EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(7/1/2007)

EPA Registration Division contact: [insert name and telephone number with area 

code]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., “[insert 

company name],” with the information specific to your action.

TEMPLATE:

[Bayer CropScience]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [Bayer 

CropScience], [P.O. Box 12014, 2 T.W. Alexander Drive, Research Triangle Park, 

NC 27709] 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.

(Options (pick one)

1. by establishing a tolerance for residues of

[Prothioconazole, 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-

hydroxypropyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione and its desthio metabolite] in 

or on the raw or processed agricultural commodity [rice, grain] at [0.25] parts per 

million (ppm), [rice, hulls] at [1.0] parts per million (ppm), [alfalfa, forage and alfalfa,

hay] at [0.02] parts per million (ppm) and [potato, tuber] at [0.02] parts per million 

(ppm). 

Bayer CropScience is also proposing use of the currently established tolerances for 

residues of Prothioconazole, 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-

hydroxypropyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione and its desthio metabolite, in or 

on the raw agricultural commodity [pea and bean, dried shelled, except soybean, 

subgroup 6C], [soybean, forage], [soybean, hay], [soybean, seed] to support the use of 

prothioconazole as a seed treatment on these crops. Bayer CropScience is also proposing 

that the above proposed tolerances on rice, based on foliar data, also support the use of 

prothioconazole as a seed treatment on rice.
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EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408 (d)(2) of 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. [In plants, the metabolism of prothioconazole is adequately

understood for purposes of establishing these proposed tolerances. Prothioconazole was 

extensively metabolized in plants with the major residue found in all crops (wheat, 

peanuts and sugar beets) being JAU6476-desthio with smaller amounts of various 

isomers of JAU6476-hydroxy-desthio, and their conjugates also being found. 

Triazolylalanine, triazolylhydroxypropionic acid, and triazolylacetic acid, metabolites 

common to the triazole-derivative class of fungicides, were also found. Based on the 

above data the residues of concern in plants are prothioconazole and its metabolite 

JAU6476-desthio. The risk assessment for the common metabolites arising from the 

triazole-derivative fungicides is being addressed by the US Triazole Task Force. In large 

animals, the nature of residues is also adequately understood for purposes of establishing 

the proposed tolerances. The residues of concern in edible tissues and milk are 

prothioconazole, its metabolites JAU6476-desthio, JAU6476-4-hydroxy, and their 

conjugates that can be converted to these three compounds by acid hydrolysis.]

2. Analytical method. [The analytical method for determining residues of concern 

in plants extracts residues of prothioconazole and JAU6476-desthio and converts the 

prothioconazole to JAU6476-desthio and JAU6476-sulfonic acid. Following addition of 

internal standards the sample extracts are analyzed by LC/MS/MS. Radiovalidation and 

independent laboratory validation have shown that the method adequately quantifies 

prothioconazole residues in treated commodities. The validated LOQ for total 

prothioconazole-derived residues in rice grain was 0.02 ppm. The validated LOQs were 0.01 

ppm for 1H-1,2,4-triazole and 0.05 pm for the triazole conjugates for grain. The analytical 

method for analysis of large animal tissues includes extraction of the residues of concern, 

followed by addition of an internal standard to the extract. The extract is then hydrolyzed 

to release conjugates, partitioned and analyzed by LC/MS/MS as prothioconazole, 

JAU6476-desthio and JAU6476-4-hydroxy. The method for analysis of milk eliminated 

the initial extraction step in the tissue method.]

3. Magnitude of residues. [A total of 16 field trials (14 harvest and 2 decline) 

were conducted as part of the supervised crop field trial study for rice to measure the 

prothioconazole derived residues in/on rice following two foliar spray applications of 

JAU6476 480 SC at a target rate of 0.18 lb ai/acre/application (0.20 kg ai/ha/application), 

with a 13 to 16 day spray interval. Rice grain and straw were collected from each treated 

plot with PHIs ranging from 40 to 67 days. At two locations additional samples were 

taken to determine residue decline. The average prothioconazole derived residue was 

0.03 ppm in/on rice grain with a maximum residue of 0.22 ppm. Results of the rice 

processing study indicated that prothioconazole residues concentrated in rice hulls 
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(4.4X), but not in polished grain or bran. Residues of 1H-1,2,4-triazole were less than the 

LOQ (<0.01 ppm) in/on rice grain. Maximum residues of the triazole conjugates were 

0.571 ppm (rice grain).

