded at 2,500 ppm in males 

based on decreased survival and body weight. Increased incidence of liver tumor was seen in 
these males but no evidence of carcinogenicity was seen at the next lower dose of 500 ppm in 

either sex. In a 24 month chronic feeding/oncogenicity study in the rat, a NOAEL of 100 ppm 

(5 mg/kg) was based on body weight and blood chemistry. The MTD was 2,500 ppm based on 

reduction in body weight gain and no evidence of oncogenicity was seen. Based on the 

available chronic toxicity data, Syngenta believes the Reference dose (RfD) for propiconazole is 

0.0125 mg/kg/day. This RfD is based on a 1 year feeding study in dogs with a NOAEL of 1.25 

mg/kg/day (50 ppm) and an uncertainly factor of 100. No additional modifying factor for the 

nature of effects was judged to be necessary as stomach mucous hyperemia was the most 

sensitive indicator of toxicity in that study. 

Using the Guidelines for Carcinogenic Risk Assessment published on September 24, 1986 (51 

FR 33992), the USEPA has classified propiconazole in group C for carcinogenicity (evidence of 

possible carcinogenicity for humans). The compound was tested in 24 month studies with both 

rats and mice. The only evidence of carcinogenicity was an increase in liver tumor incidence in 

male mice at a dose level that exceeded the maximum tolerated dose (MTD). Dosage levels in 

the rat study were appropriate for identifying a cancer risk. The Cancer Peer Review 

Committee recommended the RfD approach for quantitation of human risk. Therefore, the RfD 

is deemed protective of all chronic human health effects, including cancer. 

6. Animal metabolism. Metabolism in animals is similar to plant metabolism. In animals both the 

rat and the goat rapidly metabolize and excrete propiconazole. Neither animal retains 

significant amounts of propiconazole or its metabolites in tissues. Significant quantities of 

parent or metabolites do not appear in goat’s milk. Similar metabolites are produced by both 

species, and unconjugated (phase I) metabolites are similar in plants and animals. 

The metabolism profile supports the use of an analytical enforcement method that accounts for 

combined residues of propiconazole and its metabolites that contain the 2,4-dichlorobenzoic acid 

(DCBA) moiety.

7. Metabolite toxicology. There are no metabolites of concerned based on a differential 

metabolism between plants and animals. 

8. Endocrine disruption. Developmental toxicity studies in rats and rabbits and reproduction 

studies in rats gave no indication that propiconazole might have any effects on endocrine 

function related to development and reproduction. The subchronic and chronic studies also 

showed no evidence of a long–term effect related to the endocrine system. Further, due to the 

moderate rate of degradation of the product, there is no risk that propiconazole may accumulate 

in the environment. In animals, propiconazole is quickly excreted and has no tendency for 

accumulation in the body. Based on these results, it is very likely that propiconazole has no 

potential to interfere specifically with the endocrine system. 

C. Aggregate Exposure

1. Dietary exposure. Tier I acute, short-term, and chronic aggregate exposure assessments were 

performed for propiconazole using the Dietary Exposure Evaluation Model software with the 

Food Commodity Intake Database (DEEM-FCIDTM, version 2.16) from Exponent. 

Propiconazole is currently registered for use on alfalfa (indirect), avocado (Section 18), bananas, 
barley, berries (Crop Groups 13-07A, 13-07B, and 13-07G), carrots, cilantro, corn (field, sweet, 

and popcorn), cranberries (regional), garden beets, grasses, leaf petioles (Crop Subgroup 4B), 

mushrooms, nectarines and peaches (Section 18, expires 31-Dec-2013), oats, onions (bulb and 

green), parsley, peanuts, peppermint, pineapples (seed piece treatment), pistachios, rice, rye, 

sorghum, soybeans, spearmint, stone fruits (Crop Group 12), strawberries, sugar beets, tree nuts 

(Crop Group 14), wheat, wild rice (regional), and turf and ornamental uses. A revised use on 

mint (7-day PHI) and revised use patterns for Propi-ShieldTM brand paint and stain additive 

products are pending. Proposed new IR-4 uses include succulent and dried legumes (Crop 

