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**EPA Registration Division contact: Hope Johnson; (703) 305**  **- 5410** 

**Bayer CropScience 4F8291**  EPA has received a pesticide petition **( 4F**  **8291 )**  from **Bayer CropScience ,**  **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 by establishing a tolerance for residues of **p yrimethanil (4,6**  **- dimethyl** **- N**  **- phenyl** **- 2**  **- pyrimidinamine)**  in or on the raw agricultural commodities **berries and small fruit: caneberr** **y (crop subgroup 13**  **- 07A** **)** at **15.0** parts per million (ppm) **and berries and small fruit:**  **bushberr y (crop**  **subgr oup 13**  **- 07B**  **)** at **8.0** parts per million (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. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. **The metabolic profile of pyrimethanil has been investigated following application**  **to five different crops (apple, carrots, grapes, lettuce and tomatoes) and is well understood.**  **In plants, pyrimethanil is the only significant residue ranging from essentially all of the Total Radioactive Residues**  **(TRR) in carrots and tomatoes to 44% in lettuce.**  **Limited metabolism of pyrimethanil occurs with minor amounts (less than 10%) of the phenyl and**  **pyrimidyl hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE C621312) being released after acid hydrolysis.**  **Analysis of the foliage from**  **apples and carrots confirmed that the metabolism of pyrimethanil in plants proceeded primarily via hydroxylation of the aromatic ring structures as well as the**  **methyl groups.** 2. Analytical method. **The plant metabolism studies demonstrated that analy**  **sis for the parent compound, pyrimethanil is sufficient to enable the assessment of the relevant residues in crop commodities.**  **Py rimethanil was**  **extracted from crops**  **by homogenization with aceto ne. An aliquot of the extract wa**  **s diluted with a mixture of a**  **cetonitrile and water with subsequent residue**2

**determination by HPLC -** **MS/MS. The method allows the detection and measurement of residues in or on agricultural commodities at or above the proposed**  **tolerance level.** 3. Magnitude of residues. **Magnitude of res idue trials were conducted for**  **pyrimethanil on blackberry/raspberry as representative of the**  **caneberry (Crop**  **Subgroup 13 -**  **07 A) and**  **blueberry as a representative of bushberry (Crop Subgroup 13**  **- 07**  **B). Trials were conducted in the various required regions acro ss the United**  **States in accordance with EPA guidance for crop field trials under OPPTS 860.1500.**  B. Toxicological Profile 1. Acute toxicity. **Pyrimethanil shows low toxicity by the oral (toxicity category III), inhalation (toxicity category III), and de**  **rmal (toxicity category IV) routes. It is slightly irritating to the eyes and non**  **- irritating to the skin in rabbit**  **studies. Pyrimethanil is not a dermal sensitizer. Acute neurotoxicity of pyrimethanil in the rat was assessed, the NOAEL was 100 mg/kg due t**  **o reduced body temperature in males, and transient behavioral effects observed at the high dose**  **tes ted (HDT).**  2. Genotoxicty. **Pyrimethanil is not mutagenic or genotoxic in any assay in either the presence or absence of metabolic activation.**  3. Reproduc tive and developmental toxicity. **Py rimethanil is not a**  **developmental or reproductive toxicant. An oral developmental toxicity study in the Sprague Dawley rat did not reveal any evidence of teratogenic potential. The**  **ma ternal and developmental NOAEL was 85**  **mg/kg/day. An oral developmental toxicity study in New Zealand rabbits did not reveal any evidence of teratogenic**  **potential and the NOAEL was 45 mg/kg/day. The maternal and developmental LOAEL was 300 mg/kg/day due to reduced body weights, reduced fecal**  **production, and food consumption in the dams and decreased mean body weight, body weight**  **gain, food consumption, and an increased incidence of fetuses with 13 thoracic vertebrae and ribs. A two**  **- generation reproduction study in the Sprague**  **- Dawley**  **rats did n ot indicate any disruption of reproductive function. The NOAEL for**  **ma ternal and developmental toxicity was 20.9 mg/kg/day due to reduced body**  **weights at higher dose levels, and the reproductive NOAE L was 266.7 mg/kg/day,**  **the HDT.** 4. Subchronic toxicity. **A 28**

**– day dietary toxicity study was conducted in CD**  **- 1**  **mice established a NOAEL of 202 mg/kg/day. A 90 -**  **day dietary toxicity study in Sprague**  **- Dawley rats showed a NOAEL of 54.5 and 66.7, in males and females,**  **respectively. A 90 -**  **day dietary toxicity study was conducted in CD**  **- 1 mice and**  **demonstrated a NOAEL of 139 and 203 mg/kg/day in males and females, respectively, based on changes found in the kidney, liver, thyroid, and urinary**  **bladder at higher dose levels. A 90 -**  **day oral toxicity study in dogs showed a NOAEL of 80 mg/kg/day due to decreased body weight and food consumption and** 3

