**COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (8**  **/ 7/2007)**  **EPA Registration Division contact: [**  **Erin Malone, (703) 347**  **- 0253; PM Team 20**  **Fungicide Branch ]** 
**Dow AgroSciences Petition # 2F8034**  EPA has received a pesticide petition **( 2F**  **8034 )**  from **Dow AgroSciences LLC ,**  **9330 Zionsville Road**

**– Indianapolis, Indiana 46268**  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. 381. **1. by amending an established tolerance for residues of**  **fenbu co**  **nazole ,**  **alpha**

**– [2** 

**– (4** 

**– chlorophenyl)** 

**– ethyl]** 

**– alpha** 

**– phenyl** 

**– 3** 

**– (1H** 

**– 1,2,4** 

**– triazole)** 

**– 1** 

**– propanenitrile, and its metabolites RH** 

**– 9129, cis** 

**– 5** 

**– (4** 

**– chlorophenyl)** 

**– dihydro** 

**– 3** 

**– phenyl** 

**– 3** 

**– (1H** 

**– 1,2,4** 

**– triazole** 

**– 1** 

**– ylmethyl)** 

**– 2** 

**– 3 H** 

**– furanone, and RH** 

**– 9130, trans** 

**– 5** 

**– (4** 

**– chlorophenyl)**  **- dihydro** 

**– 3** 

**– phenyl** 

**– 3** 

**– (1H** 

**– 1,2,4** 

**– triazole** 

**– 1** 

**– ylmethyl)** 

**– 2** 

**– 3 H** 

**– furanone**  in or on th e raw agricultural commodity **pepper** 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. A. Residue Chemistry 1. Plant metabolism **[ The qualitative nature of fenbuconazole residues in**  **plants is adequately understood based on acceptable metabolism studies on wheat, peaches, sugarbeets and peanuts. The metabolism of fenbuconazole was**  **qualitatively similar in all crops and proceeded via three pathways. Based on these**  **metabolism studies, the residue of concern for dietary exposure and tolerance setting purposes in pepper is the combined residues of the parent compound,**  **fenbuconazole and its metabolites, RH -**  **9129 and RH -**  **9130 [ cis**  **and trans**  **- 5**  **- (4**  **- chlorophenyl)**  **- dihydro**  **- 3**  **- phenyl**  **- 3**  **- (1**  **H -**  **1,2,4 -**  **triazole -**  **1 -** **ylmethyl) -**  **2 -**  **3 H**  **- furanone)]**  **. The total residue is expressed as fenbuconazole.**  **]** 2. Analytical method. **[ Adequate analytical methods are available to enforce**  **the tolerances of fenbuconazole residues in plant commodities. The analytical**  **methods vary depending on the matrices being analyzed. These methods had undergone successful independent laboratory validation.**  **For pepper, samples from the residue trials were analyzed for fenbuconazole (RH**   ** 7592)** **and its lactone metabolites, RH -**  **9129 and RH -**  **9130, using Rohm & Haas analytical method Technical Report Number 34**  **- 90**  **- 47 or Technical Report Number**  **34 -**  **90 -**  **47R. The method had undergone an independent method validation and was also successfully**  **accepted by E**  **PA with minor modifications suggested by the Agency that included procedure for the standardization of the silica gel and Florisil**  **column clean -**  **up elution pattern (TR -**  **34 -**  **90 -**  **47R). The limits of quantitation and detection of the method are 0.01 μg/g and 0.0**  **03 μg/g, respectively. ]**  3. Magnitude of residues. **[ The magnitude of residues of fenbuconazole**  **and its two metabolites, RH**  **- 9129 and RH**  **- 9130, in**  **was determined following four foliar broadcast applications of either ENABLE 2F at 12 fl oz/A or INDAR 75 WSP at 4**  **oz/A per application , in side**  **- by**  **- side treatments**  **. The active ingredient in both**  **test substance**  **s was fenbuconazole. Target rates were**  **0.188 lb ai/A per application with a total treatment rate of 0.752 lb**  **ai/A. The applications were made with a nominal 10**  **- day retreatment interval, approximately 37, 27, 17 and 7 days prior to harvest.**  **Application rates ranged from 98% to 104% of the targ et rate and spray volumes**  **ranged from 30 to 47 gal/A. Non**  **- ionic surfactant was used for all applications.**  **This study contained**  **six RAC (raw agricultural commodity) trials**  **, including one decline**  **trial to obtain residue data to satisfy EPA regulatory requir ements for**  **fenbuconazole. A total of six trials were conducted. Residues of fenbuconazole and two metabolites**  **in bell peppers were determined using gas chromatography with a NP**  **- specific**  **detector. The limit of quantitation (LOQ) of the method was 0.01 pp m and limit of**  **detection (LOD) was 0.003 ppm for each analyte. Residue data show fenbuconazole residues in bell pepper to be similar when treated**  **with either of the two formulations used in this study. Fenbuconazole residues, in the individual samples, r**  **ange from 0.029 to 0.668 ppm (**  **μg/g ). The highest**  **fenbuconazole residues were found in trial**  **A conducted in Alabama where pepper**  **ma turity was delayed**  **by weather a month beyond normal growth. There were no**  **metabolite residues (<0.01 ppm) found in any of th**  **e 7 -**  **day pepper samples collected. Average fenbuconazole residues in peppers from the decline trial**  **are calculated .**  **The difference in residue levels was minimal in bell peppers treated with the two formulations while residues in both**  **treated plots showed**  **fairly rapid degradation for**  **both Enable and Indar formulations, respectively. Metabolite**  **s residues were** **found only in the 0 -**  **day pepper samples in this trial with the highest residue level of**