Group 6) and post-harvest applications to citrus fruit (Crop Group 10-10), stone fruit (Crop 

Group 12), and tomatoes (Crop subgroup 8–10A). Existing (40CFR180.434) or estimated 

tolerances were used for all commodities. No adjustments were made for “percent crop 

treated,” i.e., 100%CT was assumed. DEEMTM (version 7.87) default processing factors were 

used for all processed commodities except citrus oil (185X), orange juice (0.011X), pineapple 

juice (0.11X), and pineapple process residue (1.49X). Anticipated residues in milk (0.12 ppm) 

were calculated by constructing a theoretical “maximum reasonably balanced diet” (MRBD) 

livestock diet using the June 2008 revisions to the OPPTS 860.1000 Table 1 feedstuffs; 

established tolerances were used for meat, liver, fat, and kidney. Drinking water estimates were 

selected using the higher of the estimated drinking water concentrations (EDWCs) for surface 

and ground water. All consumption data for these assessments were taken from the USDA’s 

Continuing Survey of Food Intake by individuals (CSFII) with the 1994-1996 consumption 

database and the Supplemental CSFII children’s survey (1998) consumption database. 

 

i. Food. The acute dietary (food only) risk assessment was performed for all population 

subgroups with an acute reference dose of 0.3 mg/kg-bw/day based on an acute no observable 

adverse effect level (NOAEL) of 30 mg/kg-bw/day from an acute neurotoxicity study in rats and 

an uncertainly factor of 100X. The 100X safety factor included intra- and inter-species 

variations. No additional FQPA safety factor was applied. For the purpose of the aggregate 

risk assessment, the exposure value was expressed in terms of margin of exposure (MOE), which 

was calculated by dividing the NOAEL by the exposure for each population subgroup. In 

addition, exposure was expressed as a percent of the acute reference dose (%aRfD). At the 95th 

percentile, acute exposure to the U.S. population resulted in a MOE of 654 or 15.3% of the aRfD 

(Benchmark = 100; aRfD = 0.3 mg/kg-bw/day). Acute exposure to the most sensitive 

subpopulation (children 1-2 years old) resulted in a MOE of 271 or 36.8% of the aRfD 

(Benchmark = 100; aRfD = 0.3 mg/kg-bw/day). Since the Benchmark MOE for this assessment 

is 100 and since EPA generally has no concern for exposures above the benchmark or below 

100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm 

will result from acute dietary (food) exposure to residues arising from all current, pending, and 

proposed uses for propiconazole. 

Chronic Food Risk: The chronic dietary (food only) risk assessment was performed for all 

population subgroups with a chronic reference dose of 0.1 mg/kg-bw/day based on a 24-month 

oncogenicity study in mice with a NOAEL of 10 mg/kg-bw/day and an uncertainly factor of 

100X. The 100X safety factor included intra- and interspecies variations. No additional FQPA 

safety factor was applied. For the purpose of the aggregate risk assessment, the exposure values 

were expressed in terms of margin of exposure (MOE), which was calculated by dividing the 

NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as 
a percent of the chronic reference dose (%cRfD). Chronic exposure to the U.S. population 

resulted in a MOE of 699 or 14.3% of the cRfD (Benchmark = 100; cRfD = 0.1 mg/kg-bw/day). 

Chronic exposure to the most exposed sub-population (children 1-2 years old) resulted in a MOE 

of 261 or 38.3% of the cRfD (Benchmark = 100; cRfD = 0.1 mg/kg-bw/day). Since the 

Benchmark MOE for this assessment is 100 and since EPA generally has no concern for 

exposures above the benchmark or below 100% of the reference dose, Syngenta believes that 

there is a reasonable certainty that no harm will result from chronic dietary (food) exposure to 

residues arising from all current, pending, and proposed uses for propiconazole. 

Cancer Risk: A quantitative risk assessment using a cancer endpoint was not performed. The 

chronic risk assessment is adequately protective for cancer risk as well as other chronic effects. 

