**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 tolerance s for residues of tebuconazole, alpha

- [2
- (4

- chlorophenyl)eth yl ]
- alpha

- (1,1

- dimethylethyl)

- 1H
- 1,2,4
- triazole

- 1
- ethanol, including its metabolites and degradates, in or on the raw agri cultural 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 t o delete the existing tolerance vegetable, fruitin g, 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. Plan t 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. B ay er CropScience has previousl y provided US EPA with residue studies which support the existing US toleranc es 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
.2

In a magnitude of residue study on cantaloupe conducted by I R
- 4, two trials were conducted in California (regi on 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 act

ual total amount applied in each trial was 0.684 and 0.695 lb ai/A. Applications were made 10

– 13 day s apart with a 6 or 7 day PHI. A magnitude of residue study was also conducted by

I R
- 4 on Barley . In this study , three trials were conducted, one in re gion 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 ran ged from 0.1088 to 0.1149 lb ai/A w ith a PHIof 29 or 31 day s. Residues in trials conducted according to the critical GAP range on canta loupe 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 LD 50 = 3,933 milligram/kilogram (mg/kg) (category I II); the rabbit acute dermal LD 50 > 5,000 mg/kg (category

IV); and the rat acute i nhalation L C 50 > 0.371 milligram/ L iter (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 s ynthesis assay with rat hepatocytes provided no evidence of mutag enicity
. 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 day s 6 and 15 of gestation. The maternal no - observ ed 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 delay ed 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 leve ls of 0, 10, 30, or 100 mg/kg/day between day s 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/d ay 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 delayed3 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 day s 6 and 15 of gestation (part 1 of study) or at levels of 0, 10, 20, 30, or 100 mg/kg/day between day s 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 mi nimal 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 w as 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 day s 6 and 15 of gestation. Equivocal maternal toxicity was observed 1,000 mg/kg/day . The maternal NOAEL was <nearl y - 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 level s 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 concentr ation 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 d ose 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 vag inal 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 completel y 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 LOAELfor offspring toxicity in this study

is 100 ppm. Technical grade tebuconazole did not cause an y s pecific neurobehavioral effects in the offspring when administered to the dams during gestation and lactation at dietary concentrations up to and inclu ding 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 34.84 mg/kg/day

and the LOAEL was 171.7 mg/kg/day based on decreased body weight and decreased bod y weight gain, adrenal vacuolation and spleen hemosiderosis. In females, the NOAEL was 10. 8 mg/kg/day and the L OAEL 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, 7 3, 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 bod y weight and decreased bod y 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 dermall y to technical tebuconazole 5 day s a week at doses of 0, 50, 250, or 1, 000 mg/kg/day . No significant s ys temic effects were seen. The s ys temic 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. Ina 2
- ye ar combined chronic feeding/carcinogenicity study , rats we re 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 h yperplasia in the thy roid gland. In females, the NOAEL was 7.4 mg/kg/day

and the LOAELwas 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 enzy mes. No evidence of carcinogenicity was found at the levels tested. b. In a 1
- ye ar 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 LOAELwas 5 mg/kg/day based on ocular lesions (lenticular and corneal opacit y) and hepatic toxicity (changes in the appearance of the liver and increased siderosis). c. In a 1
- ye ar 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 NOAELwas 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 h ypertroph y 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 hy perplasia in the cortex (2/4) at 150 ppm vs. (1/4) for both effects at 100 ppm and control dogs. In females there was h yp ertroph y 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. F att y changes in the zona glomerulosa of the female adrenal amounted to 2/4 at 150 ppm and to 1/4 at 1005 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 carc inomas (26.1%) at 1,500 ppm in females. Statistically significant decreased bod y 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 ch emistry 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 atroph y 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 do sing), total residue (

- GItract) 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 meth yl 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 L ist 1 of the EPA Endocrine Disruptor Screening Program (EDSP)
. BCS has recei ved 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. populat ion or any population subgroup will result from the use of tebuconazole on currently registered uses when incorporating6

the additional residue results. i. Food. A tier 3 dietary

assessment (using DEEM FCID Version 2.0, 1994

- 1996, 98 CSFII) including a ll 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 fo od only equal to 11. 5 % of the aPAD. The chronic anal ys is 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 th e cPAD. These exposure estimates are below EPA’s level of concern. ii. Drinking water. Acute and chronic exposure estimates f or 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 l evel of 15.2 ppb, the chronic analy sis for food plus water showed that the most highly

exposed population subgroup was infants < 1 y ear 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 co mposite 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 s ystemic 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 onl y 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 b y the US Triazole Task Force. E. Safety Determinat ion 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 tebuconazole7

will not result in harm to infants and children. F. International Tolerances Internationa l tolerances/MRL s for tebuconazole have been established for many crops including, barel y and cucurbits . Codex MRL s have been established on barley grain at 0.2 ppm , on cucumber at 0.2 ppm and on summer squash at 0. 0 2 ppm
. EU MRL s are 2 ppm for barley , 0.5 ppm for cucumber, 0.2 ppm for muskmelon and 0.2 ppm on summer squash
.