**0.017 ppm.**  **]** B. Toxicological Profile 1. Acute toxicity. **[ Fenbuconazole**  **is practically non -**  **toxic after administration by the oral and dermal routes, and was not significantly toxic to rats**  **after a 4 hour inhalation exposure. Fenbuconazole is classified as not irritating to skin and inconsequentially irritating to**  **the eyes. It is not a skin sensitizer. The toxicological profile and endpoints for fenbuconazole which supports this**  **petition to establish tolerances were previously published in the Federal Register of July 20, 2005 (70 FRL**  **- 7702**  **- 7).**  **For acute dietary r isk assessments, EPA ha**  s **established a**  **reference dose (acute RfD) of 0.3 mg/kg/day for females 13 -**  **49 years old**  **, the population sub -**  **group of concern. The aRfD is based on the developmental**  **toxicity study in the rat with a maternal and developmental NOAEL of 30 mg/kg/day and an uncertainty factor of 100. A decrease in maternal body weight,**  **an increase in post -**  **implantation loss and a significant decrease in the number of live**  **fetuses per dam were observed at the LOAEL of 75 mg/kg/day. No appropriate endpoint was available for analyzing the acute exposure of the overall U. S.**  **population.** 2. Genotoxicty. **[ Fenbuconazole was negative (non**  **- mutagenic) in an Ames**  **assay with and without hepatic enzyme activation. Fenbuconazole was negative in a**  **hypoxanthine guanine phosphoribosyl transferase (HGPRT) gene mutation assay using Chinese hamster ovary (CHO) cells in culture when tested with and without**  **hepatic enzyme a ctivation.**  **In isolated rat hepatocytes, fenbuconazole did not induce unscheduled DNA synthesis (UDS) or repair.**  **Fenbuconazole did not produce chromosome effects in rats in vivo.**  **On the basis of the results from this battery of tests, it is concluded tha**  **t, fenbuconazole is not mutagenic or genotoxic. ]**  3. Reproductive and developmental toxicity . **[ i**  **. Developmental toxicity in the rat.**  **In the developmental study in rats, the maternal (systemic) no observed adverse effect level (NOAEL) was 30 mg/kg/day based on decreases in body weight**  **and body weight gain at the lowest observed adverse effect level (LOAEL) of 75 mg/kg/day.**  **The developm ental (fetal) NOAEL was 30 mg/kg/day based on an**  **increase in post implantation loss and a significant decrease in the number of live fetuses per dam at the LOAEL of 75 mg/kg/day.**  **ii. Developmental toxicity in the rabbit. In the developmental study in rabbits, the ma**  **ternal (systemic) NOAEL was 10 mg/kg/day based on decreased body weight gain at the LOAEL of 30 mg/kg/day.**  **The developmental (fetal) NOAEL was 30 mg/kg/day based on**  **increased resorptions at the LOAEL of 60 mg/kg/day. iii. Reproductive toxicity.**  **In the 2 -**  **generation reproduction toxicity study in rats, the maternal (systemic) NOAEL was 4 mg/kg/day based on decreased body weight**  **and food consumption, increased numb er of dams delivering nonviable offspring,** **and increases in adrenal and thyroid weights at the LOAEL of 40 mg/kg/day. The** 

