Document ID: EPA-HQ-OPP-2016-0600-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-07-26T04:00Z

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

EPA Registration Division contact: [Shaja Joyner, Product Manager 20,
703-308-3194]

TEMPLATE:

BASF

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
BASF Corporation, 26 Davis Drive, P.O. Box 13528, Research Triangle
Park, NC 27709 requesting, 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 increasing an established tolerance for residues of
boscalid,
3-pyridinecarboxamide,2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl) in or
on the raw commodity Vegetable, legume, edible-podded, subgroup 6A to 5
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  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. Nature of the residue studies (OPPTS Harmonized
Guideline 860.1300) were conducted in grapes, lettuce and beans as
representative crops in order to characterize the fate of boscalid (BAS
510 F) in all crop matrices.  In all three crops the boscalid (BAS 510
F) Residues of Concern (ROC) were characterized as parent boscalid (BAS
510 F).  A confined 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 glucuronic 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 chromatography 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 510 F) in dry
and succulent beans and peas to satisfy the requirements for a tolerance
of boscalid in Legume Vegetables (Succulent or Dried), Crop Group 6. 
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 applications, and the minimum pre-harvest
interval.  This action proposes increasing the tolerance for boscalid
residues in or on Edible-podded legume vegetables, Crop Subgroup 6A from
1.6 ppm to 5.0 ppm under the Office of Pesticide Programs (OPP) proposed
pilot program for US Import Tolerances. 

B. Toxicological Profile

	1. Acute toxicity.  Based on available 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 acute inhalation.  Boscalid is category IV for both eye and skin
irritation and it is not a dermal sensitizer. For Edible-podded legume
vegetables, Crop Subgroup 6A, the product proposed is Endura® fungicide
(BAS 510 02/04 F) containing boscalid (BAS 510 F) as the active
ingredient.  Endura® fungicide (BAS 510 02/04 F) 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
neurotoxicity.

	2. Genotoxicity. 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 total 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
teratology 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, respectively), 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 the high
dose of 1,000 mg/kg b.w./day, a maternal body weight gain decrease
compared to controls of 81% was observed during 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
dose 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 uncertainties 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 offspring.  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),
this difference is 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
LOAEL'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 addition, 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 reproduction 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
chemistry 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, respectively).

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 study, 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
boscalid 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 primarily 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 8000 ppm, increased liver weights and an
increased incidence of peripherial hypertrophy of the liver were
observed.  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
discontinued 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 histopathological
changes in the thyroid which included follicular cell hypertrophy,
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
studies.

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.  Based 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 metabolism. 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. 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 pathway was the Cl
substitution in the 2-chloropyridine ring by SH due to coupling with
glutathione.  No major differences were observed.  In hens and goats the
residues of concern were determined to be parent, the hydroxylated
metabolite M510F01
(2-chloro-N-(4'chloro-5-hydroxy-biphenyl-2-yl)nicotinamide), and the
glucuronic acid metabolite M510F02.

	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, teratology 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 values and covers the proposed tolerance
increase for Edible-podded legume vegetables, Crop Subgroup 6A from 1.6
ppm to 5.0 ppm.

	i. Food. Acute Dietary Exposure Assessment

An acute assessment was not needed since the U.S. EPA Toxicological
Endpoint Selection (TES) Committee had previously evaluated the boscalid
toxicity data and determined that there were no toxic effects
attributable 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 residues, experimentally determined
processing factors, and crop treated factors for some 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 CFR § 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.  The dietary exposure included food and drinking
water.  Results of the chronic dietary assessments are listed in the
Table 1.  The estimated chronic dietary exposure from crops, animal
commodities, and drinking water was less than 32% of the cPAD for all
subpopulations.  The results in Table 1 demonstrate that the exposure
from food and drinking water do not result in an unacceptable risk from
the use of boscalid.

 

Table 1.  Summary of Chronic Dietary Exposure Assessment

Considering Crops with Established Tolerances, Proposed Tolerance
Increase and Drinking Water from the use of Boscalid.

Population

Subgroups	Exposure Estimate

(mg/kg b.w./day)	% cPAD

U.S. Population	0.025342	12

All Infants	0.067373	31

Children 1-2 years	0.047659	22

Children 3-5 years	0.03714	17

Children 6-12 years	0.024133	11

Youth 13-19 years	0.017378	8

Adults 20-49 years	0.023999	11

Adults 50+ years	0.024369	11

Females 13 – 49	0.023882	11

% cPAD = percent of chronic population adjusted dose 

]

	ii. Drinking water. The drinking water concentrations were determined
using PRZM/EXAMS and SCI-GROW models for all uses.  The use resulting in
the highest estimated concentrations was the turf grass use.  These
estimated drinking water concentrations were included in the dietary
exposure modeling. 

Acute Aggregate Exposure and Risk (food and water)

Since the U.S. EPA Toxicological Endpoint Selection (TES) Committee has
evaluated the boscalid toxicity data and determined there was no
toxicological endpoints for acute dietary 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 account
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 exposure.  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 weight assumptions.  The MOE values are
presented in the Table 2.

Table 2.  Estimated Short/Intermediate Term Aggregate Exposure and Risk
of Boscalid   

 (target MOE = 100)

Population	Oral NOAEL (mg/kg/day)	Food + Water  Exposure (mg/kg/day)
Oral MOE	Dermal NOAEL (mg/kg/day)	Residential Exposure (mg/kg/day)
Dermal MOE	Total Combined MOE

Children 6-11 years old	21.8	0.024133	903	21.8	0.022	991	473

Youth 11-16 years old	21.8	0.017378	1254	21.8	0.0018	12111	1137

Adult	21.8	0.025342	860	21.8	0.032	681	380

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

	

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. 

Chronic Aggregate Exposure and Risk (food and water) 

The aggregate chronic risk includes residues of boscalid from food and
water (Table 1). 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. 

	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 conducted 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
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity.”  Boscalid (BAS 510 F) is a foliar
fungicide chemically belonging to the carboxin class of fungicides.
Boscalid (BAS 510 F) acts 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. Boscalid (BAS 510 F) shares this mode of action with other
currently registered U.S. fungicides, such as fluxapyroxad and
fluopyram.

. 

The EPA is currently developing methodology to perform cumulative risk
assessments.  At this time, there is no available data to determine
whether boscalid (BAS 510 F) 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,
boscalid (BAS 510 F) does not appear to produce a toxic metabolite
produced by other substances.

E. Safety Determination

	1. U.S. population. Based on this risk assessment, BASF concludes that
the aggregate exposure to boscalid from all currently registered and
proposed new tolerances does not result in an unacceptable risk.  

	2. Infants 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

	A Codex maximum residue level (MRL) of 3.0 ppm exists for residues of
boscalid in or on edible-podded beans and peas.    

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