EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITION 

Docket ID Number: EPA-HQ-OPP-2012-0427

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

Interregional Research Project Number 4 

Pesticide Petition Number: PP 2E8012

EPA has received a pesticide petition (PP 2E8012) from [Interregional Research 

Project No. 4, 500 college Road East, Suite 201 W, 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 180.474 by amending the tolerances for residues 

of tebuconazole, alpha-[2-(4-chlorophenyl)ethyl]-alpha-(1,1-dimethylethyl)-1H-1,2,4-

triazole-1-ethanol, including its metabolites and degradates, in or on the raw agricultural 

commodity barley, grain at 0.3 parts per million (ppm); vegetable, cucurbit group 9 at 0.4 

parts per million (ppm); and vegetable, fruiting group 8-10 at 1.3 ppm. Further, this 

petition proposes to delete the existing tolerance vegetable, fruiting, group 8 at 1.3 ppm 

once the proposed tolerance has been established since the proposed new tolerance will 

supersede the existing tolerance. 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 support granting of the petition. Additional data may be needed before EPA rules 

on the petition.

A. Residue Chemistry

1. Plant metabolism. The nature of the residue in plants and animals is adequately

understood. The residue of concern is the parent compound only, as specified in 40 CFR 

180.474.

2. Analytical method. An enforcement method for plant commodities has been 

validated on various commodities. It has undergone successful EPA validation and has 

been submitted for inclusion in PAM II. The animal method has also been approved as 

an adequate enforcement method.

3. Magnitude of residues.

Bayer CropScience has previously provided US EPA with residue studies which support 

the existing US tolerances of 0.09 ppm on cucurbits and 0.15 ppm on barley grain. 

Additional trials to fulfill conditional requirements of registration were conducted. As a 

result, this petition proposes increasing the US tolerances for cucurbit vegetables to 0.4 

ppm and for barley grain to 0.3 ppm.
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In a magnitude of residue study on cantaloupe conducted by IR-4, two trials were 

conducted in California (region 10) as requested by US EPA as a condition of 

registration. In each trial, three broadcast foliar applications of Folicur 3.6F were made 

at a target label rate of 0.225 lb a.i./A/application for a total target application rate of 

0.675 lb ai/A. The actual total amount applied in each trial was 0.684 and 0.695 lb ai/A. 

Applications were made 10 – 13 days apart with a 6 or 7 day PHI.

A magnitude of residue study was also conducted by IR-4 on Barley. In this study, three 

trials were conducted, one in region 10 (California) and two in region 11 (Idaho and 

Washington) as requested by US EPA as a condition of registration. In each trial, one 

foliar application of Folicur 3.6F was made at a target label rate of 0.1125 lbs ai/A. 

Actual application rates ranged from 0.1088 to 0.1149 lb ai/A with a PHI of 29 or 31 

days. 

Residues in trials conducted according to the critical GAP range on cantaloupe from 0.05 

to 0.24 ppm (n=4), and on barley from 0.0666 ppm to 0.280 ppm (n=6).

B. Toxicological Profile

1. Acute toxicity. Tebuconazole exhibits moderate toxicity. The rat acute oral 

LD50 = 3,933 milligram/kilogram (mg/kg) (category III); the rabbit acute dermal LD50 > 

5,000 mg/kg (category IV); and the rat acute inhalation LC50 > 0.371 milligram/ Liter 

(mg/L) (category II). Technical tebuconazole was slightly irritating to the eye (category

III) and was not a skin irritant (category IV) in rabbits. Tebuconazole was not a dermal 

sensitizer.

2. Genotoxicty. An Ames test with Salmonella sp., a mouse micronucleus assay, a 

sister chromatid exchange assay with Chinese hamster ovary cells, and an unscheduled 

DNA synthesis assay with rat hepatocytes provided no evidence of mutagenicity.

3. Reproductive and developmental toxicity.

a. In a developmental toxicity study, pregnant female rats were gavaged with 

technical tebuconazole at levels of 0, 30, 60, or 120 mg/kg/day between days 6 

and 15 of gestation. The maternal no-observed adverse effect level (NOAEL) was 

30 mg/kg/day and the maternal lowest-observed adverse effect level (LOAEL)

was 60 mg/kg/day based on increased absolute and relative liver weights. The 

developmental NOAEL was 30 mg/kg/day and the developmental LOAEL was 60 

mg/kg/day based on delayed ossification of thoracic, cervical and sacral vertebrae, 

sternum and limbs plus an increase in supernumerary ribs.

