EPA REGISTRATION DIVISION - COMPANY NOTICE OF

FILING FOR PESTICIDE PETITION

Docket ID Number: EPA-HQ-OPP-2014-0788

EPA Registration Division C ontact: Sidney Jackson (703) 305-7610

Interregional Research Project Number 4 

Pesticide Petition Number: 4E8321

EPA has received a pesticide petition, PP# 4E8321, 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 

tolerances for residues 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 the stoichiometric equivalent of 

propiconazole, in or on the raw agricultural commodities: Dill, fresh at 30 parts per 

million (ppm); Dill, dried at 80 ppm; Dill, seed at 15 ppm; Leafy brassica greens, 

subgroup 5B at 20 ppm; Radish, tops at 0.2 ppm; Radish, roots at 0.04 ppm; Ti 

palm, leaves at 10 ppm; Ti palm, roots at 0.3 ppm, Watercress at 6 ppm, Fruit, 

stone, group 12-12, except plum at 4.0 ppm and Nut, tree, group 14-12 at 0.1 ppm.

Upon approval of proposed tolerances, the petitioner requests removal of the 

established tolerances under 40 CFR 180.434 in or on Fruit, stone, group 12 except 

plum at 4.0 ppm, and Nut, tree, group 14 at 0.1 ppm that are superseded by this 

action. 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 support granting of the petition. Additional data may be needed before 

EPA rules on the petition.

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 use of propiconaozle 

in/on on dill, leafy brassica greens, radish and watercress. These residue trials 

satisfy the requested tolerance on these crops. 

EPA's Chemistry Science Advisory Council (ChemSAC) agreed that for Ti palm 

roots, A tolerance of 0.3 ppm covers the representative crops in crop sub-group 1B 

and a garden beet root tolerance and therefore, should adequately cover Ti palm 

root residue when Ti palm is treated with the same use pattern as other 1B crops.

ChemSAC also agreed that for Ti palm leaves: A tolerance of 10 ppm can be 

translated from the sugar beet tops established tolerance of 10 ppm, and should 

adequately cover Ti palm leaves when it is treated with the same use pattern as 

leaves of root and tuber vegetables.

B. Toxicological Profile

1. Acute toxicity. Propiconazole exhibits low toxicity. Available data 

indicated the following: a rat acute oral lethal dose (LD)50 of 1,517 

milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a rat 

inhalation lethal concentration (LC)50 >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 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 

maximum tolerated dose (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 MTD. Dosage levels in the rat study were appropriate for 

identifying a cancer risk. The EPA 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 (DEEM-FCIDTM Version 3.16) from Exponent and consumption 
data from the USDA NHANES “What We Eat in America” survey, 2003-2008. 

Propiconazole is currently registered for uses on alfalfa; avocados; banana; beans 

(dry and succulent); beets (garden); beets (sugar); berries (Crop Groups 13-07A, 13-

07B, 13-07G); bulb vegetables (Crop Group 3); carrots; cilantro (leaves); citrus 

fruits (Crop Group 10); corn (field, pop, sweet); cranberries; grasses; leaf petioles 

(Crop Group 4B); mushrooms; nectarines; ornamentals; parsley (fresh, dried); 

peaches; peanuts; peppermint; pineapple; pistachio; rice; small cereal grains 

(barley, oats, rye, wheat); sorghum; soybean; spearmint; stone fruit (Crop Group 

12); strawberries; sugarcane; tomatoes; tree nuts (Crop Group 14); turf grass, and 

wild rice. A use on canola is pending. IR4 minor uses on dill, Ti palm, radish, 

watercress, and leafy Brassica (Crop Group 5B) are proposed. Existing 40 CFR

180.434 or proposed tolerances were used for all commodities. Experimental 

processing factors were used for canola meal (1.48X), canola oil (0.03X), orange 

juice (0.011X), pineapple juice (0.11X), pineapple process residue (1.49X), soybean 

oil (0.08x), sugarcane sugar (0.02X), sugarcane molasses (0.49X), wheat bran (2.4x), 

wheat flour (0.2x). DEEMTM Version 7.87 default processing factors were used for 

all other commodities. No adjustments were made for “percent crop treated,” i.e., 

