EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR
PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

Interregional Research Project No. 4 (IR

- 4)

Petition #3E8215

EPA has received a pesticide petition (3E8215 ) from IR

- 4, Rutgers, The State

Uni versity of New Jersey, 500 College Road East, Suite 201W, Princeton, NJ 08540
request ing, 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 o f boscalid, 3

- Pyridinecarboxamide,2

- chloro

- N

- (4'

- chloro[1,1'

- biphenyl]

- 2

- yl) in or on the raw agricultural commodity for H erb subgroup 19A at 190 parts per million (ppm)

, dill, seed at 300 ppm and updating existing crop groups to Fruit, stone, group 12

- 12 at 3.5 ppm and Nut, tree, group 14

- 12 at 0.70 ppm

. Additionally, it was proposed that upon establishment of the stone fruit group 12

- 12 and tree nut group 14

- 12 tolerances, that the existing tolerances for fruit, stone, group 12; nut, tree, group 14; and pistachio be removed as unnecessary. 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 ti me 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. Nature of the residue studies (OPPTS Harmonized Guideline 860.1300) were conducted in gra pes, lettuce and beans as representative crops in order to characterize the fate of boscalid (BAS 510F) in all crop matrices. In all three crops the boscalid (BAS 510F) Residues of Concern (ROC) were characterized as parent boscalid (BAS 510F). A confine d rotational crop study also determined that parent was the residue of concern in the representative crops of radish, lettuce and wheat.

2. Analytical method. In plants, the parent residue is extracted using an aqueous organic solvent mixture followed by liquid/liquid partitioning and a column clean up. Quantitation is by gas chromatography using mass spectrometry (GC/MS). In livestock the residues are extracted with methanol. The extract is treated with enzymes in order to release the conjugated glucu ronic acid metabolite. The residues are then isolated by liquid/liquid partition followed by column chromatography. The hydroxylated metabolite is acetylated followed by a column clean

- up. The parent and acetylated metabolite are quantitated by gas chrom atography with electron capture detection.

3. Magnitude of residues. Field trials were carried out in order to determine the magnitude of the residue of boscalid (BAS 510F) in fresh chives, fresh and dry basil

, fresh dill, and dill

, seed to satisfy the r equirements for a tolerance of boscalid in H erb s
, subgroup 19A and dill, seed

. The number and locations of field trials are in accordance with OPPTS Guideline 860.1500. Field trials were carried out using the maximum use rate, the maximum number of appli cations, and the minimum pre

- harvest interval. Field2

trials in the representative commodities for the following crop groups were previously

submitted and accepted and crop group tolerances were established for Stone fruits group and Tree nuts group. This a ction proposes updating these crop groups to the current Fruit, stone, group 12

- 12 and Nut, tree, group 14

- 12

. No new residue data was generated or needed in support of these crop group updates.

B. Toxicological Profile

1. Acute toxicity. Based on ava ilable acute toxicity data, boscalid and its formulated products do not pose acute toxicity risks. The acute toxicity studies place technical Boscalid (BAS 510 F) in toxicity category IV for acute oral; category III for acute dermal and category IV for ac ute inhalation. Boscalid is category IV for both eye and skin irritation and it is not a dermal sensitizer. For the proposed Oilseed Crop Group 20, the product proposed is Endura® fungicide (BAS 510 02/04F) containing boscalid (BAS 510F) as the active ing redient. Endura® fungicide (BAS 510 02/04F) has an acute oral toxicity category of III, acute dermal of category III, acute inhalation of category IV, eye irritation of category III, skin irritation of category IV, and is not a dermal sensitizer.

An acute neurotoxicity study in rats was conducted up to 2000 mg/kg bw/day with no

evidence of neurotoxi ci ty

2. Genotoxic i ty

. Ames Test (1 Study; gene point mutation): Negative; In Vitro CHO/HGPRT Locus Mammalian Cell Mutation Assay (1 Study; point gene mutation ): Negative; In Vitro V79 Cell Cytogenetic Assay (1 Study; Chromosome Damage): Negative; In Vivo Mouse Micronucleus (1 Study; Chromosome Damage): Negative; In Vitro Rat Hepatocyte (1 Study; DNA damage and repair): Negative. Boscalid has been

tested in a to tal of 5 genetic toxicology assays consisting of in vitro and in vivo studies. It can be stated that Boscalid did not show any mutagenic, clastogenic or other genotoxic activity when tested under the conditions of the studies mentioned above. Therefore, boscalid does not pose a genotoxic hazard to humans.

