![](media/image1.wmf)

**UNITED STAES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF**

**PREVENTION, PESTICIDES**

**AND TOXIC SUBSTANCES**

**[MEMORANDUM]{.underline}**

DATE: July 10, 2007

SUBJECT: **Boscalid. Human Health Risk Assessment for a Section 3
Tolerance on Endive, an Amendment to the Tolerances for Strawberries and
Berries, Crop Group 13, and an Increase in Tolerances in/on Cucumber and
Vegetable, Root, Subgroup 1A, except Sugar Beet, Garden Beet, Radish,
and Turnip.**

  ------------- ---------------- --------------- -------------------------
  Petition \#   5E7013, 5F6986   PC Code:        128008

  DP #:         327906           Class:          Fungicide

  Decision #:   363130           40 CFR:         §180.589
  ------------- ---------------- --------------- -------------------------

FROM: Breann Hanson, Biologist

Alternative Risk Integration and Assessment (ARIA) Team

Risk Integration Minor Use and Emergency Response Branch
(RIMUERB)/Registration Division (RD) (7505P)

THROUGH: William Cutchin, Acting Senior Scientist

ARIA Team

RIMUERB/RD (7505P)

AND

Douglas Dotson, Ph.D., Chemist

Christina Swartz, Branch Chief

Registration Action Branch 2 (RAB 2)

Health Effects Division (HED) (7509P)

TO: Barbara Madden, RM Team 05

RIMUERB/RD (7505P)

TABLE OF CONTENTS

[**1.0** **EXECUTIVE SUMMARY** 3](#__RefHeading___Toc169599906)

[**2.0** **INGREDIENT PROFILE** 12](#__RefHeading___Toc169599907)**2**

[**2.1** **Proposed Use** 12](#__RefHeading___Toc169599908)**2**

[2.2 Identification of Active Ingredient
16](#__RefHeading___Toc169599909)

[2.3 Physical and Chemical Properties 16](#__RefHeading___Toc169599910)6

[**3.0** **HAZARD CHARACTERIZATION**
16](#__RefHeading___Toc169599911)**6**

[3.1 Hazard and Dose-Response Characterization
16](#__RefHeading___Toc169599911)

[3.2 Endocrine Disruption](#__RefHeading___Toc169599911) **19**

[**4.0** **PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA**
19](#public-health-and-pesticide-epidemiology-data)

[**5.0** **DIETARY EXPOSURE/RISK CHARACTERIZATION**
19](#__RefHeading___Toc169599913)

[5.1 Pesticide Metabolism and Environmental Degradation
19](#__RefHeading___Toc169599914)

[5.1.1 Metabolism in Primary Crops 19](#__RefHeading___Toc169599915)

[5.1.2 Metabolism in Rotational Crops 20](#__RefHeading___Toc169599916)

[5.1.3 Metabolism in Livestock 20](#__RefHeading___Toc169599917)

[5.1.4 Analytical Methodology 20](#__RefHeading___Toc169599918)

[5.1.5 Environmental Degradation 21](#__RefHeading___Toc169599920)

[5.1.6 Comparative Metabolic Profile 21](#__RefHeading___Toc169599920)

[5.1.7 Drinking Water Residue Profile 21](#__RefHeading___Toc169599921)

[5.1.8 Food Residue Profile 22](#__RefHeading___Toc169599922)

[5.1.9 International Residue Limits 23](#__RefHeading___Toc169599923)

[5.2 Dietary Exposure and Risk 24](#__RefHeading___Toc169599924)

[5.2.1 Acute Dietary Exposure/Risk 24](#__RefHeading___Toc169599925)

[5.2.2 Chronic Dietary Exposure/Risk 24](#__RefHeading___Toc169599926)

[5.2.3 Cancer Dietary Risk 25](#__RefHeading___Toc169599927)

[5.3 Anticipated Residue and Percent Crop Treated (%CT) Information
25](#__RefHeading___Toc169599928)

[**6.0** **RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK
CHARACTERIZATION** 26](#__RefHeading___Toc169599929)

[**7.0** **AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION**
26](#__RefHeading___Toc169599930)

[7.1 Acute Aggregate Risk 27](#__RefHeading___Toc169599931)

[7.2 Short-Term Aggregate Risk 27](#__RefHeading___Toc169599932)

[7.3 Intermediate/Long-Term Aggregate Risk
27](#__RefHeading___Toc169599932)

[7.4 Chronic Aggregate
Risk.............................................................
27](#__RefHeading___Toc169599933)

[7.5 Cancer Aggregate Risk 28](#__RefHeading___Toc169599934)

[**8.0** **CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT**
28](#__RefHeading___Toc169599935)

[**9.0** **OCCUPATIONAL EXPOSURE/RISK PATHWAY**
28](#__RefHeading___Toc169599936)

[**10.0** **DATA NEEDS AND LABEL RECOMMENDATIONS**
33](#__RefHeading___Toc169599939)

[10.1 Toxicology 33](#__RefHeading___Toc169599940)

[10.2 Residue Chemistry 33](#__RefHeading___Toc169599941)

[10.3 Occupational and Residential Exposure
35](#__RefHeading___Toc169599942)

[**Appendix A: TOXICOLOGY ASSSESSMENT**
37](#__RefHeading___Toc169599943)

[A.1 Toxicology Data Requirements 37](#__RefHeading___Toc169599944)

[A.2 Toxicity Profiles 38](#__RefHeading___Toc169599945)

[A.3 Executive Summaries 38](#__RefHeading___Toc169599946)

[**Appendix B: REFERENCES (in MRID Order)**
57](#__RefHeading___Toc169599943)

[Appendix C: REVIEW OF HUMAN RESEARCH 59](#__RefHeading___Toc169599943)

[]{#__RefHeading___Toc169599906 .anchor}**1.0 EXECUTIVE SUMMARY**

The Interregional Research Project No. 4 (IR-4) has submitted a
petition, per the California Department of Pesticide Regulation, for use
of the fungicide boscalid,
2-chloro-*N*-(4\'-chloro\[1,1\'-biphenyl\]-2-yl)-3-pyridinecarboxamide,
on endive (PP# 5E7013) while BASF Corporation has submitted a request
for a change in the tolerance levels in/on strawberries and berries,
crop group 13 (PP# 5F6986). BASF has also submitted additional field
trial data for boscalid on cucumbers, mustard greens, and sunflower
seeds as a condition of registration for these crops and supplemental
field trials on fruiting vegetables, spearmint and peppermint, radishes,
stone fruits, and grapes to support the use of boscalid on these crops
in Canada (PP#1F6313, DP#: 278385, M. Nelson, 8/15/2003).

Boscalid is a carboxamide (anilide) fungicide that inhibits
mitochondrial respiration, thereby inhibiting spore germination, germ
tube elongation, mycelial growth, and sporulation of pathogenic fungi on
the leaf surface. Boscalid is registered to BASF Corporation for use on
food/feed crops as two water-dispersible granular (WDG) formulations, a
70% WDG (Endura^®^ Fungicide; EPA Reg. No. 7969-197) and a 25% WDG
(Pristine^®^ Fungicide; EPA Reg. No. 7969-199, which also contains 12.8%
pyraclostrobin). These formulations are registered for use on a wide
variety of field, vegetable, fruit and nut crops as multiple broadcast
foliar applications using ground or aerial equipment. For purposes of
this risk assessment only the boscalid portion will be addressed.

Tolerances for residues of boscalid are established under 40CFR
§180.589. Tolerances listed in 40 CFR §180.589(a)(1) are expressed in
terms of boscalid*.* Under this section, current tolerances range from
0.05 ppm in/on peanuts and tuberous and corm vegetables (subgroup 1C) to
60 ppm in leafy greens, subgroup 4A, except head and leaf lettuce.

Tolerances listed in 40 CFR §180.589(a)(2) are expressed in terms of the
combined residues of boscalid and its metabolites
2-chloro-N-(4'-chloro-5-hydroxy-biphenyl-2-yl)nicotinamide and
glucuronic acid conjugate of
2-chloro-N-(4'-chloro-5-hydroxy-biphenyl-2-yl)nicotinamide. Under this
section, current tolerances range from 0.02 ppm in/on egg to 0.35 ppm in
livestock, meat byproducts.

A time-limited 2.0 ppm tolerance for tangerine is listed in 40 CFR
§180.589(b) in connection with use of the pesticide under Section 18
Emergency Exemptions granted by EPA. The tolerance is set to expire at
the end of 2008.

Indirect or inadvertent tolerances listed in 40 CFR §180.589(d) are
expressed in terms of boscalid when present as a result of application
of boscalid to the growing crops listed in 40 CFR §180.589(a)(1). Under
this section, current tolerances range from 0.05 ppm in animal feed,
nongrass, group 18 seed; cotton, undelinted seed and vegetable, legume,
foliage, group 7 vines to 8 ppm in hay of the grasses crop group (group
17).

**Proposed Tolerances**

The tolerance request for post-harvest use of boscalid on endive has
been submitted by IR-4 (PP# 5E7013) with a proposed tolerance of 12 ppm.
For Belgian endive treatment, chicory roots, from which endive is
induced to grow, are treated by an overhead spray bar as the roots pass
underneath on a conveyor belt headed for cold storage bins.

BASF's petition (PP#56986) proposes increasing tolerances on strawberry
to 4.0 ppm. The Agency has already reviewed the recent strawberry field
trial data and has revised the strawberry tolerance to 4.5 ppm (DP#:
322235, D. Dotson, 11/3/2005). This tolerance is now published in the
CFR, so no further action on the strawberry tolerance is required. This
petition also proposes an increased tolerance on Berries crop group 13
to 8.0 ppm.

BASF submitted field trial data on cucumbers, mustard greens, and
sunflower. These field trials were requested by the Agency as a
condition for the registration of boscalid on these crops (PP#1F6313,
DP#: 278385, M. Nelson, 8/15/2003). BASF has also submitted supplemental
field trials on fruiting vegetables, spearmint and peppermint, radishes,
stone fruits, and grapes, which were conducted to support the use of
boscalid on these crops in Canada. Adequate field trial data supporting
the use of boscalid on these crops or crop groups in the U.S. were
previously reviewed (DP#: 278385, M. Nelson, 8/15/2003). Existing
tolerances are adequate for the stone fruits, grapes, peppermint and
spearmint tops, sunflower seeds, *Brassica* leafy greens (subgroup 5B)
cucurbit vegetables, except cucumber, and fruiting vegetables. Existing
tolerances were not adequate for berries crop group, cucumber, and root
vegetables, except sugar beet, garden beet, radish, and turnip (subgroup
1A). Thus, new tolerances should be proposed for caneberry crop group
13A at 6.0 ppm, and for bushberry crop group 13B at 10 ppm, cucumbers at
0.5 ppm, and root vegetables, except sugar beet, garden beet, radish,
and turnip (subgroup 1A) at 1.0 ppm.

Under [PP# 5E7013]{.underline}, IR-4 requests the establishment of a
tolerance for boscalid in/on the following raw agricultural commodities
(RACs): Belgian endive at 16 ppm.

Under [PP# 5E6986,]{.underline} BASF requests the establishment of
amended tolerances for boscalid in/on the following RACs: caneberry,
crop group 13A at 6.0 ppm; bushberry, crop group 13B at 13.0 ppm;;
cucumber at 0.5 ppm; fruit, stone, group 12 at 1.7 ppm; grape at 3.5
ppm; peppermint, tops at 30 ppm; spearmint, tops at 30 ppm; strawberry
at 4.5 ppm; sunflower, seed at 0.6 ppm; vegetable, *Brassica* leafy,
leafy greens, subgroup 5B at 18.0 ppm; vegetable, cucurbit, group 9,
except cucumber at 1.6 ppm; vegetable, fruiting, group 8 at 1.2 ppm and
vegetable, root, subgroup 1A, except sugar beet, garden beet, radish and
turnip at 1.0 ppm.

The most recent human health risk assessment for boscalid was conducted
in conjunction with a request for the establishment of permanent
tolerances for residues of boscalid in/on leafy greens subgroup 4A,
except head and leaf lettuce, and leaf petioles subgroup 4B (DP #:
327353, S. Brothers, 10/20/2006).