The maximum storage interval of crop samples from harvest to analysis for total 

prothioconazole-derived residues was 1240 days (40.8 months). The degree of loss of 

prothioconazole-derived residues and prothioconazole-desthio residues is not expected to 

exceed 30% after 40.8 months in rice samples.

For alfalfa, results from a TRR study indicate a no residue situation. The TRR in alfalfa 

forage from three successive cuttings from plants grown from seed treated with [triazole3,5-14C] prothioconazole at a target rate of 5 g a.i./100 kg seed and 15 g a.i./100 kg seed 

loading was <0.005 ppm. The TRR in alfalfa hay from the second and third cuttings from

plants grown from seed treated with [triazole-3,5-14C] prothioconazole at both 

application rates was also <0.005 ppm. Although the TRR in alfalfa hay from the first 

cutting was not measured, the percent dry matter for forage from the first cutting was 

measured and when adjusted to reflect the typical percent dry matter in alfalfa hay

(89%)5 the net residues in alfalfa hay at both treatment levels are <0.005 ppm.

For potato, results from a TRR study indicate a no residue situation for components of the 

residue definition. Potato seed, treated with [triazole-UL-14C] prothioconazole at a rate 

of 0.36 g ai/100 kg seed (3.7 ppm; 1.02X the target rate of 0.36 g ai/100 kg seed), was 

planted and potato was grown to maturity. The potato raw agricultural commodity

(RAC) of tubers was collected at harvest time. The total radioactive residue (TRR) in the 

tubers was 0.0061 ppm. The residues in tubers were extracted and characterized. Mainly

highly polar degradation products were found in potato; only very small amounts (5% or 

<0.001 ppm) of the components of the residue definition were detected.]

B. Toxicological Profile

1. Acute toxicity. [Prothioconazole exhibits very low acute oral, dermal and 

inhalation toxicity. The acute oral LD50 for prothioconazole in rats was >6200 

mg/kg/day while the dermal LD50 was >2000 mg/kg/day and the four-hour rat inhalation 

LC50 >4990 mg/m3. Prothioconazole was not irritating to the eye or skin of rabbits and 

did not cause skin sensitization in guinea pigs.]

2. Genotoxicty. [Prothioconazole is not mutagenic. Slightly positive and equivocal 

responses seen in in vitro cytogenetic and UDS assays were negative in in vivo tests.]

3. Reproductive and developmental toxicity. [Prothioconazole is not considered a 

primary reproductive toxicant in a two-Generation rat reproduction study. The NOAEL 

for parental toxicity as well as the NOAEL for reproductive and neonatal effects is 95.6 

mg/kg bw/day. In the rat oral developmental toxicity study the fetal NOAEL was 500 

mg/kg bw/day and the maternal NOAEL was 80 mg/kg bw/day. A dose level of 1000 

mg/kg bw/day administered to the rat by the dermal route does not elicit developmental 

toxicity. In the rabbit, prothioconazole does not produce developmental toxicity at dose 

levels exceeding the maximum tolerated dose. Thus, prothioconazole is not teratogenic in 
4

either the rat or rabbit.]

4. Subchronic toxicity. [90-day feeding studies conducted in rats, mice, and dogs 

showed the liver and/or kidney to be the target organs. In these subchronic studies 

NOAELs were established at 100 mg/kg/day for the rat and 25 mg/kg/day for the mouse 

and dog.]

5. Chronic toxicity. [Prothioconazole is not carcinogenic in either the rat or the 

mouse even at dose levels in the rat exceeding the maximum tolerated dose. The liver and 

kidney are target organs of prothioconazole for non-neoplastic toxicity in the rat, mouse 

and dog. The lowest NOAEL established on the basis of long-term toxicity studies is 5 

mg/kg bw/day in the rat chronic toxicity/carcinogenicity study and the dog 52-week 

toxicity study.]

6. Animal metabolism. [Metabolism and pharmacokinetic studies in the rat 

demonstrate that prothioconazole is rapidly absorbed, metabolized and eliminated. The 

primary metabolites included JAU6476-desthio, as well as S- and O-glucuronides of 

prothioconazole.]