3. Reproductive and developmental toxicity. The potential reproductive and developmental toxicity of boscalid was investigated in a two

- generation rat reproduction study as well as in rat and rabbit t eratology studies. There were no adverse effects on reproduction in the two

- generation study at any dose tested. The reproductive NOAEL is 10,000 ppm (1165 and 1181 for males and females, respecti vely), the highest dose tested. Toxicity to the offspring was seen at 1,000 ppm in the form of decreased pup weights in the F2 males, and at 10,000 ppm in the form of decreased pup weights for both males and females of both the F1 and F2 generations. The offspring NOAEL is 100 and 1000 ppm (11 and 116 mg/kg b.w ./day) for males and females, respectively. In males of the F1 generation, reduced body weight and reduced body weight gain were observed at 10,000 ppm. Additionally, hepatocyte degeneration was observed in male animals of both the F0 and F1 generations at 10,000 ppm. The parental systemic NOAEL is 1000 and 10,000 (113 and 1181 mg/kg b.w./day) for males and females, respectively

. No teratogenic effects were noted in either the rat or rabbit developmental studies. In the rat study, evidence of maternal or developmental toxicity was not observed at any dose (highest dose tested of 1,000 mg/kg b.w./day). In the rabbit teratology study, at the3

high dose of 1,000 mg/kg b.w./day a maternal body weight gain decrease compared to
controls of 81% was observed durin g the treatment period. Reduced food consumption, reduced body weight and abortions in three dams, were also seen at 1,000 mg/kg b.w./day. The NOAEL for both maternal and developmental toxicity was determined to be 300 mg/kg b.w/day. Neurotoxicity was not observed at any dose in the developmental neurotoxicity study. Reduced pup body weights were observed at the high and mid dose levels of 1000 and 10,000 ppm (118 and 1,183 mg/kg b.w./day, respectively). No developmental toxicity was seen at the low d ose of 14 mg/kg b.w./day (100 ppm). Although no maternal toxicity was seen in this study, other studies which evaluated more parameters at similar doses of boscalid demonstrated maternal toxicity. The Agency concluded that there are no residual uncertaint ies for pre

- and postnatal toxicity as the degree of concern is low for the susceptibility seen in the above studies, and the dose and endpoints selected for the overall risk assessments will address the concerns for the body weight effects seen in the off spring. Although the dose selected for overall risk assessments (21.8 mg/kg b.w./day) is higher than the NOAEL's

in the 2

- generation reproduction study (11 mg/kg b.w./day) and the developmental neurotoxicity study (14 mg/kg b.w./day), these differences ar e considered to be an artifact of the dose selection process in these studies. For example, there is a 10

- fold difference between the LOAEL (113 mg/kg b.w./day) and the NOAEL (11 mg/kg b.w./day) in the two generation reproduction study. A similar pattern was seen with regard to the developmental neurotoxicity study, where there is also a 10

- fold difference between the LOAEL (147 mg/kg b.w./day) and the NOAEL (14 mg/kg b.w./day). There is only a 2

- 3

- fold difference between the LOAEL (57 mg/kg b.w./day) and the NOAEL (21.8 mg/kg b.w./day) in the critical chronic dog study which was used for risk assessment. Because the gap between the NOAEL and LOAEL in the 2

- generation reproduction and developmental neurotoxicity studies was large and the effects at the LO AEL's were minimal, the true no

- observed

- adverse

- effect

- level was probably considerably higher. Therefore, the selection of the NOAEL of 21.8 mg/kg b.w./day from the 1

- year dog study is conservative and appropriate for the overall risk assessments. In add ition, the endpoints for risk assessment are based on thyroid effects seen in multiple species (mice, rats and dogs) and after various exposure durations (subchronic and chronic exposures)

which were not observed at the LOAEL's in either the 2

- generation r eproduction or the developmental neurotoxicity studies. Based on these data, the Agency concluded that there are no residual uncertainties for pre

- and post

- natal toxicity.

4. Subchronic toxicity. The subchronic toxicity of boscalid was investigated in

90

– day feeding studies with rats, mice and dogs, and in a 28

– day dermal administration study in rats. Additionally a 90

– day neurotoxicity study in rats was performed. Generally, mild toxicity was observed including alterations in various clinical chemist ry parameters and effects on the liver and thyroid. In the rat, effects observed were increased thyroid weight and increased incidence of thyroid hyperplasia as well as follicular epithelial hypertrophy. Increased liver weights and an increased incidence of marked fatty changes in the liver were observed in mice

. Changes observed in dogs were increased serum alkaline phosphatase and liver weights. The lowest subchronic toxicity NOAEL was from the dog study (7.6/8.1 mg/kg b.w./day in males and females,

re spectively).4

No evidence of immunotoxicity was observed in a 28

- day immunotoxicity study

in rats.