**Human Health Risk Assessment**

[Toxicology/Hazard]{.underline}

Acute toxicity data indicated that all studies were in toxicity category
III or IV. The dermal sensitization guinea pig study was considered to
be unacceptable because the concentration used for the challenge was
inadequate.

There were no maternal or developmental effects observed in the rat
developmental toxicity study when BAS 510 F was administered at the
limit dose. In the rabbit developmental study, the limit dose appeared
to cause an increase in the incidence of abortions or early deliveries;
this was considered to be an effect on either the mothers, fetuses or
both. In the 2-generation rat reproduction study, parental effects of
decreases in body weight/body weight gain and hepatocyte degeneration
were noted at the limit dose. No effects on reproduction were
identified. For offspring, there was a decrease in body weight/body
weight gains at the next to highest dose in males and at the limit dose
in females.

In both 2-year rat toxicity studies as well as in the 90-day rat study,
the following effects were noted regarding the thyroid: increased
weights as well as increased incidences of follicular cell hyperplasia
and hypertrophy**.** The 1-year and 90-day dog studies showed elevated
alkaline phosphatase activities and elevated hepatic weights. Only the
90-day (not the 18-month) mouse study showed an increase in liver
weights and increased incidence of marked fatty change in the liver
(males only).

Carcinogenicity, thyroid follicular cell adenomas, was noted in both
2-year rat studies, but not in the 18-month mouse study. When data were
combined from both rat studies, males showed a significant increasing
trend and significant differences in the pair-wise comparison. There was
no treatment-related increase in thyroid follicular cell carcinomas. The
increased incidence of the thyroid follicular cell adenomas exceeded the
historical control mean and range. The CARC considered the increase in
these adenomas to be treatment-related in males. The CARC classified BAS
510 F into the category "Suggestive Evidence of Carcinogenicity, but Not
Sufficient to Assess Human Carcinogenic Potential."

BAS 510 F was negative in a battery of five mutagenic assays.

In rat metabolism and pharmacokinetic studies, BAS 510 F was readily
absorbed and excreted following a single oral dose of 50 mg/kg. At
single 500 mg/kg or 15 doses of 500 mg/kg, absorption was saturated.
Excretion was mainly by feces (80-98%). Biliary excretion was 40-50% of
fecal activity at 50 mg/kg and 10% at 500 mg/kg. Urinary content was
about 16% at 50 mg/kg and 3-5% at 500 mg/kg. Absorption was about 56% at
50 mg/kg and 13-17% at 500 mg/kg. Excretory patterns were similar by
gender or radiolabel position. Metabolites (hydroxylation and
conjugation products) were consistent with Phase I oxidation reactions
followed by Phase II conjugation with glucuronic acid or sulfate, or by
conjugation of the parent with glutathione with cleavage to sulfate
metabolites.

The overall toxicology database is sufficient for a determination of
potential hazard to infants and children. The data provide no indication
of an increased susceptibility to rats or to rabbits from *in utero* or
post-natal exposure to boscalid.

[Dose Response Assessment]{.underline}

On September 5, 2002 and January 23, 2003, HED's Hazard Identification
Assessment Review Committee (HIARC) selected endpoints for chronic
dietary exposure (all populations), incidental oral short- and
intermediate-term residential only, dermal (all durations) and
inhalation (all durations). As there were no toxic effects attributable
to a single dose, an endpoint of concern was not identified to
quantitate acute-dietary risk to the general population or to the
subpopulation females 13-50 years old. Therefore, there is no acute
reference dose (aRfD) or acute population-adjusted dose (aPAD). For all
of the endpoints selected, liver and thyroid effects were chosen from
the chronic toxicity study in rats, the carcinogenicity study in rats
and the 1-year study in dogs. The NOAEL was 21.8 mg/kg/day. The
uncertainty factor (UF) was 100. For the dermal route, the absorption
rate was 15% relative to oral. For the inhalation route, the absorption
rate was assumed to be 100%. The cPAD for the chronic dietary (all
populations) exposure scenario = 0.218 mg/kg/day. The residential and
occupational level of concern (LOC) for all routes is an MOE of 100.

[FQPA Assessment]{.underline}

The FQPA safety factor is reduced to 1X because the existing data
indicate that there are no/low concerns and no residual uncertainties
with regard to pre- and/or postnatal toxicity. Conservative residue
assumptions are used in the dietary risk assessments; there are no uses
that will result in residential exposure except golf course and
pick-your-own fruits; and the residue chemistry and environmental fate
databases are relatively complete (evaluated by the risk assessment
team). A 1X database factor is to be applied to all dietary and
residential exposure endpoints as there are no toxicology data gaps.

**Dietary Exposure (Food/Water)**

[Residue Chemistry and Risk]{.underline}

Boscalid is registered to BASF Corporation for use on food/feed crops as
two water-dispersible granular (WDG) formulations, a 70% WDG (Endura^®^
Fungicide; EPA Reg. No. 7969-197) and a 25% WDG (Pristine^®^ Fungicide;
EPA Reg. No. 7969-199, which also contains 12.8% pyraclostrobin). These
formulations are registered for use on a wide variety of field,
vegetable, fruit and nut crops as multiple broadcast foliar applications
using ground or aerial equipment at 0.13-0.55 lb ai/A/application, for
maximum seasonal rates of 0.5-1.8 lb ai/A, and the labels specify
pre-harvest intervals (PHI) ranging from 0 to 30 days.

To continue with the Section 3 registration on endive, the following are
needed: use directions in Section B must match the application method
used in Section D for residue data collection; the tolerance proposal in
Section F must be supported by the application method used in Section D
for residue data collection and additional residue data that adequately
reflect the use direction in Section B must be submitted.

HED recommends that the label rate be revised to clearly define the
amounts to be used per application and the total per season. In
addition, the petitioner should define how the spray is applied to the
roots in the forcing trays. A revised Section B must be submitted to
reflect more adequately the petitioner's intentions as to application
rates and directions.

For purposes of tolerances and dietary risk assessment, HED has
concluded that the residue of concern in plant commodities is boscalid,
and the residues of concern in livestock commodities include boscalid,
its 5-hydroxy metabolite and the glucuronic acid conjugate of the
5-hydroxy metabolite.

An adequate gas chromatographic-mass spectrometric (GC/MS) method
(Method D0008) is available for enforcing tolerances in plant
commodities, and an adequate GC/electron capture detection method
(Method DFG S19) is available for enforcing tolerances in animal
commodities. These methods have been validated or approved by the
Analytical Chemistry Branch (ACB) of BEAD.

Adequate cattle and poultry feeding studies for boscalid were reviewed
in an earlier petition (DP#: 278385, M. Nelson, 8/15/2003), and the
adequacy of the existing tolerances on animal commodities was recently
assessed in a separate petition (DP#: 322235, D. Dotson, 11/3/2005).
Reassessment of animal tolerances is not necessary for this review,
since sunflower meal is the only regulated feedstuff associated with any
of the crops or crop groups under review for tolerances, and residues in
sunflower meal are not expected to substantially impact the dietary
exposure of livestock. Endive roots are fed to cattle but are not an
important feed item to consider.

The field trials for endive are not considered adequate to support a
Section 3 registration, but if a Section 18 request is submitted, HED
will consider supporting that request using the information from some of
these trials. Field trials on mustard greens, cucumbers and sunflower
were requested by the Agency as a condition for the registration of
boscalid on these crops (PP#1F6313, DP#: 278385, M. Nelson, 8/15/2003)
and reviewed by HED (DP#: 323288, D. Soderberg, 6/14/2007. Supplemental
field trials on fruiting vegetables, spearmint and peppermint, radishes,
stone fruits, and grapes were previously reviewed (DP#: 278385, M.
Nelson, 8/15/2003) and support the existing uses of boscalid on these
crops. Field trial data for cotton were submitted and deemed adequate,
but no registration or tolerance is proposed for cotton at this time.

Adequate processing studies are available and were previously reviewed
for the crops or crop groups being evaluated in this review (grapes,
spearmint, peppermint, plums, tomatoes and sunflowers; DP#: 278385, M.
Nelson, 8/15/2003). Based on the available data, the Agency established
a 8.5 ppm tolerance on raisins. None of the tolerance changes being
considered in this review will affect tolerances for residues in
regulated processed commodities. The cotton processing study is also
adequate, but there is no petition for use of boscalid on cotton at this
time.

Adequate confined and limited field rotational crop studies are
available, and tolerances for indirect or inadvertent residues have been
established based on extensive rotational crop field trials on legume
vegetables, cereal grains, grasses, alfalfa, clover, cotton and root
crops. The available data support the 14-day plant-back interval (PBI)
on the labels for rotated crops without primary uses of boscalid. There
are currently no deficiencies pertaining to rotational crops

[Water Exposure and Risk]{.underline}

EFED provided Tier I Estimated Drinking Water Concentrations (EDWCs) for
boscalid in surface water and in groundwater for use in the human health
risk assessment. EFED used the simulation models FQPA Index Reservoir
Screening Tool (FIRST) to calculate the surface water EDWCs and
Screening Concentration in Ground Water (SCI-GROW) to calculate the
groundwater concentration. The turf use still represents the highest
annual application rate for boscalid. The EDWC from FIRST for chronic
exposures is 25.77 ppb. The SCI-GROW estimate for groundwater exposure
is 0.63 ppb. The surface water number of 0.02577 ppm was used in the
analysis.

[Acute and Chronic Dietary Exposure Results and
Characterization]{.underline}

No toxic effects attributable to a single (i.e., acute) exposure to
boscalid have been identified; therefore, an acute reference dose (aRfD)
has not been established for boscalid and an acute dietary exposure
assessment has not been conducted.

The unrefined chronic dietary risk assessment for boscalid used
tolerance level residues, default and empirical processing factors and
100% crop treated (%CT) assumptions. The highest chronic EDWC of 0.02577
ppm was used in this analysis. The results of the analysis indicate that
chronic risk from the dietary (food + drinking water) exposure to
boscalid will not exceed HED's level of concern (i.e. \<100% chronic
population adjusted doses (cPAD)) for the general U.S. population, and
all population subgroups.

**Non-Occupational and Residential Exposure/Risks**

The current petition for boscalid is not expected to result in any
non-occupational/ residential exposures. However, HED previously
assessed the two potential non-occupational/residential exposure
scenarios for boscalid; pick your own fruit and, golf course treatment
(HED/ORE memorandum dated 6/23/2003; DP#: 290072). HED did not assess
the "pick your own" scenario for boscalid since no toxicological
endpoints were identified for this exposure duration. However, HED did
estimate risks to adults (and adolescents) from boscalid use on golf
courses and found that risks were not of concern. MOEs ranged from
27,000 -- 74,000.

**Aggregate Exposure/Risks**

*Acute Aggregate Exposure*

There were no toxic effects attributable to a single dose. An endpoint
of concern was not identified to quantitate acute-dietary risk to the
U.S. general population or to the subpopulation females 13-50 years old.
Therefore, an acute aggregate risk assessment was not performed.

*Short-term Aggregate Exposure*

Post-application exposure from golf courses is considered short-term,
and is applicable to both adults and youth. The non-occupational use to
be aggregated with dietary exposure is turf on golf courses. The target
maximum daily exposure to boscalid residues is 0.22 mg/kg/day. The sum
of the food, water, and residential exposures is 0.024 mg/kg/day. The
estimated MOE is 960; therefore, the short-term aggregate risk and
exposure is not of concern to the Agency.

*Intermediate/Long-Term Aggregate Exposure*

Intermediate/Long-term exposures are not anticipated; therefore, an
intermediate-term aggregate risk assessment was not performed.

*Chronic Aggregate Exposure*

Chronic aggregate risk estimates do not exceed HED\'s level of concern.
Since the chronic aggregate risk assessment includes only food and
water, and the chronic dietary analysis included both, no further
calculations are necessary. Since the chronic dietary risk does not
exceed HED's level of concern, the chronic aggregate risk does not
exceed HED's level of concern.