**reproductive (pup) NOAEL was 40 mg/kg/day, the highest dose tested. ]**  4. Subc hronic toxicity. **[ i. Rat 90**  **- day oral study. A**  **Subchronic feeding study in rats conducted for 13**  **- weeks resulted in a NOAEL of 80 parts per million**  **(ppm) (5.1 and 6.3 mg/kg/day in males and females, respectively).**  **The only effect observed at 80 ppm was minimal centrilobular hypertrophy (seen in one mal**  **e) and hepatocytic centrilobular vacuolation (3 males) with no concomitant increase in**  **liver weight or clinical chemistry correlates and no analogous effects in females. As**  **such, these observations are not considered to be adverse.**  **Increased liver weight,**  **hepatic hypertrophy, thyroid hypertrophy, and decreased body weight were observed at the higher doses of 400 and 1,600 ppm.**  **ii. Dog 90 -**  **day oral study. A subchronic feeding study in dogs conducted for 13 -**  **weeks resulted in a NOAEL of 100 ppm (3. 3 and 3.5 mg/kg/day in males and**  **females, respectively). At the LOAEL of 400 ppm, increased liver weight, clinical**  **chemistry parameters, and liver hypertrophy (males) were observed. iii. Rat 4**  **- week dermal study. In a 21**  **- day dermal toxicity in the rat study, the**  **NOAEL was greater than 1,000 mg/kg/ day, with no effects seen at this limit dose. ]**  5. Chronic toxicity. **[ i. Dog. A 1**  **- year feeding study in dogs resulted in a**  **NOAEL of 15 ppm (0.62 mg/kg/day) for females and 150 ppm (5.2 mg/kg/day) for**  **males. Decreased body weight, increased liver weight, liver hypertrophy, and**  **pigment in the liver were observed at the LOAEL of 150 and 1,200 ppm in females**  **and males, respectively. ii. Mouse. A 78**  **- week chronic/oncogenicity study was conducted in male and**  **female mice at 0, 10, 200 (males only), 650, and 1,300 ppm (females only). The NOAEL was 10 ppm (1.4 mg/kg/day), and the LOAEL was**  **200 ppm (26.3 mg/kg/day) for males and 650 ppm**  **(104.6 mg/kg/day) for females**  **based on increased liver weight and histopathological effects on the liver, which were**  **consistent with chronic enzyme induction. There was no statistically significant increase of any tumor type in males. However, there was**  **a statistically significant increase in combined liver adenomas and carcinomas in females at the high dose**  **only (1,300 ppm; 208.8 mg/kg/day). There were no liver tumors in the control**  **females, and liver tumor incidences in the high -**  **dose females just excee ded the**  **historical control range. In ancillary mode -**  **of -**  **action studies in female mice, the increased tumor incidence was associated with changes in several parameters in**  **mouse liver following high doses of fenbuconazole, including an increase in P450 enzyme**  **s (predominately of the CYP 2B type), an increase in cell proliferation, an increase in hepatocyte hypertrophy, and an increase in liver weight.**  **Changes in these liver parameters, as well as the occurrence of the low incidence of liver**  **tumors, were non -**  **li near with respect to dose (i.e., effects were observed only at high**  **dietary doses of fenbuconazole). Similar findings have been shown with several pharmaceuticals, including phenobarbital, which is not carcinogenic in humans.** **The non -**  **linear dose response r elationship observed with respect to liver changes** 