**changes in clinical chemistry endpoints at 800 mg/kg/day. A subchronic neurotoxicity study in Sprague**  **- Dawley rats indicated no treatment** **- related findings**  **in behavioral assessment s, neuropathology or brain morphometrics. The NOAEL**  **was 44.3 mg/kg/day in females based upon decreased mean body weight, body weight gain and food consumption at 429.9 mg/kg/day. There were no treatment**  **related effects in males at any dose level up to 391. 9 mg/kg/day. A 28**  **- day**  **immunotoxicity study conducted in female Sprague -** **Dawley rats revealed no evidence of immune suppression at dose levels up to and in**  **cluding 652 mg/kg/day, the HDT.**  5. Chronic toxicity. **A 12 -**  **month chronic toxicity study in the dog de**  **monstrated a NOAEL of 30 mg/kg/day due to a decrease in mean body weight gain and mean consumption of food and water at higher dose levels. Two**  **oncogenicity studies were conducted using CD -**  **1 mice continually exposed to pyrimethanil by administration in the**  **diet. These lifetime feeding studies demonstrated no evidence of oncogenic potential at dose levels up to, and including**  **984 mg/kg/day (males) and 1217 mg/kg/day (females), the HDT. A 2 -** **year combined chronic toxicity/oncogenicity study conducted in the Sp**  **rague -** **Dawley rat showed a NOAEL of 17 mg/kg/day (males) and 22 mg/kg/day (females) due to decreased body**  **weight gain and food consumption, and effects on the liver and thyroid at 221 mg/kg/day (males) and 291 mg/kg/day (females). The results of mechanisti**  **c studies, demonstrate that the thyroid effects are likely secondary due to induction of**  **enzymes in the liver involved in metabolism of thyroid hormones, a well characterized**  **, threshold -**  **mediated mechanism.** 6. Animal metabolism. **Metabolism and pharmacokin etic studies in the rat**  **show rapid absorption and elimination within 24 -**  **hours of pyrimethanil administration. The major routes of elimination were the urine (approximately 72%**  **of the administered dose), and the feces (17 -**  **18% of the administered dose). The main pathways of metabolism involved oxidation to phenols in either or both**  **aromatic rings. The minor pathway of metabolism involved oxidation of the methyl grou**  **p to the corresponding alcohol.** 7. Metabolite toxicology

. **Not applicable. The primary residue of concern in**  **both crop and animal commodities is pyrimethanil.** 8. Endocrine disruption

. **There is no evidence to suggest that pyrimethanil has any potential primary endocrine disruption. Chronic, life span, and multi** **** **generational bioassays in mammals a nd acute and subchronic studies on aquatic**  **organisms and wildlife did not reveal any potential endocrine effects. Changes in the thyroid are secondary to induction of metabolic enzymes in the liver, and not due to**  **a direct effect o n endocrine mediated func** **tions.** C. Aggregate Exposure 1. Dietary exposure

. **Fo r dietary analysis, an acute reference dose (aRfD) of**  **0.45 mg/kg/day was derived for females 13** 

**– 49 yrs.**  **from an NOAEL of 45**4

**mg/kg/day in the rabbit developmental study,**  **based on an increased**  **incidenc e of**  **fetuses with 13 thoracic vertebrae and ribs, and an uncertainty factor of 100. For**  **the general population including infants and children, the acute reference dose is 1 mg/kg/day**  **from on an NOAEL of 100 mg/kg/day in the acute rat neurotoxicity study,**  **based on transient behavioral effects, and an uncertainty factor of 100.**  **A chronic reference dose (cRfD) of 0.17 mg/kg/day for all populations was derived**  **from the chronic toxicity study in the rat, based on decreased body weight gain and**  **food consumptio**  **n, increased liver weights and histopathological changes, and an uncertainty factor of 100.**  **EPA has evaluated the potential for increased susceptibility of infants and children from exposure to pyrimethanil and has**  **determined there was no quantitative or qualitative evidence of increased**  **susceptibility following prenatal exposure (in rats and rabbits), or postnatal exposure (in rats). There were no effects on fertility or reproduction in the two**  **** **generation reproduction study in rats. The special FQPA safet** **y factor has been**  **reduced to 1X based on toxicological considerations, the nature of the assumptions used**  **in the dietary exposure risk assessments, the completeness of the residue chemistry and environmental fate databases, and the lack of the potential fo**  **r residential exposures**  **. Acute and chronic Population Adjusted Doses (aPAD and**  **cPAD) are, therefore, the same as the reference doses for the populations and**  **subpopulations of interest.** i. Food. **Dietary exposure to pyrimethanil**  **was estimated from potenti al**  **residues on food using DEEM** **- FCID Ver. 3.16**  **software for**  **dietary analyses .**  **Consumption data used in this program were taken from NHANES WWEIA 2003**  **- 2008**  **. The**  **acute Tier**  **1 assessments used 100% crop treated and tolerance level**  **residue values. The**  **chroni c**  **Tier 2 assessment is**  **based on tolerances, average residue values for key crops and percent crop treated values for key crops from the**  **2004 EPA assessment. All registered uses plus proposed uses on the caneberries and**  **bushberries crop subgroups were incl uded in the assessment.**  **A cute**  **exposure (95 th**  **percentile) for food only utilize**  **s 12.5% of the a PAD for Females 13**  **- 49 yrs. old**  **and 9.6%**  **and 34%**  **of the aPAD for the US Populatio n and Children 1**  **- 2 yrs. old**  **respectively. C hronic**  **exposure utilize**  **s 13.5%**  **for th e US Population and**  **75 % for**  **Children 1 -**  **2 yrs. old**  **, the most highly exposed subpopulation**  **. These are**  **conservative estimates and actual exposures are likely to be much less.** ii. Drinking Wa ter