**Occupational Exposure/Risks**

To gather handler (mixer/loader, applicators) information, HED consulted
Dr. David Thompson, Plant Pathology Program Manager, IR-4 Project
Headquarters at Rutgers, The State University of New Jersey. Dr.
Thompson indicated that post-harvest treatment of Belgian endive roots
is mechanically performed as a dip or a spray. He also stated that for a
spray application, the handler mixes up a tank of fungicide solution and
then lets it run through the sprayer, (no one is standing at the sprayer
during the application). HED also consulted Dr. Stephen Flanagan in the
IR-4 Western Region office. Dr. Flanagan confirmed that Belgian endive
root forcing trays are sprayed using overhead mounted sprayers, where
trays are passed below on a conveyor belt at a fixed speed. Based upon
these correspondences, HED assessed risk to mixers/loaders only, not to
applicators. HED was also informed by Dr. Rich Collins at California
Vegetable Specialties that inhalation exposure to handlers is minimal
since the spray area is in a shrouded/enclosed area over the conveyor
belt.

Total MOEs for handlers (mixers and loaders) supporting post-harvest
applications to Belgian endive root are not of concern to HED (MOEs
range from 27,000 to 94,000). Therefore no additional mitigation is
necessary for mixers and loaders for this proposed use from potential
exposure to boscalid.

**Environmental Justice Consideration**

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, \"Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,\"
<http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf>).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup's
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting. Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide. These data
are analyzed and categorized by subgroups based on age, season of the
year, ethnic group, and region of the country. Additionally, OPP is able
to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant. Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated. Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

**Review of Human Research**

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies (listed in Appendix D) have been determined to
require a review of their ethical conduct, and have received that
review.

**Additional Data Needs**

*Residue Chemistry*

HED did not recommend for the establishment of a Section 3 registration
in/on Belgian endive.

If IR-4 wants to continue with this Section 3 registration, then the
following are needed:

1)  Use directions in Section B must match the application method used
    in Section D for residue data collection.

2)  The tolerance proposal in Section F must be supported by the
    application method used in Section D for residue data collection.

3)  Additional residue data that adequately reflect the use direction in
    Section B must be submitted. HED recommends that the petitioner
    submit a protocol for HED review and comments before any residue
    data collection begins.

For a more detailed explanation of deficiencies/issues with this
petition, please see the residue chemistry data review memorandum (DP#:
323288, D. Soderberg, 6/14/2007).

*Other*

Although no other major deficiencies are noted in the current review, RD
notes that there are outstanding deficiencies/issues from earlier
petitions (DP#: 278385, M. Nelson, 8/15/2003) that must still be
addressed by the petitioner. See Section 10.2, Data Needs and Label
Recommendations, Residue Chemistry, for a list of outstanding data
deficiencies.

**Recommendations for Tolerances/Registration**

ARIA concludes that due a number of problems with the endive submission
(PP# 5E7013) we cannot recommend for a Section 3 registration on endive
using the submitted data, but if a section 18 request were submitted, RD
would recommend a tolerance of 16 ppm based upon the two selected field
trials designated CA02 and CA03.

Provided the outstanding residue chemistry deficiencies are addressed,
ARIA recommends for the tolerances noted in Table 1.2, below.

+-----------------------------------------+----------------------------+
| **Table 1.2. Tolerance Summary for      |                            |
| Boscalid.**                             |                            |
+=========================================+============================+
| Commodity                               | Recommended Tolerance      |
|                                         | (ppm)                      |
+-----------------------------------------+----------------------------+
| Berry, group 13                         | 6.0                        |
|                                         |                            |
|                                         | (caneberry, 13A)           |
+-----------------------------------------+----------------------------+
|                                         | 13.0                       |
|                                         |                            |
|                                         | (bushberry, 13B)           |
+-----------------------------------------+----------------------------+
| Cucumber                                | 0.5                        |
+-----------------------------------------+----------------------------+
| Fruit, stone, group 12                  | 1.7                        |
+-----------------------------------------+----------------------------+
| Grape                                   | 3.5                        |
+-----------------------------------------+----------------------------+
| Peppermint, tops                        | 30                         |
+-----------------------------------------+----------------------------+
| Spearmint, tops                         | 30                         |
+-----------------------------------------+----------------------------+
| Strawberry                              | 4.5                        |
+-----------------------------------------+----------------------------+
| Sunflower, seed                         | 0.6                        |
+-----------------------------------------+----------------------------+
| Vegetable, *Brassica* leafy, leafy      | 18.0                       |
| greens, subgroup 5B                     |                            |
+-----------------------------------------+----------------------------+
| Vegetable, cucurbit, group 9, except    | 1.6                        |
| cucumber                                |                            |
+-----------------------------------------+----------------------------+
| Vegetable, fruiting, group 8            | 1.2                        |
+-----------------------------------------+----------------------------+
| Vegetable, root, subgroup 1A, except    | 1.0                        |
| sugar beet, garden beet, radish, and    |                            |
| turnip                                  |                            |
+-----------------------------------------+----------------------------+
| Belgian endive                          | 16                         |
+-----------------------------------------+----------------------------+

1 Proposed tolerance

[]{#__RefHeading___Toc169599907 .anchor}**2.0 INGREDIENT PROFILE**

The physical and chemical properties are specific to the chemical
boscalid. For further information on the properties of boscalid, please
view the following assessments: *Boscalid Summary of Analytical
Chemistry and Residue Data* (DP #: 322235, D. Dotson, 11/3/2005), and
*Boscalid Human Health Risk Assessment* (DP #: 290022, Y. Donovan,
9/8/2003).

[]{#__RefHeading___Toc169599908 .anchor}**2.1 Proposed Use**

The approved use directions for the crops on the labels of the 70% and
25.2% WDG formulations are summarized in Table 2.1 for comparison with
the use patterns from the submitted field trials. Of the crops addressed
in this report, the 25% WDG formulation is registered for use only on
berries, cucurbit vegetables, grapes, carrot (member of subgroup 1A),
and stone fruits; and the most recent version of the 70% WDG (dated
2/24/2006) is registered for use only on carrots, fruiting vegetables,
and grapes.

The current label for the 70% WDG does not include use directions for
stone fruits, berries, cucurbit vegetables, *Brassica* vegetables, root
vegetables or sunflowers. The use directions for the 70% WDG on stone
fruits and berries were obtained from an approved label dated 10/31/03,
and use directions for the 70% WDG on cucurbit vegetables, *Brassica*
leafy greens, root vegetables, and sunflowers were obtained from an
approved supplemental label dated 8/20/2003. Although there are no
registered uses for boscalid on radishes, the use pattern in the radish
field trials were compared to the use pattern for root vegetables
(subgroup 1A), as the radish residue data were originally used to
support this subgroup tolerance.

There are no use directions for boscalid on mint, and none have ever
been proposed. The use pattern for mint listed in Table 2.1 reflects the
use patterns from the original mint field trials (45623408.der), which
were used as the basis for establishing the U.S. tolerances on mint.

*Endive*

A new use for Pristine WDG (25.2% boscalid, 12.8% pyraclostrobin), aka
BAS 516 (EPA Reg. No. 7969-199) on Belgian endive is proposed in
PP#5E7013. A label has been submitted to support this proposal; however,
this label needs to be revised. Based upon a revised Section D that has
been submitted, IR4 has defined the 1x rate as 0.022 lb ai/850 lb roots
in each of two applications, one prior to cold storage and one prior to
forcing. The total 1x rate is 0.044 lb ai/850 lb roots. HED suggests
that data be reported as 0.052 lb ai/100 lb of roots.

<table style="width:100%;">
<colgroup>
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 22%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="17"><strong>Table 2.1. Summary of Directions for Use of
Boscalid.</strong></th>
</tr>
<tr class="odd">
<th colspan="2">Applic. Timing, Type, and Equip. <sup>1</sup></th>
<th><p>Formulation <sup>2</sup></p>
<p>[EPA Reg. No.]</p></th>
<th colspan="3"><p>Applic. Rate</p>
<p>(lb ai/A)</p></th>
<th colspan="3">Max. No. Applic. per Season</th>
<th colspan="4"><p>Max. Seasonal Applic. Rate</p>
<p>(lb ai/A)</p></th>
<th colspan="3"><p>PHI</p>
<p>(days)</p></th>
<th>Use Directions and Limitations <sup>3</sup></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="17"><strong>Berry Group</strong></td>
</tr>
<tr class="even">
<td colspan="2">Broadcast foliar applications during fruiting; ground or
aerial equipment</td>
<td><p>70% WDG <sup>4</sup></p>
<p>[7969-197]</p>
<p>25.2% WDG</p>
<p>[7969-199]</p></td>
<td colspan="3">0.36-0.39</td>
<td colspan="3">4</td>
<td colspan="4">1.40-1.45</td>
<td>0</td>
<td colspan="3"><p>For aerial applications, use a minimum of 5 gal/A</p>
<p>The minimum RTI is 7 days.</p></td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Cucurbit Vegetables</strong></td>
</tr>
<tr class="even">
<td colspan="2">Broadcast foliar applications from flowering to
fruiting; ground or aerial equipment</td>
<td><p>70% WDG <sup>5</sup></p>
<p>[7969-197]</p>
<p>25.2% WDG</p>
<p>[7969-199]</p></td>
<td colspan="3">0.28-0.29</td>
<td colspan="3">4</td>
<td colspan="4">1.14-1.17</td>
<td>0</td>
<td colspan="3">For aerial applications, use a minimum of 5 gal/A The
minimum RTI is 7 days.</td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Fruiting Vegetables</strong></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2">Broadcast foliar applications during crop
development and fruiting; ground or aerial equipment</td>
<td rowspan="2"><p>70% WDG</p>
<p>[7969-197]</p></td>
<td colspan="3">0.15</td>
<td colspan="3">6</td>
<td colspan="4">0.92</td>
<td rowspan="2">0</td>
<td colspan="3" rowspan="2">For aerial applications, use a minimum of 5
gal/A. The minimum RTI is 7 days.</td>
</tr>
<tr class="odd">
<td colspan="3"><p>0.54</p>
<p>(tomato only)</p></td>
<td colspan="3">2</td>
<td colspan="4"><p>1.09</p>
<p>(tomato only)</p></td>
</tr>
<tr class="even">
<td colspan="17"><strong>Grape</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Broadcast foliar applications during fruit development;
ground or aerial equipment</td>
<td><p>70% WDG</p>
<p>[7969-197]</p>
<p>25.2% WDG</p>
<p>[7969-199]</p></td>
<td colspan="3">0.35-0.36</td>
<td colspan="3">3</td>
<td colspan="4">1.09</td>
<td>14</td>
<td colspan="3"><p>For aerial applications, use a minimum of 10
gal/A.</p>
<p>The minimum RTI is 10 days</p></td>
</tr>
<tr class="even">
<td colspan="17"><strong>Spearmint and Peppermint
<sup>6</sup></strong></td>
</tr>
<tr class="odd">
<td colspan="2">Broadcast foliar applications during crop development;
ground or aerial equipment</td>
<td>No labeled uses</td>
<td colspan="3">0.40</td>
<td colspan="3">4</td>
<td colspan="4">1.60</td>
<td>14</td>
<td colspan="3">None</td>
</tr>
<tr class="even">
<td colspan="17"><strong><em>Brassica</em> Leafy Vegetables (leafy
greens)</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Broadcast foliar applications; ground or aerial
equipment</td>
<td><p>70% WDG <sup>5</sup></p>
<p>[7969-197]</p></td>
<td colspan="3">0.39</td>
<td colspan="3">2</td>
<td colspan="4">0.79</td>
<td>14</td>
<td colspan="3"><p>The minimum RTI is 7 days.</p>
<p>For aerial applications, use a minimum of 5 gal/A</p></td>
</tr>
<tr class="even">
<td colspan="17"><strong>Root Vegetables (carrot, ginseng, horseradish,
skirret)</strong></td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2">Broadcast foliar applications; ground or
aerial equipment</td>
<td colspan="2"><p>70% WDG <sup>5</sup></p>
<p>[7969-197]</p></td>
<td colspan="3">0.20</td>
<td colspan="3">5</td>
<td colspan="3">0.98</td>
<td rowspan="2">0</td>
<td colspan="3" rowspan="2"><p>The minimum RTI is 7 days.</p>
<p>For aerial applications, use a minimum of 5 gal/A</p>
<p>Do not use on sugar beets, garden beets, turnips, and radishes</p>
<p>25.2% WDG is labeled only for use on carrots</p></td>
</tr>
<tr class="even">
<td colspan="2"><p>25.2% WDG</p>
<p>[7969-199]</p></td>
<td colspan="3">0.17</td>
<td colspan="3">6</td>
<td colspan="3">0.99</td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Stone Fruits</strong></td>
</tr>
<tr class="even">
<td colspan="2">Broadcast foliar applications from pink bud through
fruit development; ground or aerial equipment</td>
<td><p>70% WDG <sup>4</sup></p>
<p>[7969-197]</p>
<p>25.2% WDG</p>
<p>[7969-199]</p></td>
<td colspan="3">0.22-0.23</td>
<td colspan="3">5</td>
<td colspan="4">1.14-1.16</td>
<td>0</td>
<td colspan="3"><p>The minimum RTI is 7 days.</p>
<p>For aerial applications, use a minimum of 10 gal/A</p></td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Sunflowers</strong></td>
</tr>
<tr class="even">
<td>Broadcast foliar applications during plant growth; ground or aerial
equipment</td>
<td colspan="4"><p>70% WDG <sup>5</sup></p>
<p>[7969-197]</p></td>
<td colspan="3">0.39</td>
<td colspan="3">2</td>
<td>0.79</td>
<td colspan="3">21</td>
<td colspan="2"><p>The minimum RTI is 7 days.</p>
<p>For aerial applications, use a minimum of 5 gal/A</p></td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Endive</strong></td>
</tr>
<tr class="even">
<td>Manual<sup>7</sup> Spray application to roots</td>
<td colspan="4">25.2% WDG [7969-199]</td>
<td colspan="3">0.022 lbs ai/875 lbs roots</td>
<td colspan="3">2</td>
<td>0.044 lbs ai/875 lbs roots</td>
<td colspan="3">20</td>
<td colspan="2">The minimum RTI is 11 days. Apply prior to cold storage
and prior to forcing</td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Cotton</strong></td>
</tr>
<tr class="even">
<td colspan="2">Foliar broadcast applied during boll development</td>
<td>70% WD [7969-197]</td>
<td colspan="3">0.39-0.48</td>
<td colspan="3">2</td>
<td colspan="4">0.80-0.88</td>
<td>11-39</td>
<td colspan="3">RTI varied from 5 – 9 days</td>
</tr>
</tbody>
</table>