**(including the low incidence of tumors) in the mouse indicates that these findings should be carefully considered in deciding the relevance of high**  **- dose animal tumors**  **to human dietary exposure. iii. R**  **at. A 24 -**  **month chronic/oncogenicity study in male and female rats was conducted at 0, 8, 80, and 800 ppm fenbuconazole, and a second 24**  **- mo**  **nth chronic/oncogenicity study was conducted in male rats at 0, 800, and 1,600 ppm.**  **The NOAEL was 80 ppm (3 and 4 mg/k g/day in males and females, respectively),**  **and the LOAEL was 800 ppm (31 and 43 mg/kg/day in males and females, respectively) based on decreased body weight, increased liver and thyroid weights,**  **and liver and thyroid hypertrophy. Fenbuconazole produced a**  **minimal but statistically significant increase in the incidence of combined thyroid follicular cell**  **benign and malignant tumors. These findings occurred only in male rats following**  **life -**  **time ingestion of very high levels (800 and 1,600 ppm in the diet) of fenbuconazole.**  **For chronic dietary risk assessments, EPA has established the chronic reference dose (cRfD) for fenbuconazole at 0.03 mg/kg/day. The cRfD is based on the 2**  **- year**  **combined chronic feeding -**  **carcinogencity study in rats with a NOAEL of 3.0 and 4.0**  **mg/kg/day in males and females, respectively, and uncertainty factor of 100 accounting for both interspecies extrapolation (10x) and intraspecies variability**  **(10x). The FQPA safety factor is 1X. In general, the primary organs for toxicity were the l**  **iver (hepatocellular enlargement in females and hispathological lesions in both sexes) and thyroid (histopathological lesions and thyroid weight increase in**  **both sexes). iv. Carcinogenicity. The Agency has concluded, that the available data provide**  **li mited evidence of the carcinogenicity of fenbuconazole in both mice and rats and**  **has classified fenbuconazole as a Group C carcinogen (possible human carcinogen) in accordance with Agency guidelines, published in the Federal Register (51 FR**  **33992, Septembe r 24, 1986), and recommended that for the purpose of risk**  **characterization a low -**  **dose extrapolation model applied to the experimental animal tumor data should be used for quantification of human risk (Q**  **1** ***). EPA's 26 Feb**  **1998 Hazard Identification Assessme nt Review Committee (HIARC) report**  **concluded that 0.00359 (mg/kg/day) -**  **1 is the appropriate Q**  **1** *** for fenbuconazole; this Q**  **1** *** is based on the fenbuconazole mouse liver tumor data, along with a power surface area scaling factor.**  **]** 6. Animal metabolism. **[ The absorption, distribution, excretion, and**  **metabolism of fenbuconazole in rats, goats, and hens were investigated. Following oral administration, fenbuconazole was completely and rapidly absorbed,**  **extensively metabolized by oxidation/hydroxylation and c onjugation, and rapidly**  **and essentially completely excreted, predominately in the feces. Fenbuconazole did**  **not accumulate in tissues. ]** 7. Metabolite toxicology
. **[ There are no toxicological concerns for** 