In the 28

– day repeat dose dermal study, no systemic effects were noted up to the highest dose tested of 1,000 mg/kg b.w./day.

In a 90

– day rat neurotoxicity s tudy, no signs of neurotoxicity were observed in the pups or adults. The NOAEL is the highest tested of 15,000 ppm (1,050/1,272 mg/kg b.w./day in males and females, respectively).

5. Chronic toxicity. The chronic toxicity/oncogenicity studies with bosca lid

include a 12

– month feeding study with Beagle dogs, an 18

– month B63CF1 mouse feeding study, a 24

– month Wistar rat chronic feeding study and a 24

– month Wistar rat oncogenicity study. At the highest dose tested in dogs, effects observed consisted primaril y of increased liver and thyroid weights and some serum clinical chemistry changes. The NOAEL was 800 ppm (21.8 mg/kg b.w./day males; 22.1 mg/kg b.w./day females). In the mouse oncogenicity study, decreased body weights were seen in both males

and females at 8000 ppm (1345 and 1804 mg/kg b.w./day for males and females, respectively) and in males at 2000 ppm (331 mg/kg b.w./day). Also in males at 800 0 ppm, increased liver weights and an increased incidence of peripherial hypertrophy of the

liver were obser ved. The NOAEL was 400 ppm and 2000 ppm (65 and 443 mg/kg b.w./day) for male and female mice, respectively. In both the rat chronic and oncogenicity studies, the highest dose tested of 15,000 ppm exceeded a maximum tolerated dose (MTD) and was discontin ued after 17 months. Effects observed at the next highest dose of 2,500 ppm (110/ 150 mg/kg b.w./day for males and females, respectively) were increased thyroid weights and histopatholo gical changes in the thyroid which included follicular cell hypertroph y, hyperplasia and

adenomas. The NOAEL was 500 ppm (22 and 30 mg/kg b.w./day for male and female rats, respectively).

No evidence of treatment

- induced oncogenicity was observed in the mouse study. In the rat, a slight increase in thyroid follicular cell adenomas was seen in both sexes at the high dose when the data from both chronic and oncogenicity bioassays are combined.

A non

- genotoxic (threshold) mode of action (MOA) for the thyroid follicular cell

adenomas was demonstrated from results of several st udies. Based on review of the available data, the Reference Dose (RfD) for boscalid was based

on a 1

- year feeding study in dogs with a NOAEL of 21.8 mg/kg b.w./day. Using an uncertainty factor of 100, the RfD is calculated to be 0.218 mg/kg b.w./day. Ba sed on the acute toxicity data, an acute dietary risk assessment is not needed. Threshold effects.

Boscalid was shown to be non

- carcinogenic in mice. There was a slight increase in thyroid follicular cell adenomas at the high dose in both sexes in the rat. A non

genotoxic (threshold) MOA was demonstrated for the thyroid tumors. The Agency concluded a carcinogenicity classification of “suggestive evidence of carcinogenicity” and that a dose response assessment for cancer was not needed.

6. Animal met abolism. In the rat, the predominant route of excretion of boscalid (BAS 510F) is fecal with urinary excretion being minor. The half

- life of boscalid is less than 24 hours. Saturation of absorption appears to be occurring at the high dose level.5

Boscalid is rapidly and intensively metabolized to a large number of biotransformation products. The hydroxylation of the diphenyl moiety was the quantitatively most important pathway. Second most important was the substitution of the Cl of the 2

- chloropyridine part against SH by conjugation with glutathione. No major differences were observed. In hens and goats the residues of concern were determined to be parent, the hydroxylated metabolite M510 F01 (2

- chloro

- N

- (4'chloro

- 5

- hydroxy

- biphenyl

- 2

- yl)nicotinamide), and the glucuronic acid of the metabolite M510 F02.

7. Metabolite toxicology

. No additional studies were required for metabolite toxicology.

8. Endocrine disruption

. No specific tests have been conducted with boscalid to

determine whether the chemical may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen or other endocrine effects. However, there were no significant findings in other relevant toxicity studies (i.e., subchronic and chronic toxicity, teratol ogy and multi

- generation reproductive studies) which would suggest that boscalid produces endocrine related effects.