 

ii. Drinking Water. The Estimated Drinking Water Concentrations (EDWCs) of propiconazole 

were determined using Tier l SCI-GROW (version 2.3) which estimates pesticide concentration 

in ground water and Tier II PRZM/EXAMS (PE version 5.0) which estimates pesticide 

concentration in surface water. This drinking water assessment was conducted to assess all 

currently registered uses, the pending change to the use pattern for mint, and the proposed use on 

legume vegetables (succulent and dried) as well as proposed post-harvest uses on citrus, stone 

fruit, and tomatoes. The post-harvest uses have no impact on drinking water because 

post-harvest treatment is an indoor use posing negligible impact to drinking water 

concentrations. For groundwater, the currently registered use on turf provided the highest 

EDWC of 0.725 ppb (acute and chronic). For surface water, the currently registered use on turf 

provided an acute EDWC of 101.826 ppb and a chronic EDWC of 52.438 ppb. No Percent 

Cropped Area (PCA) adjustments were made for surface water EDWCs. Since the surface 

water EDWCs exceed the ground water EDWC, the surface water values were used for risk 

assessment purposes and will be considered protective for any ground water exposure concerns. 

Acute Exposure from Drinking Water. The acute surface water EDWC of 101.826 ppb was 

input directly into the DEEM-FCIDTM software as “water, direct and indirect, all sources” to 

model the acute drinking water exposures. Exposure contributions at the 95%-ile of exposures 

were determined by taking the difference between the aggregate (food + drinking water) 

exposures and the food (alone) exposures for each population subgroup. Acute drinking water 

exposure U.S. population resulted in a MOE of 3,654 (0.8% of the aRfD of 0.30 mg/kg-bw/day). 

The most exposed sub-population was all infants (<1 year old) with a MOE of 2,363 (1.3% of 

the aRfD of 0.30 mg/kg/day). Since the benchmark MOE for this assessment was 100 and since 

EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that 

there is a reasonable certainty that no harm will result from acute drinking water exposure to 

residues arising from all current, pending, and proposed uses for propiconazole. 

 

Chronic Exposure from Drinking Water. The chronic surface water EDWC of 52.438 ppb was 

input directly into the DEEM-FCIDTM software as “water, direct and indirect, all sources” to 

model the chronic drinking water exposures. Chronic drinking water exposure to the U.S. 

population resulted in a MOE of 9,048 (1.1% of the cRfD of 0.10 mg/kg-bw/day). Chronic 

drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in a 

MOE of 2,760 (3.6% of the cRfD of 0.10 mg/kg-bw/day). Since the Benchmark MOE for this 

assessment was 100 and since EPA generally has no concern for exposures below 100% of the 
cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic 

drinking water exposure to residues arising from all current, pending, and proposed uses for 

propiconazole. 

 

2. Non-dietary exposure. Short-term exposure assessments were conducted to assess exposures 

resulting from non-dietary uses of propiconazole arising from registered turf and ornamental 

uses and from Propi-ShieldTM brand paint and stain additive products containing propiconazole. 

Adult turf and ornamental handler scenarios assessed included low-pressure hand wand sprayer, 

garden hose-end sprayer, granular push spreader, hand held belly grinder spreader, and spreading 

granular formulation by hand. Adult and youth post-application exposure scenarios included 

high contact activities (lawns) and golf. For children, re-entry to treated turfgrass areas resulted 

in dermal and non-dietary oral exposures via hand-to-mouth, object-to-mouth, and ingestion of 

treated soil. A dermal absorption value of 40% was used to calculate exposure for turf and 

ornamental uses. For Propi-ShieldTM brand paint additive products, adult applicator scenarios 

assessed included paintbrush and roller applications of in-can treated paint and stain, airless 

sprayer application of in-can treated paint and stain, and low-pressure hand wand sprayer 

application of wood preservative stains. Dermal absorption values of 1.0% and 26.6% for 

consumers applying paint or stain, respectively, were taken from a recent EPA assessment (DP# 