b. In a developmental toxicity study, pregnant female rabbits were gavaged with 

technical tebuconazole at levels of 0, 10, 30, or 100 mg/kg/day between days 6 

and 18 of gestation. The maternal NOAEL was 30 mg/kg/day and the maternal 

LOAEL was 100 mg/kg/day based on minimal depression of body weight gains 

and food consumption. The developmental NOAEL was 30 mg/kg/day and the 

developmental LOAEL was 100 mg/kg/day based on increased postimplantation 

losses, malformations in 8 fetuses out of 5 litters (including peromelia in 5 

fetuses/4 litters; palatoschisis in 1 fetus/1 litter), hydrocephalus and delayed 
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ossification.

c. In a developmental toxicity study, pregnant female mice were gavaged with 

technical tebuconazole at levels of 0, 10, 30, or 100 mg/kg/day between days 6 

and 15 of gestation (part 1 of study) or at levels of 0, 10, 20, 30, or 100 mg/kg/day

between days 6 and 15 of gestation (part 2 of study). The maternal NOAEL was 

10 mg/kg/day and the maternal LOAEL was 20 mg/kg/day. Maternal toxicity

(hepatocellular vacuolation and elevations in AST, ALP and alkaline 

phosphatase) occurred at all dose levels but was minimal at 10 mg/kg/day. 

Reduction in mean corpuscular volume in parallel with reduced hematocrit 

occurred at doses greater than or equal to 20 mg/kg/day. The liver was the target 

organ. The developomental NOAEL was 10 mg/kg/day and the developmental 

LOAEL was 30 mg/kg/day based on an increase in the number of runts. 

d. In a developmental toxicity study, pregnant female mice were administered 

dermal doses of technical tebuconazole applied at levels of 0, 100, 300, or 1,000 

mg/kg/day between days 6 and 15 of gestation. Equivocal maternal toxicity was 

observed 1,000 mg/kg/day. The maternal NOAEL was <nearly-eq> 1,000 

mg/kg/day. The developmental NOAEL was 1,000 mg/kg/day.

e. In a 2-generation reproduction study, rats were fed technical tebuconazole at 

levels of 0, 100, 300, or 1,000 ppm, (0, 5, 15, or 50 mg/kg/day, males and 

females). The parental maternal NOAEL was 15 mg/kg/day and the parental 

LOAEL was 50 mg/kg/day based on depressed body weights, increased spleen 

hemosiderosis and decreased liver and kidney weights. The reproductive NOAEL 

was 15 mg/kg/day and the reproductive LOAEL of 50 mg/kg/day based on 

decreased pup body weights from birth through 3 - 4 weeks. 

f. In a developmental neurotoxicity study, pregnant female rats were fed a nominal 

concentration of 0, 100, 300 or 1000 ppm of tebuconazole in the diet. The 

NOAEL for maternal toxicity in this study was 300 ppm (based on mortality, 

body weight and feed consumption reductions, and prolonged gestation in 

the1000 ppm dosage group). The 1000 ppm dose level was considered to be 

excessively toxic for the F1 offspring, based on mortality, marked reductions in 

pup body weight and body weight gain, reduction in pup absolute brain weight (at 

postpartum day (PD) 12 and adult), a developmental delay in vaginal patency, and 

decreased cerebellar thickness. The effects on brain weight and morphology are 

considered to represent incomplete compensation for the marked decrease in body

weight gain during development. By approximately day 80 postpartum, the body

weight had completely recovered in the females but was still reduced (89% of the 

control group value) in the males. The brain weights had shown an incomplete 

recovery (90% to 93% of the control group values) in both sexes. The EPA has 

determined that the LOAEL for offspring toxicity in this study is 100 ppm. 

Technical grade tebuconazole did not cause any specific neurobehavioral effects 

in the offspring when administered to the dams during gestation and lactation at 

dietary concentrations up to and including 1000 ppm.

4. Subchronic toxicity.

a. In a 90-day oral feeding study, rats were administered technical tebuconazole at 

levels of 0, 100, 400, or 1,600 ppm (0, 8, 34.8, or 171.7 mg/kg/day for males or 0, 

10.8, 46.5, or 235.2 mg/kg/day for females). In males, the NOAEL was 34.8 
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mg/kg/day and the LOAEL was 171.7 mg/kg/day based on decreased body weight 

and decreased body weight gain, adrenal vacuolation and spleen hemosiderosis. In 

females, the NOAEL was 10.8 mg/kg/day and the LOAEL of 46.5 mg/kg/day was 

based on adrenal vacuolation.

b. In a 90-day oral feeding study, Beagle dogs were administered technical 

tebuconazole at levels of 0, 200, 1,000, or 5,000 ppm (0, 74, 368, or 1,749 

mg/kg/day for males or 0, 73, 352, or 1,725 mg/kg/day for females). In females, 

the NOAEL was 73 mg/kg/day and the LOAEL was 352 mg/kg/day based on 

decreased body weight and decreased body weight gain, decreased food 

consumption and increased liver N-demethylase activity. At the highest dose 

tested (HDT), lens opacity was seen in all males and in one female and cataracts 

were seen in three females.