C. Aggregate Exposure

1. Dietary exposure. An assessment was conducted to evaluate the potential risk due to chronic dietary exposure of the U.S. population and sub

- populations to residues of boscalid. Tolerance values for boscalid (BOSCALID) have previously been established and are listed in U.S. 40 CFR § 180.589.

This analysis included all crops with established boscalid tolerance v alues, replacing crop group 12

- stone fruits group with new Crop Group 12

- 12

- Stone Fruit Group, replacing Crop Group 14

– Tree Nuts Group with new Crop Group 14

- 12

– Tree Nut Group, and

new tolerance for Herb subgroup 19 A, at 190 ppm and dill, seed at 300 ppm.

i. Food. Acute Dietary Exposure Assessment An acute assessment was not needed since the U.S. EPA Toxicological Endpoint Selection (TES) Committees had previously evaluated the boscalid toxicity data and

determined there were no toxic effects attrib utable to a single dose. Therefore, a quantitative acute dietary exposure and risk assessment were not required.

Chronic Dietary Exposure Assessment A partially refined Tier 1 chronic dietary exposure assessment was conducted assuming

tolerance level res idues, experimentally determined processing factors, 100% crop treated factors for all crops. Residues in animal commodities (i.e. meat, meat byproducts, fat, milk, eggs) were included at the tolerance levels currently established and listed in U.S.

40 CF R § 180.589.

Dietary exposure estimates were compared against the established boscalid chronic Population Adjusted Dose (cPAD) of 0.218 mg/kg b.w./day for all populations. Results of the chronic dietary assessments are listed in the Table 1. The estim ated chronic dietary exposure from crops and animal commodities was less than 29% of the cPAD for all6

subpopulations. Additional refinements such as the use of anticipated residues and adjusted crop treated factors would further reduce the estimated chron ic dietary exposure. The results in Table 1 demonstrate there are no safety concerns for any subpopulation based on established and new uses, and the results clearly meet the FQPA standard of reasonable certainty of no harm.

Table 1. Summary of Chronic Dietary Exposure Assessment Considering Crops with Established and Proposed Tolerances

for Boscalid

Population Subgroups Exposure Estimate (mg/kg b.w./day) %cPAD

U.S. Population 0.02 1653 9.9

All Infants 0.0 33679 15.4

Children 1

- 2 years 0.0 62963 2 8.9

C hildren 3

- 5 years 0.0 46996 2 1.6

Children 6

- 12 years 0.02 6324 1 2 .1

Youth 13

- 19 years 0.015085 6. 9

Adults 20

- 49 years 0.01 8058 8.3

Adults 50+ years 0.01 94898 8. 9

Females 13

- 49 0.01 8243 8. 4
%cPAD = percent of chronic population adjusted dose Exposure estimates based on tolerance values, default processing

factors, and 100% CT for all crops/commodities.

ii. Drinking water

. Based on PRZM/EXAMS and SCI

- GROW models, the estimated drinking water exposure concentrations of boscalid for chronic exposur e were 26 ppb for surface water and 0.63 ppb for ground water. Drinking water contributions were assessed based on the maximum estimated boscalid water concentrations (26 ug/L), and water consumption and body weights. The chronic estimated water exposure values are summarized in Table 2. Minimal exposure of boscalid occurs through drinking water with < 1.0% cPAD for all subpopulations.7

Table 2. Results for Boscalid Chronic Water Exposure Analysis Considering the Maximum Estimated Chronic Drinking Water C oncentration using

DEEM

- FCID

Population Water Exposure Estimate %aPAD

Subgroups (mg/kg b.w./day)

U.S. Population 0.000544 0.2

All Infants (< 1 year old) 0.001404 0.6

Children (1

- 2 years old) 0.000785 0.4

Children (3

- 5 years old) 0.000662 0.3

Child ren (6

- 12 years old) 0.000477 0.2

Youth (13

- 19 years old) 0.000397 0.2

Females (13

- 49 years old) 0.000543 0.2

Adults (20

- 49 years old) 0.000537 0.2

Adults (50+ years old) 0.000541 0.2 cPAD = chronic population adjusted dose

Based on estimated acute s urface water value of 26 ug/L

Acute Aggregate Exposure and Risk (Food and water) Since the U.S. EPA Toxicological Endpoint Selection (TES) Committees has evaluated the Boscalid toxicity data and determined there was no toxicological endpoints for acute

di etary exposure, the determination of an acute aggregate exposure and risk evaluation was not required.