**fenbuconazole based on differential metabolic pathways in plants and animals. Triazole fungicides are known to produce three common metabolites, 1,2,4**  **- triazole,**  **triazolylalanine and triazole acetic acid. To support**  **the extension of existing parent triazole**  **- derivative fungicide tolerances, EPA conducted an interim human health**  **assessment for aggregate exposure to 1,2,4 -**  **triazole. This interim assessment was**  **summarized in the Federal Register notice dated August 4, 2004 and titled Propiconazole; Time**  **- Lim**  **ited Pesticide Tolerances. EPA concluded, that for all**  **exposure durations and population subgroups, aggregate exposures to 1,2,4 -**  **triazole are not expected to**  **exceed its level of concern.**  **]** 8. Endocrine disruption
. **[ The mammalian endocrine system includes**  **estrogen and androgens as well as other hormonal systems. Fenbuconazole is not**  **known to interfere with reproductive hormones; thus , fenbuconazole**  **should not be considered to be estrogenic or androgenic.**  **There are no known instances of proven or alleged adverse reproductive or developmental effects to people, domestic**  **animals, or wildlife as a result of exposure to fenbuconazole or its residues. ]**  C. Aggregate Exposure 1. Dietary exposure. [ **The exposure and risk resulting from agricultural uses of**  **fenbuconazole was considered for the U.S. population and special**  **sub -**  **populations. There are two**  **direct sources of exposure to humans considering fenbuconazole’s**  **uses across all labels: from food intake**  **and from consuming**  **drinking water .**  **The exposure and risk are estimated in this report for different durations of**  **both routes of exposure and their aggregated contribution. In an**  **aggregate assessme nt, exposures from food residues were combined with**  **conservative estimates of potential water residues. The current approach of the EPA Office of Pesticide Programs (OPP) is to use a tiered approach for acute**  **dietary risk assessment that proceeds from ver y conservative assumptions about**  **food residues, to inclusion of more realistic residue values measured closer to the point of consumption**  **. ]**  i. Food. **[ The process of dietary risk assessment of pesticides considers**  **chronic and acute exposures to the U.S. population and sensitive population sub**  **** **groups. Additional exposures from potential residues in drinking water were also estimated.**  **The Dietary Exposure Evaluation Model (DEEM -**  **FCID, version 2. 1**  **4), a commercially available software package, was used to es**  **timate exposure to fenbuconazole**  **via food consumption by the general U.S. population and certain subgroups. The model combined the consumption data and residue data for a given**  **pesticide to analyze dietary risk. Food consumption data from the USDA Cont** **inuing Survey of Food Intakes by Individuals (CSFII) conducted from 1994 through 1998 including the children's** **supplemental survey were used in this assessment. The food consumption data, i.e.,**

**foods as consumed, were translated into raw agricultural comm odities and their**  **food forms using recipe translation files contained within the DEEM software. F**  **or chronic assessments,**  **exposure assessment was conducted that is more refined because it uses average residues from field trials**  **. ]**  **a. Acute dietary exposure.**  **Although, no acute adverse effect was observed as a result of exposure to a single dose, EPA has established an acute reference dose**  **(aRfD) for the purpose of the acute dietary assessment. This aRfD was set at 0.3 mg/kg/day for females**  **13 -**  **49 years old , the population sub**  **- group of concern.**  **This was based on the developmental rat toxicity study with a NOAEL of 30 mg/kg/day**  **and an uncertainty factor of 100. The 100**  **- fold safety factor includes intraspecies**  **and interspecies variations. Exp**  **osures from all existing and proposed residues**  **result in very low acute exposures .**  **Using the above assumptions for Tier 1 assessment, the food exposure**  **to fenbuconazole for females 13**  **- 49 years old**  **at the 95**  **th percentile was estimated to be 0.0**  **09159 mg/kg/day**  **that utilized**  **3.1 % of the**  **aRfD. b. Chronic dietary exposure.**  **EPA has established a chronic reference dose (cRfD) for fenbuconazole at 0.03 mg/kg/day for all population subgroups.**  **The cRfD is based on the 2**  **- year combined chronic feeding**  **- carcin**  **ogenicity study in rats with a NOAEL of 3.03 and 4.02 mg/kg/day in males and females respectively, and an**  **uncertainty factor of 100. The 100**  **- fold safety factor includes intraspecies and**  **interspecies variations. No additional FQPA safety factor is require**  **d. The food**  **exposure for the overall U.S. population was estimated for the Tier 2**  **assessment to be 0.00**  **0739 mg/kg/day**  **that utilize**  **d 2.5**  **% of the cRfD using the**  **refined Tier**  **2 conservative exposure assumptions of 100% crop treated and**  **average residues from field**  **trials .**  **The population subgroup with the highest potential for exposure was All Infants (< 1 year old)**  **with food + water**  **exposure of 0.0 02032**  **mg/kg/day that represented 6**  **.8 % of the cRfD.**  **c. Cancer dietary exposure.**  **EPA has classified fenbuconazo le as a Group C**  **carcinogen (possible human carcinogen) and has established a Q 1**  *** of 0.00359 (mg/kg/day)**  **- 1**  **in human equivalents. The group used in this analysis was the general U. S. population.**  **A Tier 3**  **cancer dietary assessment**  **used the same food residue**  **inputs as those used in the chronic non -**  **cancer assessment. The cancer analysis is further refined in that it makes use of average percent crop treated estimates**  **. The cancer risk estimate using these food residue inputs and a worst case use patter**  **n assumption for water is 1.9 x 10**  **- 6**  **. Typically, HED is concerned when the risk estimate associated with food and drinking water exceeds 3 x 10**  **- 6**  **. As a result, cancer risk to the general U.S. population is below HED’s level of concern.**  **]** ii. Drinking Wa ter. **[ Direct measurements of fenbuconazole in drinking water**  **were not available. Estimates of potential water concentrations resulting from agricultural use of fenbuconazole were estimated using three environmental models,**  **assuming certain environmental degradation properties for fenbuconazole and** **modeled dynamics of ground water and surface water bodies. The acute drinking** 