1 Ground application may be made through the following types of
irrigation systems: center pivot, lateral move, end tow, side wheel
roll, traveler, big gun, solid set, or hand move.

2 Unless otherwise specified, the use directions are from the most
recent labels of the 70% WDG (approved 2/24/06) and the 25.2% WDG
(approved 4/26/06).

3 Use directions allow for the use of spray adjuvants, and specify a 14
day plant-back interval for rotational crops without registered uses for
boscalid.

4 Use directions were obtained from a label for the 70% WDG dated
10/31/03.

5 Use directions were obtained from a supplemental label for the 70% WDG
dated 8/20/03.

6 There are no registered uses for boscalid on spearmint or peppermint
in the U.S.; the use pattern listed is the one used to establish the
current tolerances on peppermint and spearmint.

7 Intended use is for automatic application but field trials only
support manual application.

8 There are no approved uses of boscalid on cotton. This is the use
pattern from the submitted field trials.

HED recommends that the label rate be revised to clearly define the
amounts to be used per application and the total per season. In
addition, the petitioner should define how the spray is applied to the
roots in the forcing trays (.i.e., trays are stationary or are moving on
conveyor belt). A revised Section B must be submitted to reflect more
adequately the petitioner's intentions as to application rates and
directions.

[Suggested label changes:]{.underline}

[Prior to Cold Storage]{.underline}

The label currently states: "Make one........... Apply 0.7 to 1.4 oz
Pristine® fungicide in 2 to 2.5 gallons of water per 850 lbs roots."

HED suggests that label state the following: "Make one........... Apply
0.08 to 0.16 oz of Pristine® fungicide in 2 to 2.5 gallons of water per
100 lb of roots"

[Prior to Forcing]{.underline}

The label currently states: "Make one........... Apply at the rate of
0.15 to 0.4 oz Pristine® fungicide in approximately 3 quarts of water
per 10 square feet of forcing tray.

HED suggests that label state the following: "Make one...........Apply
the rate of 0.015 to 0.03 oz of Pristine® fungicide in approximately 3
quarts of water per 1 square foot of forcing tray.

[]{#__RefHeading___Toc169599909 .anchor}**2.2 Identification of Active
Ingredient**

+-------------------+--------------------------------------------------+
| **Table 2.2.      |                                                  |
| Boscalid          |                                                  |
| Nomenclature.**   |                                                  |
+===================+==================================================+
| Compound          | !                                                |
|                   | [](media/image2.wmf){width="1.479861111111111in" |
|                   | height="1.4986111111111111in"}                   |
+-------------------+--------------------------------------------------+
| Common name       | Boscalid                                         |
+-------------------+--------------------------------------------------+
| Company           | BAS 510 F                                        |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | 2-c                                              |
|                   | hloro-*N*-(4\'-chlorobiphenyl-2-yl)-nicotinamide |
+-------------------+--------------------------------------------------+
| CAS name          | 3-pyridinecorboxamide,                           |
|                   | 2-chloro-*N*-(4\'-chloro\[1,1\'-biphenyl\]-2-yl  |
+-------------------+--------------------------------------------------+
| CAS registry      | 188425-85-6                                      |
| number            |                                                  |
+-------------------+--------------------------------------------------+
| End-use product   | 70% WDG (Endura^®^ Fungicide; EPA Reg. No.       |
| (EP)              | 7969-197)                                        |
|                   |                                                  |
|                   | 25.2% WDG (Pristine^®^ Fungicide; EPA Reg. No.   |
|                   | 7969-199), which also contains 12.8%             |
|                   | pyraclostrobin.                                  |
+-------------------+--------------------------------------------------+

[]{#__RefHeading___Toc169599910 .anchor}**2.3 Physical and Chemical
Properties**

+-----------------------+----------------------------+-----------------+
| **Table 2.3.          |                            |                 |
| Physicochemical       |                            |                 |
| Properties of         |                            |                 |
| Boscalid.**           |                            |                 |
+=======================+============================+=================+
| Parameter             | Value                      | References      |
+-----------------------+----------------------------+-----------------+
| Melting point/range   | 142.8-143.8 °C             | MRIDs 45404802  |
|                       |                            | and             |
|                       |                            | 45              |
|                       |                            | 404804-45404809 |
+-----------------------+----------------------------+-----------------+
| pH                    | Does not dissociate in     |                 |
|                       | water.                     |                 |
+-----------------------+----------------------------+-----------------+
| Relative Density      | 1.381g/cm^3^               |                 |
| (20ºC)                |                            |                 |
+-----------------------+----------------------------+-----------------+
| Water solubility      | 4.64 mg/L at pH 6          |                 |
| (20ºC)                |                            |                 |
+-----------------------+----------------------------+-----------------+
| Solvent solubility    | acetone 16-20 ethyl        |                 |
| (g/100 mL at 20ºC)    | acetate 6.7-8.0 methanol   |                 |
|                       | 4-5 2-propanol \<0.01      |                 |
|                       | acetonitrile 4-5           |                 |
|                       | dichloromethane 20-25      |                 |
|                       | toluene 2-5 n-heptane      |                 |
|                       | \<0.01                     |                 |
|                       |                            |                 |
|                       | 1-octanol \<0.01 olive oil |                 |
|                       | 2.9                        |                 |
|                       |                            |                 |
|                       | N,N-DMF \>25               |                 |
+-----------------------+----------------------------+-----------------+
| Vapor pressure        | 7 x 10^-9^ hPa             |                 |
+-----------------------+----------------------------+-----------------+
| Dissociation          | None                       |                 |
| constant, pK~a~       |                            |                 |
+-----------------------+----------------------------+-----------------+
| Octanol/water         | 2.96                       |                 |
| partition             |                            |                 |
| coefficient,          |                            |                 |
| Log(K~OW~)            |                            |                 |
+-----------------------+----------------------------+-----------------+
| UV/visible absorption | UV molecular               |                 |
| spectrum              | extinc                     |                 |
|                       | tion(e\[lmol^-1^cm^-1^\]): |                 |
|                       | 3.15 x10^4^ at 228 nm;     |                 |
|                       | 1.53 x10^3^ at 290 nm      |                 |
+-----------------------+----------------------------+-----------------+

[]{#__RefHeading___Toc169599911 .anchor}**3.0 HAZARD CHARACTERIZATION**

The hazard characterization has not changed since the initial review of
boscalid. For further information than what is presented in Section 3.1,
below, on the characterization of boscalid, please view the following
assessments: *HED HIARC Report* (A. Levy, TXR No. 0051613, 3/7/2003),
and Boscalid Human Health Risk Assessment (DP #: 290022, Y. Donovan,
9/8/2003).

**3.1 Hazard and Dose-Response Characterization**

Boscalid appeared to have effects on the thyroid and/or liver of several
species. In a 90-day mouse study, there were increased liver weights and
increased incidences in marked fatty change in the liver. These liver
changes were not noted in the 18-month mouse study. In 90-day as well as
in 2-year rat studies, there were thyroid changes (increase in weights
and incidence of follicular cell hyperplasia and hypertrophy). The
thyroid changes were considered to have been the result of liver
adaptive responses. The 90-day and one-year dog studies showed increases
in the levels of alkaline phosphatase as well as hepatic weights. In
three mechanistic rat studies, the following were observed: increase in
liver microsomal activity, induction of total cytochrome P450 activity,
disruption of thyroid homeostasis by decreasing circulating T3 and T4
and increasing TSH (likely the result of hepatic microsomal
glucuronyltransferase), and reversal of thyroid and liver effects with
the cessation of test article administration (it was concluded that the
induction of liver microsomal enzyme system resulted in increased
glucuronidation of thyroxine, resulting in an increase in TSH secretion
as a compensatory response of the physiological negative feedback
system; increased TSH resulted in increased thyroid weight). There were
little or no effects on body weights or body weight gains.

In the developmental toxicity studies, no effects were noted in rats;
whereas, in the rabbit study, abortions or early delivery were observed
at the highest dose tested (1000 mg/kg/day). Regarding the 2-generation
reproduction study in rats, decreased body weights and/or body weight
gains and hepatocyte degeneration were noted in males only. No
reproductive effects were observed. The only effects noted in pups of
both generations were decreases in body weights (both sexes of both
generations) at the highest dose tested (\>1000 mg/kg/day). There was no
evidence of neurotoxicity based on an acute neurotoxicity study, a
90-day neurotoxicity study and a developmental neurotoxicity study (all
in rats). There was no evidence of increased susceptibility in the
developmental rat study (Limit Dose). Qualitative, but not quantitative,
increased susceptibility was noted in the developmental rabbit study as
characterized by an increased incidence of abortions or early delivery
at the highest dose tested (1000 mg/kg/day. There was quantitative
evidence of increased susceptibility in the two-generation reproduction
rat study where decreases in body weights and body weight gains in male
offspring were seen in the F2 generation and in females from both
generations at a dose that was lower than the dose that induced
parental/systemic toxicity. Quantitative evidence of increased
susceptibility was noted in the developmental neurotoxicity study in
rats where decreases in pup body weights (PND 4) and body weight gains
(PND 1-4) were seen in the absence of any maternal toxicity. The degree
of concern is low for the qualitative evidence of susceptibility seen in
the rabbit developmental study as the increased abortions or early
delivery was seen only at the Limit Dose and the abortions may have been
due to maternal stress. The degree of concern is low for the
quantitative evidence of susceptibility seen in the two-generation
reproduction study in rats because the decreases in body weight and body
weight gains were seen only in the F2 generation in males and in females
in both generations. The degree of concern is low for the quantitative
evidence of susceptibility in the developmental neurotoxicity study
because the decreases in pup body weights seen on post natal days 1
through 4 (at no other time periods) were most likely due to maternal
toxicity.

