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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 CropScienc e**  **, 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 **caneberr y**  **subgroup 13 -**  **07A** at **15.0** parts per million (ppm) **and bushberr** **y subgroup**  **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 analysis for the parent compound, pyrimethanil is sufficient to enable the**  **assessment of the relevant res idues 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 acetonitrile and water with subsequent residue**  **determination by HPLC -** **MS/MS. The method allows the de tection and**  **measurement of residues in or on agricultural commodities at or above the proposed tolerance level.** 2

3. Magnitude of residues. **Magnitude of residue trials were conducted for pyrimethanil on blackberry/raspberry as representative of**  **the caneber**  **ry (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 across 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 dermal (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 to reduced body**  **temperature in males, and transient behavioral effects observed at the high dose**  **test ed (HDT).**  2. Genotoxicty. **Pyrimethanil is not mutagenic or genotoxic in any assay in either the presence or absence of metabolic activation.**  3. Reproductive and developmental toxicity. **Py rimethanil is not a**  **developmental or reproductive toxicant. An o ral 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 not indicate any disruption of reproductive function. The NOAEL for**  **ma ternal and developmental toxic** **ity 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, r**  **espectively, 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 changes in clinical che**  **mistry endpoints at 800 mg/kg/day. A subchronic neurotoxicity study in Sprague**  **- Dawley rats indicated no treatment** **- related findings**  **in behavioral assessments, neuropathology or brain morphometrics. The NOAEL**3

**was 44.3 mg/kg/day in females based upon decreas ed 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 evid**  **ence of immune suppression at dose levels up to and includ ing 652 mg/kg/day,**  **the HDT.** 5. Chronic toxicity. **A 12 -**  **month chronic toxicity study in the dog demonstrated a NOAEL of 30 mg/kg/day due to a decrease in mean body weight**  **gain and mean consumption o f 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 Sprague**  **- 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 mechanistic 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 pharmacokinetic studies in the rat show rapid absorption and elimination within 24**  **- hours of pyrimethanil**  **admini stration. 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 mino r 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 and acute and subchronic studies on aquatic organisms and wildlife did not reveal any potential endoc**  **rine 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 functions.**  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 mg/kg/day**  **in the rabbit developmental study, based on**  **an increased incidence 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** 4

**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 consumption, 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 safety 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 for 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 potential 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**  **chronic Tier 2**  **assessment is based on tolerances, average**  **residue values for key crops and percent crop tr eated values for key crops from the**  **2004 EPA assessment. All registered uses plus proposed uses on the caneberries and**  **bushberries crop subgroups were included in the assessment. A**  **cute exposure (95**  **th percentile) for food only**  **utilize s 12.5% of the a**  **PAD f or 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 the 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 wate**  **r 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 Syst em)**  **. Ground water**  **EDWCs, calculated using SCI -**  **GROW (Screening Concentration in Ground Water), model were lower than the surface water EDWCs.**  **Fo r surface water, the maximum**  **estimated peak acute concentration of the combined residues is 86.5**   **g/L. The maxi**  **mu m**  **estimated annual mean non**  **- cancer chronic exposure concentration for**  **the combined residues (adjusted for regional percent cropped area) is 29.4**   **g/L. The addition**  **of the acute estimated drinking water concentration (EDWC) of 86.5**  **ppb resulted in 9.8**  **% o f 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**5

**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**  **acute and chronic**  **estimates (including drinking water)**  **are acceptable for all population subgroups exa mined. 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 “avai** **lable 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 assessments for pyrimethanil are based on**  **a complete and reliable**  **toxicity data package and highly conservativ**  **e assumptions. C hronic**  **aggregate dietary (food and water) exposure will utilize**  **about 14 % of the**  **cPAD for the US Population**  **. Acute aggregate dietary exposure (food and water) for the U.S.**  **population, utilizes 10 %**  **of the aPAD. Therefore, there is a reason**  **able 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 reduced to 1X.**  **Using the conservative assumptions described in the exposure section above,**  **chronic di etary**  **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 certainty that no harm will occur to infants and children from aggregate exposure to residues of**  **pyrimethan il.**  F. International Tolerances **Codex tolerances are currently not available for pyrimethanil on caneberries**6

**or bushberries. Tolerances have been established for caneberries and bushberries in the EU at 10 ppm and 5 ppm, respectively.**