c. In a 21-day dermal toxicity study, rabbits were exposed dermally to technical 

tebuconazole 5 days a week at doses of 0, 50, 250, or 1,000 mg/kg/day. No 

significant systemic effects were seen. The systemic NOAEL > 1,000 mg/kg/day.

d. In a 21-day inhalation toxicity study, rats were exposed to technical tebuconazole 

(15 exposures - 6 hours/day for 3 weeks) at airborne concentrations of 0, 0.0012, 

0.0106, or 0.1558 mg/L/day. The NOAEL was 0.0106 mg/L/day and the LOAEL 

was 0.1558 mg/L/day based on piloerection and induction of liver N-demethylase.

5. Chronic toxicity.

a. In a 2-year combined chronic feeding/carcinogenicity study, rats were 

administered technical tebuconazole at levels of 0, 100, 300, or 1,000 ppm (0, 5.3, 

15.9, or 55 mg/kg/day for males or 0, 7.4, 22.8, or 86.3 mg/kg/day for females). In 

males, the NOAEL was 5.3 mg/kg/day and the LOAEL was 15.9 mg/kg/day

based on C-cell hyperplasia in the thyroid gland. In females, the NOAEL was 7.4 

mg/kg/day and the LOAEL was 22.8 mg/kg/day based on body weight 

depression, decreased hemoglobin, hematocrit, mean corpuscular volume and 

mean corpuscular hemoglobin concentration and increased liver microsomal 

enzymes. No evidence of carcinogenicity was found at the levels tested.

b. In a 1-year chronic feeding study, Beagle dogs were administered technical 

tebuconazole at levels of 0, 40, 200, or 1,000 (weeks 1-39) and 2,000 ppm (weeks 

40-52) (0, 1, 5 or 25/50 mg/kg/day for males and females). The NOAEL was 1 

mg/kg/day and the LOAEL was 5 mg/kg/day based on ocular lesions (lenticular 

and corneal opacity) and hepatic toxicity (changes in the appearance of the liver 

and increased siderosis).

c. In a 1-year chronic feeding study, Beagle dogs were administered technical 

tebuconazole at levels of 0, 100, or 150 ppm (0, 3.0, or 4.4 mg/kg/day for males 

or 0, 3.0 or 4.5 mg/kg/day for females). The NOAEL was 3.0 mg/kg/day and the 

LOAEL was 4.4 mg/kg/day based on adrenal affects in both sexes. In males there 

was hypertrophy of adrenal zona fasciculata cells amounting to 4/4 at 150 ppm 

and to 0/4 at 100 ppm and in controls. Other adrenal findings in males included 

fatty changes in the zona glomerulosa (3/4) and lipid hyperplasia in the cortex 

(2/4) at 150 ppm vs. (1/4) for both effects at 100 ppm and control dogs. In females 

there was hypertrophy of zona fasciculata cells of the adrenal amounting to 4/4 at 

150 ppm and to 0/4 at 100 ppm and 1/4 in controls. Fatty changes in the zona 

glomerulosa of the female adrenal amounted to 2/4 at 150 ppm and to 1/4 at 100 
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ppm and in controls.

d. In a 91-week carcinogenicity study, mice were administered technical 

tebuconazole at levels of 0, 500, or 1,500 ppm (0, 84.9, or 279 mg/kg/day for 

males or 0, 103.1, or 365.5 mg/kg/day for females). Neoplastic histopathology

consisted of statistically significant increased incidences of hepatocellular 

neoplasms; adenomas (35.4%) and carcinomas (20.8%) at 1,500 ppm in males 

and carcinomas (26.1%) at 1,500 ppm in females. Statistically significant 

decreased body weights and increased food consumption were reported that were 

consistent with decreased food efficiency at 500 and 1,500 ppm in males and at 

1,500 ppm in females. Clinical chemistry values (dose-dependent increases in 

plasma GOT, GPT and Alkaline Phosphatase) for both sexes were consistent with 

hepatotoxic effects at both 500 and 1,500 ppm. Relative liver weight increases 

reached statistical significance at both 500 and 1,500 ppm in males and at 1,500 

ppm in females. Non-neoplastic histopathology included dose-dependent 

increases in hepatic pancinar fine fatty vacuolation, statistically significant at 500 

and 1,500 ppm in males and at 1,500 ppm in females. Other histopathology 

included significant oval cell proliferation in both sexes and dose-dependent 

ovarian atrophy that was statistically significant at 500 and 1,500 ppm. The 

Maximum Tolerated Dose (MTD) was achieved at or around 500 ppm.