7. Metabolite toxicology. [The major metabolite of prothioconazole in the rat, 

plants and large animals is JAU6476-desthio. Therefore, a comprehensive evaluation of 

the mammalian toxicity of JAU6476-desthio has been performed. 

The acute oral, dermal, and inhalation toxicity of JAU6476-desthio in the rat is low 

(LD50 values: 2806/2506mg/kg [male/female], >5000mg/kg, 4-hour LC50: 

>5077mg/m3, respectively). It is non-irritating to skin and only very slightly irritating to 

eyes and has no cutaneous sensitizing potential by topical application.

The short and long-term oral toxicity of JAU6476-desthio has been investigated by 

dietary administration in the rat, mouse and dog. The common target organ in all 3 

species is the liver. Secondary effects on the thyroid in the rat and dog were associated 

with increased hepatic enzyme induction. In the long term studies, 52 weeks in the rat 

and 30 weeks in the dog, the NOAEL for the rat and the dog were 1.1 and 10.1 mg/kg 

bw/day, respectively. JAU6476-desthio is not carcinogenic in either the rat or the mouse. 

The NOAEL selected for human risk assessment is 1.1 mg/kg bw/day established in the 

combined chronic toxicity and carcinogenicity study in the rat.

JAU6476-desthio was negative for mutagenicity and genotoxicity in all in vitro and in 

vivo studies both with and without metabolic activation.

In a two-generation reproduction study the maternal NOAEL was 2.7 mg/kg bw/day and 

the NOAEL for reproductive and neonatal effects 10.0 mg/kg bw/day. The main targets 

at the highest dose were dystocia (probably secondary to hepatic toxicity), decreased pup 

viability, growth retardation and low incidence of cleft palates.

In the developmental toxicity studies cleft palates were seen in the rat and rabbit at the 

highest dose levels and supernumerary ribs in the rat at lower dose levels. The oral 
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NOAEL is 1 mg/kg bw/day in the rat and 2 mg/kg/day in the rabbit.

A developmental neurotoxicity study (DNT) in rats was conducted with 

JAU6476-desthio as the anticipated dietary exposure is mainly to JAU6476-desthio and 

not the parent. No evidence of neurotoxicity was seen in this study, including no 

compound-related effects involving neurobehavioral tests and neuropathology. 

Compound-related effects were limited to overt toxicity and developmental effects which 

were consistent with effects seen in other developmental toxicity studies. The overall 

NOAEL was 3.6 mg/kg bw/day.]

8. Endocrine disruption. [The toxicology database for prothioconazole is current 

and complete. Studies in this database include evaluation of the potential effects on 

carcinogenic, reproduction and development effects including an evaluation of the 

pathology of the endocrine organs following short- or long-term exposure. 

Prothioconazole is considered not to have primary endocrine effects.]

C. Aggregate Exposure

1. Dietary exposure. [An aggregate risk assessment was conducted for all 

registered uses on barley; dried beans and peas (Crop Group 6C); canola; peanuts; wheat; 

triticale; soybeans; and sugar beets; the pending petition requesting tolerances be 

established on the cereal grain crop group 15 and 16 (except sweet corn, sorghum, and 

rice) and sweet corn; and this proposed petition requesting tolerances on rice, alfalfa and 

potato. In actuality, rice and potato do not contribute to the dietary burden since the TRR 

studies show a no residue situation. 

The acute toxicity endpoint used in the acute assessment was the NOAEL of 2.0 

mg/kg/day from the prothioconazole-desthio rabbit developmental toxicity study as 

described in the Agency’s HED risk assessment memorandum on prothioconazole dated 

January 5, 2009. No acute endpoint was identified for the general U.S. population; 

Females, 13-49 years of age, was the only population subgroup to be included in the 

acute assessment. Application of a 100x uncertainty factor results in an acute reference 

dose (aRfD) of 0.02 mg/kg/day. The chronic reference dose (cRfD) of 0.01 mg/kg/day

results from application of a 100x uncertainty factor to the NOAEL of 1.1 mg/kg/day

from the rat chronic\oncogenicity prothioconazole-desthio toxicity study. 