100%CT was assumed. For livestock commodities, established tolerances were 

used. Drinking water estimates were selected using the higher of the estimated 

drinking water concentrations (EDWCs) for surface and ground water. 

i. Food. Acute Food Risk: The acute dietary (food only) risk assessment was 

performed for all population subgroups with an acute reference dose (aRfD) of 0.3 

mg/kg-bw/day based on an acute no observed 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 subpopulation. 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 749 or 13.4% 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 281 or 35.6% 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 (cRfD) of 0.1 mg/kgbw/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 sub-population. 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 819 or 12.2% of the cRfD (Benchmark = 

100; cRfD = 0.1 mg/kg-bw/day). Chronic exposure to the most exposed subpopulation (children 1-2 years old) resulted in a MOE of 284 or 35.2% 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 EDWCs of propiconazole were determined using Tier l SCIGROW (version 2.3) which estimates pesticide concentration in ground water and 

Tier II PRZM/EXAMS (PE version 5.0) and the Modified Tier 1 Rice Model which 

estimate pesticide concentration in surface water for terrestrial and aquatic uses, 

respectively. This drinking water assessment was conducted to assess all currently 

registered uses, pending uses on canola as well as the proposed uses on dill, 

watercress and leafy brassica greens, crop subgroup 5B. For groundwater, the 

currently registered use on turf provided the highest EDWC of 0.725 ppb (acute and 

chronic). For surface water, the proposed use on watercress provided an acute 

EDWC of 272 ppb and a chronic EDWC of 174 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 272 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 

sub-population. Acute drinking water exposure U.S. population resulted in a MOE 

of 3,627 (2.8% of the aRfD of 0.30 mg/kg-body weight (bw)/day). The most exposed 

sub-population was infants <1 year old, with a MOE of 1,216 (8.2% 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 above the benchmark or 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 174 

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 2,745 (3.6% of 

the cRfD of 0.10 mg/kg-bw/day). The most exposed sub-population was infants <1 

year old, with a MOE of 1,064 (9.4% 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 above the benchmark or 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 the current, pending, and 

proposed uses for propiconazole

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

exposures resulting from non-dietary residential uses of propiconazole arising from 

uses on golf course and residential turf. Activity scenarios for adults (19+ years old) 

included mixer/loader/applicator, high contact dermal events, mower, and golfer. 

Activity scenarios for 11-16 year old youths included mower and golfer. Activity 

scenarios for 6-11 year old youths included golfer. Activity scenarios for children 1-

6 years included re-entry and various activities on treated turf. A dermal 

absorption value of 40% was used. For all turf and ornamental scenarios, the 

scenario producing the highest short-term exposure for each population subgroup 

selected. For adults 19+, the worst-case short-term MOE was 1,639 (adult high 

contact turf). For youths 11-16, the worst-case short-term MOE was 19,910 (youth 

golfer). For youths 6-11, the worst-case short-term MOE was 1,639 (youth golfer). 

For children 1-6, the worst-case short-term MOE was 764 (combined dermal + 

hand-to-mouth). Exposure risks were also assessed for children’s accidental 

ingestion of lawn granules (MOE = 147) and were found to be acceptable 

(Benchmark MOE = 100); the ingestion of lawn granules 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 878 

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 631 for the U.S. population. Since the worst case aggregate 

MOE of 621 (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 256 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 

377 for children 1-2 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 247 for children 1-2 years old. Since the 

worst case aggregate MOE of 247 (chronic 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 

(banana; barley; coffee beans; cranberry; maize; pecan; pineapple; popcorn; rape 

seed; rye; soya; sugar beet; sugar cane; sweet corn; triticale; wheat; and meat, milk, 

and eggs). 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.