6. Animal metabolism. Rats were gavaged with 1 or 20 mg/kg radio-labeled 

technical tebuconazole. 98.1 % of the oral dose was absorbed. Within 72 hours of dosing, 

over 87% of the dose was excreted in urine and feces. At sacrifice (72 hours post dosing), 

total residue (-GI tract) amounted to 0.63% of the dose. A total of 10 compounds were 

identified in the excreta. A large fraction of the identified metabolites corresponded to 

successive oxidations steps of a methyl group of the test material. At 20 mg/kg, changes 

in detoxication patterns may be occurring.

7. Metabolite toxicology. Not applicable

8. Endocrine disruption. Tebuconazole was one of the chemicals included in List 

1 of the EPA Endocrine Disruptor Screening Program (EDSP). BCS has received the 

EDSP Test Order and has committed to fulfilling the requirements as appropriate.

C. Aggregate Exposure

1. Dietary exposure.

The EPA’s April 18, 2008 Tebuconazole Human Health Risk Assessment used the 

LOAEL of 8.8 mg/kg/day from a tebuconazole rat developmental neurotoxicity study and 

an uncertainty factor of 300 to establish the acute and chronic population adjusted doses 

(aPAD and cPAD, respectively) at 0.029 mg/kg/day. 

The higher residue values for cucurbit vegetables and barley grain were included in the 

dietary exposure assessment. A tier 3 dietary assessment was conducted to evaluate 

exposure for the U.S. population and all appropriate subgroups. Results of this 

assessment show that no harm to the overall U.S. population or any population subgroup 

will result from the use of tebuconazole on currently registered uses when incorporating 
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the additional residue results.

i. Food. A tier 3 dietary assessment (using DEEM FCID Version 2.0, 1994-1996, 

98 CSFII) including all of the current and pending uses of tebuconazole showed that the 

most highly exposed population subgroup for food only for the acute assessment was 

children 1-2 with an exposure equal to 19.3% of the aPAD. The U.S. total population had 

an exposure for food only equal to 11.5% of the aPAD. The chronic analysis for food 

only showed that the most highly exposed population subgroup was children 1-2 with an 

exposure equal to 1.2% of the cPAD. The total U.S. population had a chronic exposure 

equal to 0.6% of the cPAD. These exposure estimates are below EPA’s level of concern.

ii. Drinking water. Acute and chronic exposure estimates for combined food plus 

water intake are also below EPA’s level of concern. Assuming an acute drinking water 

level of 33.8 ppb, the most highly exposed population subgroup for food plus water was 

infants <1 year with an exposure equal to 25.1% of the aPAD. The U.S. total population 

had an exposure for food plus water equal to 13.5% of the aPAD. Assuming a chronic 

drinking water level of 15.2 ppb, the chronic analysis for food plus water showed that the 

most highly exposed population subgroup was infants < 1 year with an exposure equal to 

4.5% of the cPAD. The total U.S. population had a chronic exposure equal to 2.8% of the 

cPAD.

2. Non-dietary exposure. Tebuconazole is currently registered for use on the 

following residential non-food sites: residential application to roses, flowers, trees and 

shrubs; the formulation of wood-based composite products; wood products for in-ground 

contact; plastics; glues and adhesives. EPA in their April 18 2008 Human Health Risk 

Assessment assessed residential handler, post-application and other exposures (drift etc.) 

to homeowners. EPA concluded that exposures to homeowners do not exceed the level of 

concern.

D. Cumulative Effects. Tebuconazole is a member of the triazole class of systemic 

fungicides. At this time, the EPA has not made a determination that tebuconazole and 

other substances that may have a common mechanism of toxicity would have cumulative 

effects. Therefore, for this tolerance petition, it is assumed that tebuconazole does not 

have a common mechanism of toxicity with other substances and only the potential risks 

of tebuconazole in its aggregate exposure are considered. The cumulative effects of the 

primary common metabolites (1,2,4-triazole and its TA and TAA conjugates) are being 

addressed by the US Triazole Task Force.

E. Safety Determination

1. U.S. population. Based on the information supplied under Aggregate Exposure 

describe above, there is reasonable certainty that exposure from tebuconazole will not 

result in harm to the U.S. population.

2. Infants and children. Based on the information supplied under Aggregate 

Exposure describe above, there is reasonable certainty that exposure from tebuconazole 
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will not result in harm to infants and children.

F. International Tolerances

International tolerances/MRLs for tebuconazole have been established for many crops 

including, barely and cucurbits. Codex MRLs have been established on barley grain at 

0.2 ppm, on cucumber at 0.2 ppm and on summer squash at 0.02 ppm. EU MRLs are 2 

ppm for barley, 0.5 ppm for cucumber, 0.2 ppm for muskmelon and 0.2 ppm on summer 

squash.