**water estimates were estimated using PRZM/EXAMS and SCI -**  **GRO models and are known to overestimate potential water residues.**  **These t hree models provide**  **conservative, screening level estimates of water concentrations. PRZM/EXAMS**  **is used for surface water while SCI**  **- GRO**  **W is used to give estimates of ground water**  **concentrations. Such water estimates are very sensitive to the input parame**  **ters; however, they can still serve as a screening estimate for exposure considerations.**  **Based on the PRZM/EXAMS and SCI -**  **GROW models the US EPA estimated EECs of fenbuconazole for acute exposures to be**  **24.1 parts per billion (ppb) for surface**  **water and 0.0 31 ppb for ground water.**  **The EECs for chronic (non -**  **cancer) and for cancer exposures are estimated to be 16.5 ppb for surface water and 0.031 ppb for**  **groundwater. Finally, the 30**  **- year annual mean surface water value of 11.7 ppb is**  **greater than the groundw ater value of 0.031 ppb. As a result, the surface water**  **value was used in the cancer dietary analysis .**  **The potential, acute, aggregate exposures from food and drinking water for females of child bearing age is approximately 0.0**  **09159 mg/kg**  **- bw/day or**  **3.1 % of the acute**  **reference dose (aRfD) for the upper 9 5**  **th %tile of the population using a Tier**  **1 assessment.**  **Potential chronic exposure to water residues was estimated using 16.5 ppb for the two commodities, i.e., “water, direct, all sources” and “water, i**  **ndirect, all sources” for input to DEEM**  **- FCID for chronic water (Tier II) analysis.**  **After considering all existing and proposed uses, the exposure to fenbuconazole residues is**  **6.8 % of the**  **chronic reference dose for the most exposed population sub -**  **group, A** **ll Infants (< 1 year old)**  **. Cancer dietary exposure with water was also calculated.**  **Incorporation of water at**  **11.7 ppb into the Tier 3 assessment resulted in an estimated exposure of 0.000**  **522 mg/kg/day including pepper use with a cancer risk estimate**  **of 1.**  **9 x 10**  **- 6**  **. ]**  2. Non

- dietary exposure
. **[ Fenbuconazole is not currently registered for use on**  **any sites that would result in residential exposure. Thus, the risk from non**  **- dietary**  **exposure would be considered negligible. ]**  D. Cumulative Effects

. **[ Fenbuconazole is a member of the triazole class of fungicides.**  **There is currently no evidence to indicate that conazoles share common mechanisms of toxicity, and EPA is not following a cumulative risk approach based on a common**  **mechanism of toxicity for t he conazoles**  **. ]**  E. Safety Determination 1. U.S. population. **[ Using the above conservative exposure assumptions and**  **taking into account the completeness and reliability of the toxicity data, chronic dietary food exposure to fenbuconazole from pepper using refinement (Tier 2) of the** **tolerance residues by adjusting for the average residues from field trials resulted in** 