The Cancer Assessment Review Committee (CARC) classified boscalid as
having "suggestive evidence of carcinogenicity, but not sufficient to
assess human carcinogenic potential," and, therefore, the quantification
of human cancer risk is not recommended. The classification was based on
data which were combined from two 2-year rat studies where males had a
significant increasing trend and significant differences in pair-wise
comparison with the controls for thyroid follicular cell adenomas. This
was supported by thyroid hypertrophy and hyperplasia of follicular
cells, increased thyroid weights and mechanistic data. Combined study
data for female rats showed only a borderline significant increasing
trend for thyroid follicular cell adenomas. No increase over controls
was noted in males or females for carcinomas. There was no increase in
the incidence of any tumors of either sex in the 18-month mouse study.
All mutagenic studies were negative with or without activation. Based on
the overall weak evidence of carcinogenic effects, the CARC indicated
that a dose-response assessment for cancer (either linear low-dose
extrapolation or margin of exposure calculation) was not needed.

+------------+----------------+--------------+------------------------+
| **Table    |                |              |                        |
| 3.1.       |                |              |                        |
| Summary of |                |              |                        |
| Tox        |                |              |                        |
| icological |                |              |                        |
| Dose and   |                |              |                        |
| Endpoints  |                |              |                        |
| of         |                |              |                        |
| Boscalid   |                |              |                        |
| for Use in |                |              |                        |
| Risk       |                |              |                        |
| Asse       |                |              |                        |
| ssments.** |                |              |                        |
+============+================+==============+========================+
| Exposure   | Dose Used in   | Level of     | Study and              |
| Scenario   | Risk           | Concern for  | Toxicological Effects  |
|            | Assessment,    | Risk         |                        |
|            | UF^a^          | Assessment   |                        |
+------------+----------------+--------------+------------------------+
| Acute      | No appropriate | NA           | NA                     |
| Dietary    | endpoint       |              |                        |
|            | identified     |              |                        |
+------------+----------------+--------------+------------------------+
| Chronic    | NOAEL = 21.8   | FQPA SF = 1X | Chronic rat,           |
| Dietary    | mg/kg/day      |              | carcinogenicity rat    |
| (All       |                | **cPAD** =   | and 1-year dog studies |
| po         | UF = 100       | [chronic     |                        |
| pulations) |                | RfD]         | LOAEL = 57-58          |
|            | **Chronic      | {.underline} | mg/kg/day based on     |
|            | RfD** = 0.218  |              | liver and thyroid      |
|            | mg/kg/day      | FQPA SF      | effects                |
|            |                |              |                        |
|            |                | = 0.218      |                        |
|            |                | mg/kg/day    |                        |
+------------+----------------+--------------+------------------------+
| Incidental | NOAEL = 21.8   | **R          | Chronic rat,           |
| Oral       | mg/kg/day      | esidential** | carcinogenicity rat    |
|            |                | LOC for MOE  | and 1-year dog studies |
| Short- and |                | = 100        |                        |
| Int        |                |              | LOAEL = 57-58          |
| ermediate- |                | **Oc         | mg/kg/day based on     |
| Term       |                | cupational** | liver and thyroid      |
| R          |                | LOC for MOE  | effects                |
| esidential |                | = 100        |                        |
| Only       |                |              |                        |
+------------+----------------+--------------+------------------------+
| Dermal     | Oral study     | Occupational | Chronic rat,           |
|            | NOAEL^b^=21.8  | LOC^c^ for   | carcinogenicity rat    |
| (All       | mg/kg/day      | MOE = 100    | and 1-year dog studies |
| Durations) |                |              |                        |
|            | (dermal        |              | LOAEL^d^ = 57-58       |
|            | absorption     |              | mg/kg/day based on     |
|            | rate = 15%)    |              | liver and thyroid      |
|            |                |              | effects                |
+------------+----------------+--------------+------------------------+
| Inhalation | Oral study     | Occupational | Chronic rat,           |
|            | NOAEL= 21.8    | LOC for MOE  | carcinogenicity rat    |
| (All       | mg/kg/day      | = 100        | and 1-year dog studies |
| Durations) |                |              |                        |
|            | (inhalation    |              | LOAEL = 57-58          |
|            | absorption     |              | mg/kg/day based on     |
|            | rate = 100%)   |              | liver and thyroid      |
|            |                |              | effects                |
+------------+----------------+--------------+------------------------+
| Cancer     | C              |              |                        |
| (oral,     | lassification: |              |                        |
| dermal,    | "Suggestive    |              |                        |
| i          | evidence of    |              |                        |
| nhalation) | ca             |              |                        |
|            | rcinogenicity, |              |                        |
|            | but not        |              |                        |
|            | sufficient to  |              |                        |
|            | assess human   |              |                        |
|            | carcinogenic   |              |                        |
|            | potential."    |              |                        |
+------------+----------------+--------------+------------------------+

**3.2 Endocrine Disruption**

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) \"may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate.\" Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system. EPA also
adopted EDSTAC's recommendation that the Program include evaluations of
potential effects in wildlife. For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations. As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency's EDSP have been developed, boscalid may be subjected
to additional screening and/or testing to better characterize effects
related to endocrine disruption.

# 4.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

No public health/epidemiology data were used in developing this risk
assessment.

[]{#__RefHeading___Toc169599913 .anchor}**5.0 DIETARY EXPOSURE/RISK
CHARACTERIZATION**

[]{#__RefHeading___Toc169599914 .anchor}**5.1 Pesticide Metabolism and
Environmental Degradation**

[]{#__RefHeading___Toc169599915 .anchor}**5.1.1 Metabolism in Primary
Crops**

45405021.der (lettuce)

45405022.der (grapes)

45405023.der (beans)

HED MARC Decision Memo DP#: 286786, 1/9/2003

The nature of the residue in plants has been summarized in a previous
residue chemistry summary document (PP# 1F06313, DP#: 278385, M. Nelson,
8/15/2003). The Metabolism Assessment Review Committee (MARC) has
concluded that the residue of concern in plants for both tolerance and
risk assessment purposes is the parent compound (9/11/2002 meeting, see
memo DP#: 286786, M. Nelson, 1/9/2003).

[]{#__RefHeading___Toc169599916 .anchor}**5.1.2 Metabolism in Rotational
Crops**

45405024.der

The nature of the residue in rotational crops is adequately understood
and was summarized in a previous residue chemistry summary document (PP#
1F06313, DP#: 278385, M. Nelson, 8/15/2003). The MARC has concluded that
the residue of concern in rotated crops for both tolerance expression
and risk assessment purposes is the parent compound (DP#: 286786, M.
Nelson, 1/9/2003).

[]{#__RefHeading___Toc169599917 .anchor}**5.1.3 Metabolism in
Livestock**

45405024.der (goats)

45405026.der (poultry)

HED MARC Decision Memo DP#: 286786, 1/9/2003

The nature of the residue in livestock has been summarized in a previous
residue chemistry summary document (PP# 1F06313, DP#: 278385, M. Nelson,
8/15/2003). The MARC has concluded that the residues of concern in
livestock for both tolerance and risk assessment purposes are the
parent, the hydroxy metabolite, and its glucuronide conjugate (9/11/2002
meeting, DP#: 286786).

[]{#__RefHeading___Toc169599918 .anchor}**5.1.4 Analytical Methodology**

*[Plants]{.underline}*

46351405.der (Data Collection Method, 445/0)

45405027.der (Data Collection Method, D9908)

45405028.der (Proposed Enforcement Method, D0008)

An adequate gas chromatographic-mass spectrometric (GC/MS) method
(Method D0008) is available for enforcing boscalid tolerances in plant
commodities. The ACB in BEAD concluded that the method is acceptable for
enforcement purposes in plants without the need for an EPA validation
(DP#: 284510, D. Swineford and E. Kolbe, 8/12/2003).

An adequate liquid chromatography with tandem mass spectrometric
detection (LC/MS/MS) method (BASF Method Number D9908) is also available
for collecting residue data on plant commodities (DP#: 278385, M.
Nelson, 8/15/2003). Boscalid residues in all of the plant commodities
associated with the current field trials were determined using this
LC/MS/MS method. BASF method 445/0 (46351405.der) is method D9908, with
some options removed. Therefore, no review of this latter method has
been needed.

For this latter method, residues are extracted with methanol:water:2N
HCl (70:25:5) and centrifuged or filtered. Residues are then partitioned
into cyclohexane, concentrated to dryness, and redissolved in buffered
methanol:water (80:20, v/v). Residues are determined by LC/MS/MS using
the *m/z* 343→307 transition for detecting and quantifying boscalid.
Residues were quantified using an external calibration curve of boscalid
standards. The validated LOQ is 0.05 ppm for boscalid in all commodities
tested, and the reported LOD is 0.004 ppm. In conjunction with each
field trial, the method was adequately validated using control samples
of each plant matrix fortified with boscalid at levels ranging from 0.05
to 40 ppm.

*[Livestock]{.underline}*

45405103.der (Method DFG S19)

45405105.der (Method 746/0)

45405106.der (Method 471/0)

An enforcement method is available for determining the residues of
concern in livestock. Method DFG S19 is a GC/electron capture detection
method that was successfully validated by ACB/BEAD (7/17/2003 Memo, D.
Swineford and E. Kolbe). In response to Agency comments, the petitioner
has also submitted revised copies of BASF Methods 471/0 and 476/0 and
the modified multi-residue method DFG S19. However, the requirement of
radiovalidation data demonstrating the efficiency of the microwave
hydrolysis step in Method 476/0 and the enzymatic hydrolysis steps in
Methods 471/1 and DFG S19 remain outstanding (DP#: 278385, M. Nelson,
8/15/2003).

[]{#__RefHeading___Toc169599920 .anchor}**5.1.5 Environmental
Degradation**

EFED has evaluated the information submitted for new uses of boscalid on
stone fruits, pome fruits and Belgian endive. The proposed uses are
post-harvest for stone fruits and pome fruits, and post- harvest for
Belgian endive. These proposed new uses can only occur indoors and
hence, the potential for boscalid to enter the environment is limited.
Given the unlikely exposure of non-target ecological receptors, EFED
does not expect any risk to these receptors or significant contamination
of drinking water sources (DP#: 327907 and 328066, C. Salice,
10/31/2006).

**5.1.6 Comparative Metabolic Profile**

There are five acceptable mutagenicity studies on technical grade BAS
510 F. Together, they satisfy the revised mutagenicity guideline of 1991
(OPP Pesticide Assessment Guideline. Subdivision F, Series 84, Addendum
9) which are applicable to all new active ingredients. Results in all
five studies were negative for mutagenic potential. For a complete
discussion of these studies, please see the HIARC memo.

[]{#__RefHeading___Toc169599921 .anchor}**5.1.7 Drinking Water Residue
Profile**

The drinking water residues used in the dietary risk assessment were
previously provided by the Environmental Fate and Effects Division
(EFED), summarized in a memo from C. Salice (Memo, DP#: 313814,
5/5/2005) and incorporated directly into this dietary assessment. Water
residues were incorporated in the DEEM-FCID into the food categories
"water, direct, all sources" and "water, indirect, all sources."

EFED provided Tier I EDWCs for boscalid in surface water and in
groundwater for use in the human health risk assessment. EFED used the
simulation models FIRST to calculate the surface water EDWCs and
SCI-GROW to calculate the groundwater concentration. The turf use still
represents the highest annual application rate for boscalid. The EDWC
from FIRST for chronic exposures is 25.77 ppb. The SCI-GROW estimate for
groundwater exposure is 0.63 ppb. The surface water number of 0.02577
ppm was used in the analysis because it is higher than the groundwater
value.

[]{#__RefHeading___Toc169599922 .anchor}**5.1.8 Food Residue Profile**

A new use for boscalid on endive has been proposed by IR-4 in petition
PP#5E7013 with a proposed tolerance of 12 ppm. Difficulties found in
this endive submission have led the Agency to a decision that this
Section 3 petition cannot be supported at this time but a Section 18
request, with a recommended tolerance of 16 ppm, based upon existing
data following application with a backpack sprayer, can be considered.

If IR-4 wants to continue with the Section 3 registration, then the
following additional materials must be submitted:

1)  Use directions in Section B must match the application method used
    in Section D for residue data collection.

2)  The tolerance proposal in Section F must be supported by the
    application method used in Section D for residue data collection.