D364956, Nov. 2009). For all turf and ornamental scenarios assessed, the worst-case combined 

short-term MOE was 181 (Benchmark = 100) for children 1-6 years old for combined dermal 

and non-dietary oral exposures resulting from post-application exposures to propiconazole 

treated turfgrass. Post-application exposure to ornamental plants is negligible; and was, 

therefore, not assessed. For all paint and stain scenarios assessed, the worst-case combined 

short-term MOE was 160 (Benchmark = 100) for all adults 20+ years old applying in-can treated 

stain with an airless sprayer. Exposure risks were also assessed for children’s accidental 

ingestion of lawn granules (MOE = 331) and paint chips (MOE = 4,500) containing 

propiconazole and were found to be acceptable (Benchmark MOE = 100); the ingestion of lawn 

granules and paint chips by children is considered to be episodic in nature and is not aggregated 

with dietary or other residential exposures. Since the Benchmark MOE for this assessment was 

100 and since the EPA generally has no concern for exposures above the benchmark, Syngenta 

believes that there is a reasonable certainty that no harm will result from short-term non-dietary 

exposures arising from all current, pending, and proposed uses for propiconazole. 

D. Cumulative Effects 

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 

408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a 

tolerance, the Agency consider “available information” concerning the cumulative effects of a 

particular pesticide’s residues and “other substances that have a common mechanism of 

toxicity”. Propiconazole is a member of the triazole-containing class of pesticides. Although 

conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not 

necessarily a relationship between this pesticidal activity and their mechanism of toxicity in 

mammals. Structural similarities do not constitute a common mechanism of toxicity. There is 

currently no evidence to indicate that conazoles share common mechanisms of toxicity and the 

EPA is not following a cumulative risk approach based on a common mechanism of toxicity for 

the conazoles. 
 

E. Safety Determination 

1. U.S. population. Using the conservative assumptions described above, and based on the 

completeness and reliability of the toxicity data, the acute aggregate (food plus water) exposure 

calculation for all current, pending, and proposed uses of propiconazole provided a MOE of 621 

for the U.S. population. For short-term exposures, chronic dietary (food and water) exposures 

were aggregated with residential exposures, resulting in a worst-case short-term aggregate MOE 

of 148 for the U.S. population. The chronic aggregate exposure analysis (food and water) 

showed that exposures from all current, pending, and proposed propiconazole uses resulted in a 

MOE of 649 for the U.S. population. Since the worst case aggregate MOE of 148 (short-term 

risk) exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty 

that no harm will occur to the U.S. population from aggregate exposures arising from all current, 

pending, and proposed uses for propiconazole.

2. Infants and children. Using the conservative assumptions described above, and based on the 

completeness and reliability of the toxicity data, the acute aggregate (food plus water) exposure 

calculation for all current, pending, and proposed uses of propiconazole provided a MOE of 265 

for children 1-2 years old. For short-term exposures, chronic dietary (food and water) 

exposures were aggregated with residential exposures resulting in a short-term aggregate MOE 

of 149 for children 1-6 years old. The chronic aggregate exposure analysis (food and water) 

showed that exposures from all current, pending, and proposed propiconazole uses resulted in a 

MOE of 250 for children 1-2 years old. Since the worst case aggregate MOE of 149 (short-term 

risk) exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty 

that no harm will occur to infants and children from aggregate exposures arising from all current, 

pending, and proposed uses for propiconazole. 

 

F. International Tolerances

The Codex Alimentarius Commission has established several maximum residue limits (MRLs) 

for propiconazole in or on various raw agricultural commodities. The Codex MRLs are 

expressed in terms of propiconazole per se. In addition, both Canada and Mexico have 

established MRLs/tolerances on several commodities which also have U.S. tolerances. The 

U.S. tolerance expression includes all metabolites determined as 2,4-dichloro-benzoic acid. In 

conjunction with the reregistration process EPA intends to revise the tolerance expression to 

propiconazole per se. To the extent possible, for the present petitions, U.S. tolerances have 

been numerically harmonized with Codex, Canadian and Mexican MRLs; however, differences 

in use patterns and the supporting residue data have precluded reducing many tolerances. A 

summary of Codex MRLs, Canadian MRLs and Mexican tolerances and the corresponding U.S. 

tolerances for propiconazole is discusses at www.regulations.gov Docket No. 

EPA-HQ-OPP-2006-0347-0004; pages 53-54