**risk estimates of 2.5**  **% of cRfD for the general U. S. population when amended pepper tolerances were included in the assessment with all existing uses of**  **fenbuconazole. Generally, EPA has no concern for e xposures below 100% of the**  **chronic reference dose (cRfD) because the cRfD represents the level at or below which daily dietary exposures over a lifetime will not pose appreciable risks to**  **human health. Likewise, the acute dietary food exposure for peppe**  **r use at 95 th**  **percentile (Tier 1) for females 13**  **- 49 years old**  **, the population sub -**  **group of concern is 3.1 % of acute reference dose (aRfD). Therefore, there is no concern for exposure because the**  **acute RfD represents the level at or below which a single daily exposure will not**  **pose appreciable risks to human health. Using refined assessment (Tier 3), the cancer risk estimate is when pepper use was**  **included in the assessment with all existing uses of fenbuc onazole, including water,**  **the cancer risk estimate was 1.9 x 10 -**  **6 . Generally, the Agency has no concern for**  **exposures that result in a cancer risk estimate below 3 x 10 -**  **6 . Considering the**  **conservative assumptions of this assessment and the screening leve l exposure from**  **drinking water, the cancer risk is not expected to exceed 1 x 10 -**  **6 for the U.S.**  **population as a whole; therefore exposure to fenbuconazole would not result in unacceptable levels of aggregate human health risk for cancer.**  **Short -**  **term and in termediate**  **- term risks are considered to be negligible because of**  **lack of significant toxicological effects. Therefore, based on these risk assessments, Dow AgroSciences concludes that there is reasonable certainty that no harm will**  **result to the U. S. pop ulation from aggregate exposure to fenbuconazole residues.**  **]** 2. Infants and children
. **[ EPA uses a weight evidence approach in determining**  **what safety factor is appropriate for assessing risks to infants and children. This approach takes into account the**  **nature and severity of the effects observed in pre**   ** and post** **- natal studies and other information such as epidemiological data. The**  **completeness and adequacy of the toxicity database is also considered. Toxicity database and exposure data for fenbuconazole are complete. No indication**  **of increased susceptibility of rats or rabbits to in utero**  **and/or postnatal exposure was noted in the acceptable developmental toxicity studies in rats and rabbits as**  **well a s in a 2**  **- generation reproductive toxicity study in rats. EPA has previously**  **determined that no additional safety factor to protect infants and children is necessary for fenbuconazole and that the RfD at 0.03 mg/kg/day is appropriate for**  **assessing risk to infants and children**  **. Using the conservative assumptions described above, the chronic dietary exposure**  **to fenbuconazole will utilize 6.8 % of the cRfD for All Infants (<1 yr old), 6.2 % of the cRfD for children 1**  **- 2 yrs old and 4.9 % of the cRfD for childr**  **en 3 -**  **5 yrs old. In assessing the potential for additional sensitivity of infants and children to** 

**residues of fenbuconazole, data from developmental toxicity studies in rats and rabbits and a 2**  **- generation reproduction study in the rat are considered. The**  **d evelopmental toxicity studies are designed to evaluate adverse effects on the**  **developing organism resulting from pesticide exposure during prenatal development. Reproduction studies provide information relating to effects from**  **exposure to the pesticide on the reproductive capability and potential systemic**  **toxicity of mating animals and on various parameters associated with the well -**  **being of offspring. The completeness and adequacy of the toxicity data base is also**  **considered. No indication of increased s usceptibility to infants and children was**  **noted in these studies for fenbuconazole. EPA has previously determined that no**  **additional safety factor to protect infants and children is necessary for fenbuconazole and that the RfD of 0.03 mg/kg/day is appropr**  **iate for assessing risk to infants and children.**  **Therefore, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, Dow AgroSciences concludes with reasonable**  **certainty that no harm will result to infants a nd children from the aggregate**  **exposure to fenbuconazole from all current and proposed ending uses. ]**  F. International Tolerances **[ MRLs for residues of fenbuconazole have been established by**  **EPA, Codex,**  **Canada, and Mexico. The residue definition for both Codex and Mexico is fenbuconazole,**  **per se. The**  **USA and Canadian residue definition, however, is the**  **combined residues of fenbuconazole and its metabolites, RH -**  **9129 and RH -**  **9130, each expressed as**  **parent (i.e .**  **, the same as the U.S. tolerance definition). US**  **tolerance was previously set by EPA at 0.4 ppm. However, new residue data has**  **shown probability of residue increase when plant paturation might be delayed by weather conditions and therefore a**  **tolerance increase to 1,0 ppm is deemed necessary.**  **As there are no established or proposed Canadian, Mexican, or Codex MRLs for fenbuconazole on peppers, there are no international harmonization**  **issues for the pepper tolerance petition .**  **]**