Short

- and Intermediate Term Aggregate Exposure and Risk ( food, water , and residential)

Short

- and intermediate

- term aggregate exposure takes into acc ount residential exposure plus chronic exposure from food and water. Residential exposure is used to refer to non

occupational and non

- dietary exposure. No new residential uses are currently being registered for boscalid that would increase non

- dietary e xposure. The boscalid residential exposure values used in this risk assessment were previously determined by the EPA (May 8, 2013). The exposure assessment was conducted using the updated HED’s 2012 Residential SOP’s along with policy changes for body we ight assumptions. The MOE values are presented in the Table 3

.

Table 3. Estimated Short/Intermediate Term Aggregate Exposur e and Risk of Boscalid (target MOE = 100)

Population Oral
NOAEL (mg/kg/day) Food +

Water Exposure (mg/kg/day) Oral
MOE Dermal
NO AEL (mg/kg/day) Residential Exposure (mg/kg/day) Dermal
MOE Total
Combined
MOE

Children 6

- 11 years old 21.8 0.026801 813 21.8 0.022 991 447

Youth 11

- 16

years old 21.8 0.015482 1408 21.8 0.0018 12111 1261

Adult 21.8 0.022197 982 21.8 0.032 681 402

Total combined MOE = 1/[(1/MOE oral) + (1/MOE dermal)8

The results demonstrate there are no safety concerns for any subpopulation based on established and new uses, and that the results clearly meet the FQPA standard of reasonable certainty of no harm.

Ch ronic Aggregate Exposure and Risk (food and water) The aggregate chronic risk includes residues of boscalid from food and water (Table 4). Exposures from residential uses are not included in the chronic aggregate assessment.

The results demonstrate there are no safety concerns for any subpopulation based on established and new uses, and that the results clearly meet the FQPA standard of reasonable certainty of no harm.

Table 4. Estimated Chronic Aggregate Exposure and Risk of Boscalid

Population Subg roup Food Exposure (mg/kg/day) Water Exposure (mg/kg/day) Total Exposure (mg/kg/day) % cPAD

U.S. Population 0.021653 0.000544 0.022197 10

All Infants (< 1 yr old) 0.033679 0.001404 0.035083 16

Children 1

- 2 years 0.062963 0.000785 0.063748 29

Children 3

- 5 years 0.046996 0.000662 0.047658 22

Children 6

– 12 years 0.026324 0.000477 0.026801 12

Youth 13

- 19 years 0.015085 0.000397 0.015482 7

Adults 20

- 49 years 0.018243 0.000541 0.018784 9

Adults + 50 0.018058 0.000543 0.018601 9

Females 13

- 49 0.019498 0.000537 0.020035 9

2. Non

- dietary exposure

. No new residential uses are currently being registered

for boscalid that would result in non

- dietary exposure. A non

- occupational dermal post

application exposure/risk assessment for boscalid was recently co nducted by EPA (May 8, 2013). The highest post

- application for adults and children (6

- 11 years of age) occurred from the use in treated gardens and the highest post

- application exposure for youth (11

– 16 years of age) occurred from the use on golf course turf. The dermal MOE’s for these uses were all greater that the limit of concern of 100

.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ‘‘availabl e information’’ concerning the cumulative effects of a particular pesticide’s residues and ‘‘other substances that have a common mechanism of toxicity.’’ BAS 510 F is a foliar fungicide chemically belonging to the carboxin class of fungicides. BAS 510 F ac ts in the fungal cell by inhibiting mitochondrial respiration through inhibition of the succinate

- ubiquinone oxidase reductase system in Complex II of the mitochondrial electron transport chain. BAS 510 F shares this mode of action with only one other curr ently registered U.S. pesticide

- carboxin. The EPA is currently developing methodology to perform cumulative risk9

assessments. At this time, there is no available data to determine whether BAS 510F has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, BAS 510F does not appear to produce a toxic metabolite produced by oth er substances.

E. Safety Determination

1. U.S. population. Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to boscalid residues.

2. Infan ts and children

. Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to infants or children from the aggregate exposure to boscalid residues.

F. International Tolerances

No Codex maximum residue le vels (MRLs) have been established for residues of

boscalid in fresh herbs or dill seed. Therefore, no tolerance discrepancies exist between

countries for this chemical.