3)  Additional residue data that adequately reflect the use direction in
    Section B must be submitted. HED recommends that the petitioner
    submit a protocol for HED review and comments before any residue
    data collection begins.

For a more detailed explanation of deficiencies/issues with this
petition, please see the residue chemistry data review memorandum (DP#:
323288, D. Soderberg, 6/14/2007).

Petition PP#5F6986 proposes increasing tolerances on strawberry to 4.0
ppm. The Agency has already reviewed the recent strawberry field trial
data and has revised the strawberry tolerance to 4.5 ppm (DP#: 322235,
D. Dotson, 11/3/2005). This tolerance is now published in the CFR, so no
further action on the strawberry tolerance is required.

BASF has submitted additional field trial data for boscalid on
cucumbers, mustard greens, and sunflower seeds. These field trials were
requested by the Agency as a condition for the registration of boscalid
on these crops (PP#1F6313, DP#: 278385, M. Nelson, 8/15/2003). BASF has
also submitted supplemental field trials on fruiting vegetables,
spearmint and peppermint, radishes, stone fruits, and grapes, which were
conducted to support the use of boscalid on these crops in Canada.
Adequate field trial data supporting the use of boscalid on these crops
or crop groups in the U.S. were previously reviewed (DP#: 278385, M.
Nelson, 8/15/2003).

Adequate cattle and poultry feeding studies for boscalid were reviewed
in an earlier petition (DP#: 278385, M. Nelson, 8/15/2003), and the
adequacy of the existing tolerances on animal commodities was recently
assessed in a separate petition (DP#: 322235, D. Dotson, 11/3/2005).
Reassessment of animal tolerances is not necessary for this review,
since sunflower meal is the only regulated feedstuff associated with any
of the crops or crop groups under review for tolerances, and residues in
sunflower meal are not expected to have a substantial impact on the
dietary exposure of livestock. Endive roots are fed to cattle but are
not an important feed item to consider.

The requested field trials on mustard greens, cucumbers and sunflower
and the supplemental field trials on blueberries, raspberries,
cantaloupes, squash, fruiting vegetables, grapes, spearmint, peppermint,
radishes, and stone fruits are adequate and support the existing uses of
boscalid on these crops. Together with the previously submitted field
trials, the number and geographic distribution of the field trials on
these crops are adequate, and the appropriate samples were collected at
the labeled PHIs. Samples were analyzed using an adequate method, and
the sample storage intervals are supported by the available storage
stability data.

Adequate processing studies are available and were previously reviewed
for the crops or crop groups being evaluated in this review (DP#:
278385, M. Nelson, 8/15/2003). Based on the available data, the Agency
established a 8.5 ppm tolerance on raisins. None of the tolerance
changes being considered in this review will affect tolerances for
residues in regulated processed commodities.

Adequate confined and limited field rotational crop studies are
available, and tolerances for indirect or inadvertent residues have been
established based on extensive rotational crop field trials. The
available data support the 14-day plant back interval (PBI) on the
labels for rotated crops without primary uses of boscalid. There are
currently no deficiencies pertaining to rotational crops.

[]{#__RefHeading___Toc169599923 .anchor}**5.1.9 International Residue
Limits**

The Codex Alimentarius Commission and Mexico have not established any
maximum residue limits (MRLs) for residues of boscalid in or on raw
agricultural commodities; however, a variety of MRLs are pending in
Canada. U.S. tolerances and Canadian MRLs are equivalent on a number of
the crops being considered in this action (spearmint, peppermint,
*Brassica* leafy greens, grapes, stone fruits, and sunflower seeds);
however, existing or recommended U.S. tolerances are higher than
Canadian MRLs for the remaining commodities.

[]{#__RefHeading___Toc169599924 .anchor}**5.2 Dietary Exposure and
Risk**

A boscalid chronic dietary-exposure assessment was conducted using
DEEM-FCID^™^ Version 2.03, which incorporates consumption data from
USDA's CSFII, 1994-1996 and 1998. The 1994-96, 98 data are based on the
reported consumption of more than 20,000 individuals over two
non-consecutive survey days. Foods "as consumed" (e.g., apple pie) are
linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA. For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events. Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (\<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For chronic dietary-exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure. Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD. This procedure is performed for each
population subgroup.

The dietary exposure analysis was performed by ARIA (B. Hanson, DP #:
338990, 6/28/2007).

[]{#__RefHeading___Toc169599925 .anchor}**5.2.1 Acute Dietary
Exposure/Risk**

There were no toxic effects attributable to a single dose. An endpoint
of concern was not identified to quantitate an acute-dietary risk to the
U.S. general population or to the subpopulation females 13-50 years old.
Therefore, an acute dietary risk assessment was not performed.

[]{#__RefHeading___Toc169599926 .anchor}**5.2.2 Chronic Dietary
Exposure/Risk**

The unrefined chronic dietary risk assessment for boscalid used
tolerance level residues, default and empirical processing factors (See
Section 5.3, below) and 100% crop treated (CT) assumptions. The highest
chronic EDWC of 0.02577 ppm was used in this analysis. The results of
the analysis indicate that chronic risk from the dietary (food +
drinking water) exposure to boscalid will not exceed HED's level of
concern (i.e. \<100% chronic population adjusted doses (cPAD)) for the
general U.S. population, and all population subgroups. The chronic
dietary risk estimate for the highest reported exposed population
subgroup, children 1-2 years old, is 32% of the cPAD. The general US
population utilizes 10% of the cPAD.

  ------------------------------------------------------------------------
  **Table 5.2.2 Summary                            
  of Chronic Dietary                               
  (Food and Drinking                               
  Water) Exposure Risk                             
  for Boscalid**                                   
  ---------------------- ------------------------- -----------------------
  Population Subgroup    Chronic Dietary           

                         Dietary Exposure          \% aPAD\*
                         (mg/kg/day)               

  General U.S.           0.020914                  10
  Population                                       

  All Infants (\< 1 year 0.048451                  22
  old)                                             

  **Children 1-2 years   **0.069579**              **32**
  old**                                            

  Children 3-5 years old 0.048713                  22

  Children 6-12 years    0.025284                  12
  old                                              

  Youth 13-19 years old  0.014351                  7

  Adults 20-49 years old 0.015886                  7

  Adults 50+ years old   0.017850                  8

  Females 13-49 years    0.016094                  7
  old                                              
  ------------------------------------------------------------------------

[]{#__RefHeading___Toc169599927 .anchor}**5.2.3 Cancer Dietary Risk**

The CARC stated that boscalid exhibited "suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential." The quantification of human cancer risk was not recommended.
Therefore, a cancer risk assessment was not performed.

[]{#__RefHeading___Toc169599928 .anchor}**5.3 Anticipated Residue and
Percent Crop Treated (%CT) Information**

For some commodities, processing studies demonstrated residues of
boscalid do not concentrate. For these commodities the raw agricultural
commodity (RAC) tolerance was used and the processing factor was set to
1.0. In some other instances the processing studies demonstrated that
there was a slight concentration of residues upon processing. In these
cases, the tolerance for the RAC was adequate to cover residues in
processed commodities. Again, the processing factor was set to 1.0. In
yet other cases, residues concentrated enough in the processing studies
that separate tolerances were established for the processed commodities.
These tolerances were used in the assessment and processing factors were
set to 1.0. See Table 5.3, below.

+-----------------+----+---------------------+----+------------+----+
| **Table 5.3.    |    |                     |    |            |    |
| Commodities     |    |                     |    |            |    |
| With Processing |    |                     |    |            |    |
| Factors Set to  |    |                     |    |            |    |
| 1.0.**          |    |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Residues That   | Ad | Tolerance Level     | Ad | Separate   | Ad |
| Do Not          | j. | Adequate to Cover   | j. | Tolerance  | j. |
| Concentrate in  |    | Slight              |    | E          |    |
| Processed       | #1 | Concentration       | #1 | stablished | #1 |
| Commodity       |    |                     |    |            |    |
|                 |    | (processing factor) |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Apple Juice     | 1  | Wheat Germ (1.2x)   | 1  | Grape,     | 1  |
|                 | .0 |                     | .0 | Raisin     | .0 |
+-----------------+----+---------------------+----+------------+----+
| Plum - Prune    | 1  | Wheat Bran (1.2x)   | 1  | Peanut Oil | 1  |
|                 | .0 |                     | .0 |            | .0 |
+-----------------+----+---------------------+----+------------+----+
| Rice Bran       | 1  | Tomato Paste (1.1x) | 1  |            |    |
|                 | .0 |                     | .0 |            |    |
+-----------------+----+---------------------+----+------------+----+
| Wheat Flour     | 1  |                     |    |            |    |
|                 | .0 |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Sunflower Oil   | 1  |                     |    |            |    |
|                 | .0 |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Mint Oil        | 1  |                     |    |            |    |
|                 | .0 |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Tomato Puree    | 1  |                     |    |            |    |
|                 | .0 |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Tomato Juice    | 1  |                     |    |            |    |
|                 | .0 |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+
| Soybean Oil     | 1  |                     |    |            |    |
|                 | .0 |                     |    |            |    |
+-----------------+----+---------------------+----+------------+----+

For the other processed commodities, for which data are not available,
DEEM (Version 7.81) default processing factors were used. No %CT
information was considered in the chronic dietary analysis.

[]{#__RefHeading___Toc169599929 .anchor}**6.0 RESIDENTIAL
(NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION**

The current petition for boscalid results in no
non-occupational/residential exposures. However, HED previously assessed
the two potential non-occupational exposure scenarios for boscalid; pick
your own fruit and, golf course treatment (HED/ORE memorandum, DP #:
290072, 6/23/2003). HED did not assess the "pick your own" scenario for
boscalid since no toxicological endpoints were identified for this
exposure duration. However, HED did estimate risks to adults (and
adolescents) from boscalid use on golf courses and found that risks were
not of concern. MOEs ranged from 27,000 -- 74,000.

[]{#__RefHeading___Toc169599930 .anchor}**7.0 AGGREGATE RISK ASSESSMENTS
AND RISK CHARACTERIZATION**

In accordance with the FQPA, ARIA must consider and aggregate pesticide
exposures and risks from non-occupational sources, including; food,
drinking water, and residential pathways. In an aggregate assessment,
exposures from relevant sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks
themselves can be aggregated. When aggregating exposures and risks from
various sources, ARIA considers both the route and duration of exposure.

[]{#__RefHeading___Toc169599931 .anchor}**7.1 Acute Aggregate Risk**

An acute aggregate-risk assessment was not performed because no
appropriate endpoint was available to determine the aRfD for the general
population or any population subgroup.

[]{#__RefHeading___Toc169599932 .anchor}**7.2 Short-Term Aggregate
Risk**

The short-term aggregate risk assessment takes into account average
exposure estimates from dietary consumption of boscalid (food and
drinking water) and non-occupational exposures.

Post-application exposure from golf courses is considered short-term,
and is applicable to both adults and youth. The non-occupational use to
be aggregated with dietary exposure is turf on golf courses. The target
maximum daily exposure to boscalid residues is 0.22 mg/kg/day. The
estimated MOE is 960, and exceeds the target MOE of 100. Therefore the
short-term aggregate risk exposure estimates are not of concern to the
Agency and do not exceed HED's level of concern (i.e. MOEs greater than
or equal to 100).

  ---------------- ---------- ---------- ----- ------ ------------ -------- ----- ------- ---------------
  **Table 7.2.                                                                            
  Short-Term                                                                              
  Aggregate Risk                                                                          
  for Boscalid**                                                                          

  **Population**   **food +                           **Dermal**                          **MOE
                   water**                                                                ~Aggregate~**

                   NOAEL      EXP        LOC   MOE    NOAEL        EXP      LOC   MOE     

  **U.S            21.8       0.020914   100   1000   21.8         0.0008   100   27000   960
  Population**                                                                            
  ---------------- ---------- ---------- ----- ------ ------------ -------- ----- ------- ---------------

LOC=Level of Concern

MOE= NOAEL (or LOAEL)/exp

MOE ~Aggregate~= 1/((1/MOE ~food~)+(1/MOE ~dermal~))

**7.3 Intermediate/Long-Term Aggregate Risk**

Intermediate/long-term exposures are not anticipated. Therefore an
intermediate-term aggregate risk assessment was not performed.