The acute and chronic dietary assessments for combined food and water exposure show 

7.33% utilization of the aRfD by females 13-49 years and 9.0% utilization of the cRfD by 

the most sensitive subgroup, all infants. Results from the dietary exposure assessments

demonstrate a reasonable certainty that no harm to the overall U.S. population or any 

population subgroup will result from the use of prothioconazole on the above crops.]

i. Food. [An acute, Tier 2 dietary (food only) risk assessment was conducted. For 

the population subgroup females 13-49 years old, the acute analysis indicates an exposure 

of 0.57% of the aRfD at the 95th percentile. Results from a chronic, Tier 2 dietary (food

only) risk assessment show that the most highly exposed population subgroup is children 

1 to 2 years with an exposure equal to 1.4% of the cRfD followed by all infants at 0.9%. 
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Chronic exposure to the overall U.S. population is 0.6% of the cRfD.]

ii. Drinking water. [No monitoring data are available for residues of 

prothioconazole in drinking water, and EPA has established no health advisory levels or 

maximum contaminant levels for residues of prothioconazole in drinking water. In order 

to address drinking water, water was included in the dietary analysis for food. DEEM 

analyses were performed using the upper bound estimates for the peanut and sugar beet 

crop scenarios; the EDWC for the acute assessment is 29 ppb from the peanut scenario 

and 13 ppb from the sugar beet scenario for the chronic assessment (the estimated 

drinking water concentrations for the proposed foliar use on rice were less than those 

used in recent acute and chronic exposure assessments and so do not factor into the 

dietary assessment). For the population subgroup females 13-49 years old, the acute 

analysis results in an exposure of 6.76% of the aRfD. Results from a chronic, Tier 2 

dietary risk assessment indicate that the most highly exposed population subgroup was all 

infants with an exposure equal to 8.1% of the cRfD. Chronic exposure to the overall U.S.

population is 2.5% of the cRfD.]

2. Non-dietary exposure. [Prothioconazole is not registered for residential uses 

nor are any registrations pending for such uses.]

D. Cumulative Effects

[Prothioconazole is a member of the conazole family of fungicides. The 

cumulative effects of the primary common metabolites are being addressed by the US 

Triazole Task Force.]

E. Safety Determination

1. U.S. population. [In the Agency’s HED risk assessment memorandum on 

prothioconazole dated October 13, 2006, it is stated that quantification of acute risk to the 

general population including infants and children is not required. Based on the 

conservative exposure assumptions described above and on the completeness of the 

toxicity data, it can be concluded that total food and drinking water exposure to 

prothioconazole from all proposed uses will utilize 7.33% of the acute RfD for females 

13-49 years old and 3.1% of the chronic RfDs for the overall U.S. population. EPA 

generally has no concerns for exposures below 100% of the RfD, because the RfD 

represents the level at or below which daily aggregate exposure over a lifetime will not 

pose appreciable risks to human health.]

2. Infants and children. [In the Agency’s HED risk assessment memorandum on 

prothioconazole dated January 5, 2009, it is stated: “There are adequate data in the 

prothioconazole (including metabolites) database to characterize the potential for prenatal or post-natal risks to infants and children: two-generation reproduction studies in 

rats; developmental studies in rats and rabbits; and a developmental neurotoxicity study

in rats. The effects seen in these studies suggest that offspring are more susceptible: 

offspring effects were seen at levels below the LOAELs for maternal toxicity and, in 
7

general, were of comparable or greater severity compared to the effects observed in 

adults. However, the point of departure for the most sensitive of these studies (the rabbit 

developmental toxicity) is lower than that of the other studies (2 mg/kg/day), and is based 

on effects observed in the fetus, not the parent. Therefore, the offspring are considered to 

be protected and there is no need to retain the 10X FQPA factor, and it is reduced to 1X.” 

EPA also stated “No acute endpoint was identified for the general U.S. population. 

Females, 13-49 years of age, was the only population subgroup included in the acute 

assessment.”

In addition to the adequacy of the toxicity database, there are also no uncertainties with 

respect to the exposure database. Both the dietary food and water exposure assessments 

are conservative in nature. Additionally, there is no potential for residential exposure.

In Bayer’s chronic exposure assessment, the most highly exposed population subgroup, 

all infants, utilized 9.0 % of the chronic RfD. EPA generally has no concerns for 

exposures below 100% of the RfD, because the RfD represents the level at or below 

which daily aggregate exposure over a lifetime will not pose appreciable risks to human 

health.]

F. International Tolerances

[Codex MRLs are not yet published; however, prothioconazole was evaluated at 

both the 2008 and 2009 JMPR, so CODEX MRLs should be established in the near 

future.]