. **EP A drinking water values (20**  **11 ) were used in the**  **assessment. EDWCs were calculated for use on strawberries (the scenario resulting**  **in the highest drinking water exposure ), and included p**  **yrimethanil and its major metabolite (2**  **- am** **ino -**  **4,6 -**  **dimethylpyrimidine) .**  **The surface water estimated drinking water concentrations**  **(EDWCs) were determined**  **using PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Modeling System)**  **. Ground water**  **EDWCs, calculated using SCI -**  **GROW (Screening Concentration in Ground Water), model were lower than the surface water EDWCs.**  **Fo r surface w**  **ater, the maximum estimated peak acute concentration of the combined residues is**  **86.5**  **g/L. The maximum estimated annual mean**  **non -**  **cancer chronic exposure concentration for the combined residues (adjusted for regional percent cropped area) is**  **29.4**  **g/L.**5

**Th e addition**  **of the acute estimated drinking water concentration (EDWC) of 86.5**  **ppb resulted in 9.8**  **% of the aPAD utilized**  **for the US Population , 13% of the aPAD**  **utilized for females 13 -**  **49 yrs. old, and**  **38 %**  **utilized for Children 1**  **- 2**  **yrs. old , the**  **most highly exposed subpopulation**  **. The addition of the chronic EDWC of**  **29.4 ppb**  **utilized 13.8**  **% of the cPAD for the US Population and 76**  **% of the cPAD for**  **Children 1 -**  **2 yrs. old**  **, the most highly exposed subpopulation. In conclusion, the**  **results of the se conservative**  **ac ute**  **and chronic estimates**  **(including drinking water) are acceptable for all population subgroups examined. Therefore, there is a**  **reasonable certainty that no harm will result from exposure to potential residues of**  **pyrimethanil in food and drinking water .**  2. Non

- dietary exposure

. **Pyrimethanil is not registered for use on any sites**  **that would result in residential exposure.**  **Therefore, the aggregate risk is the sum of**  **the risk from food and water**  **.** D. Cumulative Effects **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.” EPA has not made**  **a common mechanism of toxicity finding as to**  **pyrimethanil and any other substances**  **and pyrimethanil**  **does not appear to produce a toxic metabolite produced by other**  **substances.** E. Safety Determination 1. U.S. population. **Risk assessmen ts for pyrimethanil are based**  **on a complete**  **and reliable toxicity data**  **package and highly conservative assumptions. C hronic**  **aggregate dietary (food and water) exposure will utilize**  **about 14 % of the**  **cPAD for the US Population**  **. Acute aggregate dietary expos**  **ure (food and water) for the U.S. population, utilizes 10**  **% of the aPAD.**  **Therefore, there is a reasonable certainty that no harm will occur to the US Population from aggregate exposure (food**  **and drinking water) to residues of**  **pyrimethanil .**  2. Infants and children

. **EPA has determined that the toxicology database for pyrimethanil**  **regarding potential pre -**  **and post -**  **natal effects in children is complete and does not indicate any particular developmental or reproductive concerns.**  **The special FQPA SF has been r**  **educed to 1X. Using the conservative assumptions**  **described in the exposure section above, chronic dietary**  **exposure to residues of pyrimethanil**  **in food and water for Children 1 -** **2 yrs. old (the most highly exposed**  **sub group) is about 76% of the cPAD.**  **Acute aggregate dietary**  **exposure to**  **residues of**  **pyrimethanil in food and water for Children 1**  **- 2 yrs. old**  **(the most highly exposed sub group) is**  **38% of the aPAD. There are no non**  **- dietary concerns for infants and**  **children. Therefore, there is a reasonable certai nty that no harm will occur to**  **infants and children from aggregate exposure to residues of pyrimethanil.** 6

F. International Tolerances **Codex tolerances are currently not available for pyrimethanil on caneberries or bushberries. Tolerances have been establ** **ished for caneberries and bushberries in the EU at 10 ppm and 5 ppm, respectively.**