[]{#__RefHeading___Toc169599933 .anchor}**7.4 Chronic Aggregate Risk**

Since the chronic aggregate risk assessment includes exposure from food
and water only, and the chronic dietary analysis that was performed
included both, no further calculations are necessary. Since the chronic
dietary risk does not exceed HED's level of concern, the chronic
aggregate risk does not exceed HED's level of concern.

[]{#__RefHeading___Toc169599934 .anchor}**7.5 Cancer Aggregate Risk**

Boscalid has been classified as having "suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential." The quantification of human cancer risk was not recommended.
Therefore, a cancer risk assessment was not performed.

[]{#__RefHeading___Toc169599935 .anchor}**8.0 CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT**

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to boscalid and any other
substances, and boscalid does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that boscalid has a common mechanism of
toxicity with other substances.

For information regarding EPA's efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements released by EPA's
Office of Pesticide Programs concerning common mechanism determinations
and procedures for cumulating effects from substances found to have a
common mechanism on EPA's website at
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

[]{#__RefHeading___Toc169599936 .anchor}**9.0 OCCUPATIONAL EXPOSURE/RISK
PATHWAY**

HED provided an assessment for the post-harvest use of boscalid on
endive (T. Moriarty, DP #: 327906, 6/5/2007). This is the only new use
being proposed. For further information on the occupational exposure and
risk from boscalid, please view the following assessment: *Boscalid*
*Occupational Residential Exposure Assessment* (S. Wang, DP #: 321801,
9/20/2005).

*[Proposed Uses]{.underline}*

Two post-harvest application scenarios for boscalid are being proposed.
The first scenario is application to Belgian endive roots as they move
along a conveyor being transported from the field into cold storage. The
second scenario is application to the roots when they are packed into
forcing trays. A summary of the proposed use for Pristine® is presented
in Table 9.0.a.

+--------+---------+----------+----------+------------------+--------+
| *      |         |          |          |                  |        |
| *Table |         |          |          |                  |        |
| 9.0.a  |         |          |          |                  |        |
| Pr     |         |          |          |                  |        |
| oposed |         |          |          |                  |        |
| New    |         |          |          |                  |        |
| Occupa |         |          |          |                  |        |
| tional |         |          |          |                  |        |
| Uses   |         |          |          |                  |        |
| of     |         |          |          |                  |        |
| Bosc   |         |          |          |                  |        |
| alid** |         |          |          |                  |        |
+========+=========+==========+==========+==================+========+
| Crop   | P       | T        | App      | Maximum          | Amount |
|        | roduct, | reatment | lication | Application Rate | H      |
|        |         | Type     | E        |                  | andled |
|        | Form    |          | quipment |                  | Per    |
|        | ulation |          |          |                  | Day    |
+--------+---------+----------+----------+------------------+--------+
| B      | Pri     | Roots    | T-Jet or | 1.4 oz in 2-2.5  | 2      |
| elgian | stine®, | placed   | similar  | gallons water to | 00,000 |
| endive |         | into     | me       | 850 lb of roots  | lb/day |
| roots  | DF      | cold     | chanical |                  |        |
|        |         | storage  | spray    | (0.000026 lb     |        |
|        | EPA     |          | e        | ai/lb of endive  |        |
|        | Reg.    |          | quipment | root)            |        |
|        | No.     |          | attached |                  |        |
|        | 7       |          | to a     |                  |        |
|        | 969-199 |          | conveyor |                  |        |
|        |         |          | belt     |                  |        |
|        | 25.2%   |          |          |                  |        |
|        | B       |          |          |                  |        |
|        | oscalid |          |          |                  |        |
+--------+---------+----------+----------+------------------+--------+
|        |         | Roots    |          | 0.4 oz in 3 qt   | 2400   |
|        |         | packaged |          | water per 12     | ft^2^  |
|        |         | in       |          | ft^2^ forcing    | of     |
|        |         | forcing  |          | trays            | f      |
|        |         | trays    |          |                  | orcing |
|        |         |          |          | (0.00063 lb      | tray   |
|        |         |          |          | ai/ft^2^ forcing |        |
|        |         |          |          | tray)            |        |
+--------+---------+----------+----------+------------------+--------+

*[Non-Occupational/Residential Exposure]{.underline}*

The current petition for boscalid results in no
non-occupational/residential exposures. However, HED previously assessed
the two potential non-occupational exposure scenarios for boscalid; pick
your own fruit and, golf course treatment (HED/ORE memorandum 6/23/2003,
DP #: 290072). HED did not assess the "pick your own" scenario for
boscalid since no toxicological endpoints were identified for this
exposure duration. However, HED did estimate risks to adults (and
adolescents) from boscalid use on golf courses and found that risks were
not of concern. MOEs ranged from 27,000 -- 74,000.

*[Occupational Pesticide Handler Exposure]{.underline}*

To gather handler (mixer, loader, applicator) information, HED also
consulted Dr. David Thompson, Plant Pathology Program Manager, IR-4
Project Headquarters at Rutgers, The State University of New Jersey. Dr.
Thompson indicated that post-harvest treatment of Belgian endive roots
is mechanically performed as a dip or a spray. He also stated that for a
spray application, the handler mixes up a tank of fungicide solution and
then lets it run through the sprayer, (no one is standing at the sprayer
during the application). HED also consulted Dr. Stephen Flanagan in the
IR-4 Western Region office. Dr. Flanagan confirmed that Belgian endive
root forcing trays are sprayed using overhead mounted sprayers, where
trays are passed below on a conveyor belt at a fixed speed. Therefore,
only mixer/loaders are expected to receive exposure to boscalid, not an
applicator. Therefore, based on this information, HED concluded that the
post-harvest exposure to handlers is from mixing and loading only.
Post-harvest application of Pristine® is mechanical and, therefore, no
applicator exposure is expected. HED was also informed by Dr. Rich
Collins at California Vegetable Specialties that inhalation exposure to
handlers is minimal since the spray area is in a shrouded/enclosed area
over the conveyor belt. Therefore, the handler scenario assessed for the
proposed use on Belgian endive is: Mixing/Loading Dry Flowables for
T-Jet or Similar Mechanical Spray Equipment Attached to a Conveyor Belt
(high volume/dilute application).

Total MOEs for handlers supporting post-harvest applications to Belgian
endive root are not of concern to HED (MOEs range from 28,000 to
98,000). Therefore no additional mitigation is necessary for mixers and
loaders for this proposed use due to potential exposure to boscalid. A
summary of the exposures and risks for handlers is presented in Table
9.0.b.

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Table 9.0.b. Handler Exposures and Risks from
Post-Harvest Applications to Boscalid</strong></td>
</tr>
<tr class="even">
<td>Exposure Scenario</td>
<td>Crop or Target</td>
<td>Application Rate<sup>a</sup></td>
<td>Baseline Dermal Unit Exposure<sup>b</sup> mg/lb ai</td>
<td>Baseline Inhalation Unit Exposure<sup>c</sup> mg/lb ai</td>
<td>Amount Treated Daily<sup>d</sup></td>
<td>Baseline Daily Dermal Dose<sup>e</sup> mg/kg/day</td>
<td>Baseline Daily Inhalation Dose<sup>f</sup> mg/kg/day</td>
<td>Combined Daily Dose<sup>g</sup> (mg/kg/day)</td>
<td>Total MOE<sup>h</sup></td>
</tr>
<tr class="odd">
<td rowspan="2">Mixing/Loading Dry Flowables For T-jet or Similar
Mechanical Spray Equipment Attached To A Conveyor Belt</td>
<td>Belgian endive roots (prior to cold storage)</td>
<td><p>0.000025</p>
<p>lb ai/root</p></td>
<td>0.066</td>
<td>0.00077</td>
<td>200,000 lb root</td>
<td>0.00073</td>
<td>0.000057</td>
<td>0.00080</td>
<td>27,000</td>
</tr>
<tr class="even">
<td>Belgian endive roots (in forcing trays)</td>
<td><p>0.00063</p>
<p>lb ai/sq ft forcing tray</p></td>
<td>0.066</td>
<td>0.00077</td>
<td><p>2,400</p>
<p>sq ft</p></td>
<td>0.00021</td>
<td>0.000017</td>
<td>0.00023</td>
<td>94,000</td>
</tr>
</tbody>
</table>

a\. 1.4 oz \* 25.5% of formulation product is active ingredient = 0.352
oz ai per 850 lb roots

> 0.352 oz/850 lbs root \* 1 lb/16 oz = 2.5e^-5^ lb ai/lb root.
>
> 0.4 oz \* 25.5% of formulated product is active ingredient = 0.1 oz of
> ai per 12 ft^2^ of forcing tray
>
> 0.1 oz/10 ft^2^ \* 1 lb/16 oz = 6.3e^-4^ lbs ai/ft^2^ of forcing tray.

b\. Baseline Dermal Unit Exposure represents long pants, long sleeved
shirt, no gloves, open mixing/loading. Source: PHED Version 1.1, August,
1998.

c\. Baseline Inhalation Exposure represents no respiratory protection,
open mixing/loading. Source: PHED Version 1.1, August, 1998.

d\. Daily amount treated values are from experts\' estimates of gallons
of spray that would be mixed/loaded in a day or pounds of root that
would be treated in a day.

e\. Daily dermal dose (mg/kg/d) = \[unit dermal exposure (mg/lb ai) \*
dermal absorption (0.15) \* application rate (lb ai/gal or lb ai/lb
fruit) \* daily amount treated / body weight (70 kg)\].

Daily inhalation dose (mg/kg/d) = \[unit inhalation exposure (μg/lb ai)
\* (1mg/1000 μg) conversion \* inhalation absorption (100%) \*
application rate (lb ai/gal or lb ai/lb fruit) \* daily amount treated /
body weight (70 kg)\].

g\. Combined Daily Dose = baseline daily dermal dose + baseline daily
inhalation dose.

h\. Total MOE = NOAEL/ dermal daily dose (mg/kg/day) + inhalation daily
dose (mg/kg/day).

*[Occupational Post-Application Worker Exposure and Risk]{.underline}*

HED has determined that there is potential exposure to persons handling
Belgian endive root after post-harvest application is complete. No
chemical-specific data to assess the exposure from post-application to
Belgian endive root was submitted. Therefore, HED used surrogate data
and default assumptions. MOEs calculated for post-application activities
were not of concern to HED (MOE = 200), and therefore, no additional
mitigation is necessary for post-application handlers for this proposed
use.

*[Post-Harvest Exposure]{.underline}*

HED consulted Dr. Rich Collins at California Vegetable Specialties
regarding exposure following post-harvest applications to Belgian endive
root. He indicated that there is no dermal contact with the treated
endive roots while moving storage bins into cold storage, since bins
were moved with a forklift. However, potential exposure does occur when
workers plant the endive roots into forcing trays, which can happen
anywhere from one week to 12 months from treatment. HED also consulted
Dr. Stephen Flanagan in the IR-4 Western Region office who indicated
that there is potential dermal contact by post-application workers with
the treated endive root or the recirculating water when:

-   closing the fruit bins before cold storage,

-   moving the forcing trays into forcing rooms,

-   contact with recirculating water pumped through forcing trays,

-   contact with endive during growth check by management,

-   cutting/harvesting endive (27 days after forcing), and

-   packing harvested endive.

As a worse-case post-application exposure scenario, HED assessed the
long-term dermal exposure of workers hand-packing individual treated
roots into forcing trays. This exposure was assessed for long-term
duration, because the operation occurs on a continuous basis throughout
the entire year. The estimated exposure/risk is considered high end
because it is based on the assumption that contact with roots occurs on
the same day as treatment when, in reality, boscalid residues on the
roots is likely to have dissipated by some percentage over the one week
to twelve months between treatment and when the packing activity
actually occurs.

*[Post-Application Dermal Exposure and Risk]{.underline}*

Table 9.0.c summarizes the MOEs for workers packing/inspecting Belgian
endive root following post-harvest application. The dermal risks
associated with post-application activities are not of concern to HED
(MOE = 200) and therefore, no mitigation is necessary for
post-application handlers for this proposed use.

+-----+------+------+--------+--------+--------+------+------+-----+
| *   |      |      |        |        |        |      |      |     |
| *Ta |      |      |        |        |        |      |      |     |
| ble |      |      |        |        |        |      |      |     |
| 9.0 |      |      |        |        |        |      |      |     |
| .c. |      |      |        |        |        |      |      |     |
| P   |      |      |        |        |        |      |      |     |
| ost |      |      |        |        |        |      |      |     |
| -ap |      |      |        |        |        |      |      |     |
| pli |      |      |        |        |        |      |      |     |
| cat |      |      |        |        |        |      |      |     |
| ion |      |      |        |        |        |      |      |     |
| Exp |      |      |        |        |        |      |      |     |
| osu |      |      |        |        |        |      |      |     |
| res |      |      |        |        |        |      |      |     |
| and |      |      |        |        |        |      |      |     |
| Ri  |      |      |        |        |        |      |      |     |
| sks |      |      |        |        |        |      |      |     |
| for |      |      |        |        |        |      |      |     |
| Bo  |      |      |        |        |        |      |      |     |
| sca |      |      |        |        |        |      |      |     |
| lid |      |      |        |        |        |      |      |     |
| on  |      |      |        |        |        |      |      |     |
| B   |      |      |        |        |        |      |      |     |
| elg |      |      |        |        |        |      |      |     |
| ian |      |      |        |        |        |      |      |     |
| End |      |      |        |        |        |      |      |     |
| ive |      |      |        |        |        |      |      |     |
| Roo |      |      |        |        |        |      |      |     |
| t** |      |      |        |        |        |      |      |     |
+-----+------+------+--------+--------+--------+------+------+-----+
| Fr  | A    | Tran | D      | Conv   | Dermal | Expo | Abso | Der |
| uit | ppl. | sfer | efault | ersion | A      | sure | rbed | mal |
|     | Rat  | Co-e | Transf | Fac    | bsorpt | Tim  | De   | MOE |
|     | e^a^ | ffic | erable | tor^d^ | ion^e^ | e^f^ | rmal | ^h^ |
|     |      | ient | Resi   | (      | (%)    |      | Dos  |     |
|     |      |      | due^c^ | mg/lb) |        | (ho  | e^g^ |     |
|     |      | (c   |        |        |        | urs) | (mg  |     |
|     |      | m^2^ | (day   |        |        |      | /kg/ |     |
|     |      | /hr) | 0)     |        |        |      |      |     |
|     |      |      |        |        |        |      | day) |     |
+-----+------+------+--------+--------+--------+------+------+-----+
| B   | 4.   | 1    | 20%    | 4      | 15%    | 8    | 1.1  | 200 |
| elg | 7e-8 | ,500 |        | .5E+05 |        |      | E-01 |     |
| ian |      |      |        |        |        |      |      |     |
| end | (lb  |      |        |        |        |      |      |     |
| ive | ai/c |      |        |        |        |      |      |     |
| r   | m^2^ |      |        |        |        |      |      |     |
| oot | r    |      |        |        |        |      |      |     |
| pr  | oot) |      |        |        |        |      |      |     |
| ior |      |      |        |        |        |      |      |     |
| to  |      |      |        |        |        |      |      |     |
| c   |      |      |        |        |        |      |      |     |
| old |      |      |        |        |        |      |      |     |
| s   |      |      |        |        |        |      |      |     |
| tor |      |      |        |        |        |      |      |     |
| age |      |      |        |        |        |      |      |     |
+-----+------+------+--------+--------+--------+------+------+-----+

a\. Application rate = lb ai/cm^2^ of root

b\. Transfer coefficient = 1,500 cm^2^/hr

c\. Default transferable residue = 20% of application rate on day 0

d\. Weight unit conversion factor to convert the lb ai in the
application rate to mg

e\. Dermal Absorption Factor = (15%)

f\. Exposure time = number of hours/day of expected exposure (8 hours)

g\. Absorbed dermal dose = (application rate x 20% x 1500 x 4.5E+5 x 15%
x 8 hours) / 70 kg body weight

h\. Dermal MOE = NOAEL (21.8 mg/kg/day) / absorbed dermal dose.

*Inhalation Exposure and Risk*

HED did not estimate inhalation exposure and risk from post-application
treatment to Belgian endive root. HED believes that the inhalation
exposure from post-harvest exposure to boscalid will be negligible for
the following reasons: (1) the relatively low vapor pressure of boscalid
(7 x 10^-9^ hPa (PAI@ 20^o^ C); (2) information that workers are
standing at a distance from the application area; (3) the application
area is covered; and, (4) most airborne particles of boscalid are
assumed to dissipate by the time the packers are in contact with the
treated roots. Therefore, HED believes that a quantitative assessment
for inhalation exposure to post-application workers is not required.

[]{#__RefHeading___Toc169599939 .anchor}**10.0 DATA NEEDS AND LABEL
RECOMMENDATIONS**

[]{#__RefHeading___Toc169599940 .anchor}**10.1 Toxicology**

None.

[]{#__RefHeading___Toc169599941 .anchor}**10.2 Residue Chemistry**

*For Endive:*

If IR-4 wants to continue with this Section 3 registration, then the
following are needed:

1)  Use directions in Section B must match the application method used
    in Section D for residue data collection.

2)  The tolerance proposal in Section F must be supported by the
    application method used in Section D for residue data collection.

3)  Additional residue data that adequately reflect the use direction in
    Section B must be submitted. (HED recommends that the petitioner
    submit a protocol for HED review and comments before any residue
    data collection begins.)

HED recommends that the label rate be revised to [clearly
define]{.underline} the amounts to be used per application and the total
per season. In addition, the petitioner should define how the spray is
applied to the roots in the forcing trays (.i.e., trays are stationary
or are moving on conveyor belt). A revised Section B must be submitted
to reflect more adequately the petitioner's intentions as to application
rates and directions.

[Suggested label changes:]{.underline}

[Prior to Cold Storage]{.underline}

The label currently states:

"Make one........... Apply 0.7 to 1.4 oz Pristine® fungicide in 2 to 2.5
gallons of water per 850 lbs roots."

HED suggests that label state the following:

"Make one........... Apply 0.08 to 0.16 oz of Pristine® fungicide in 2
to 2.5 gallons of water per 100 lb of roots"

[Prior to Forcing]{.underline}

The label currently states:

"Make one........... Apply at the rate of 0.15 to 0.4 oz Pristine®
fungicide in approximately 3 quarts of water per 10 square feet of
forcing tray.

HED suggests that label state the following:

"Make one...........Apply the rate of 0.015 to 0.03 oz of Pristine®
fungicide in approximately 3 quarts of water per 1 square foot of
forcing tray.

*Outstanding Deficiencies*

Although no other major deficiencies are noted in the current review,
HED notes that there are outstanding deficiencies/issues from earlier
petitions (DP#: 278385, M. Nelson, 8/15/2003) that must still be
addressed by the petitioner. These deficiencies are listed below.

1)  Submission of radiovalidation data demonstrating the efficiency of
    the hydrolysis step in the proposed tolerance enforcement method
    (DFG S19) for livestock matrices. These radiovalidation data will
    also be used in support of the data collection method (471/0) for
    livestock matrices. These data were required as a condition of
    registration.

2)  Submission of radiovalidation data demonstrating the efficiency of
    the microwave hydrolysis step in Method 476/0, which determines
    bound residues of boscalid in milk and liver. These data were
    required as a condition of registration.

3)  Data are required demonstrating the frozen storage stability of
    boscalid residues in processed grape juice (2 months).

Note to PM: Although tolerances have been established on spearmint and
peppermint tops, there are no registered uses on these mints. If the
petitioner intends to support uses on these mints, a label having
spearmint and/or peppermint uses should be submitted to the Agency.

[]{#__RefHeading___Toc169599942 .anchor}**10.3 Occupational and
Residential Exposure**

None.

**REFERENCES:**

**Dietary Exposure Memorandum**

*Boscalid Chronic Dietary Exposure Assessment for the Section 18 Use
in/on Belgian Endive and the BASF Request for an Increase in Tolerance
Levels for Strawberries and Berries, Crop Group 13 along with an
Increase in Tolerances in/on Cucumber and Vegetable, Root, Subgroup 1A,
except Sugar Beet, Garden Beet, Radish, and Turnip. PP#s 5E7013 and
5F6986*, B. Hanson, DP#: 338990, 6/28/2007.

**Drinking Water Memorandum**

*Memo,* C. Salice, DP #: 313814, 5/5/2005.

**Residue Chemistry Data Review Memorandum**

*Boscalid. Petition for a Tolerance for Belgian Endive; Petition for
Increased Tolerances on Strawberry and the Berries Crop Group;
Submission of Requested Field Trial Data on Cucumber, Mustard Greens and
Sunflower; and Supplemental Field Trial Data on Fruiting Vegetables,
Radishes, Spearmint, Peppermint, Grapes, and Stone Fruits; and
Submission of Field Trials and a Processing Study for Cotton. Summary of
Analytical Chemistry and Residue Data. Petition Numbers 5F6986, 1F6386,
5E7013, 5E7014;* D. Soderberg; DP #s: 323288, 323570, 323871, 338480,
327906 and 326207; 6/14/2007.

**Occupational and Residential Exposure Memorandum**

*Occupational Risk Assessment of Boscalid for Post- Harvest Treatment of
Belgian Endive,* T. Moriarty, DP#: 327906; 6/5/2007.

**Risk Assessment Document**

*PP# 3E6791. Human Health Risk Assessment for Boscalid**.** Proposal for
Tolerances for Residues in/on Leafy Greens Subgroup 4A, except Head and
Leaf Lettuce, and Leaf Petioles Subgroup 4B,* S. Brothers, DP#:: 327353,
10/20/2006.

*[PP# 1F06313]{.underline} \--Human Health Risk Assessment for New
Fungicide BAS 510 F (Common Name: Boscalid) **-** Proposal for
Tolerances for Residues in/on Numerous Crops and Livestock Commodities.
Y. Donovan, DP#: 290022, 9/8/2003.*

**HIARC**

*BAS 510 F- Report of the Hazard Identification Assessment Review
Committee;* A. Levy, TXR No: 0051613, 3/7/2003.

[]{#__RefHeading___Toc169599943 .anchor}**Appendix A: TOXICOLOGY
ASSSESSMENT**

[]{#__RefHeading___Toc169599944 .anchor}**A.1 Toxicology Data
Requirements**

The requirements (40 CFR 158.589) for food use of boscalid are in Table
A.1. Use of the new guideline numbers does not imply that the new (1998)
guideline protocols were used.

+-----------------------------------------+-------------+-------------+
| **Table A.1 Toxicology Data             |             |             |
| Requirements for Boscalid**             |             |             |
+=========================================+=============+=============+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+-----------------------------------------+-------------+-------------+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | no          | \-          |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5xxx Mutagenicity---Structural      |             |             |
| Chromosomal Aberrations                 | yes         | yes         |
|                                         |             |             |
| 870.5xxx Mutagenicity---Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | no          | \-          |
| Battery (rat)                           |             |             |
|                                         | no          | \-          |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | no          | \-          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | no          | \-          |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | no          | \-          |
|                                         |             |             |
| Acute Oral (rat)                        | no          | \-          |
|                                         |             |             |
| Subchronic Oral (rat)                   | no          | \-          |
|                                         |             |             |
| Six-month Oral (dog)                    | no          | \-          |
+-----------------------------------------+-------------+-------------+

[]{#__RefHeading___Toc169599945 .anchor}**A.2 Toxicity Profiles**

+-----------+------------+------------+-----------------+------------+
| **Table   |            |            |                 |            |
| A.2 Acute |            |            |                 |            |
| Toxicity  |            |            |                 |            |
| of        |            |            |                 |            |
| B         |            |            |                 |            |
| oscalid** |            |            |                 |            |
+-----------+------------+------------+-----------------+------------+
| **Gu      | **Study    | **MRID     | **Results**     | **Toxicity |
| ideline** | Type**     | #(S).**    |                 | Category** |
|           |            |            |                 |            |
| **No.**   |            |            |                 |            |
+-----------+------------+------------+-----------------+------------+
| 81-1      | Acute Oral | 45404814   | LD~50~ =\>5,000 | IV         |
|           |            |            | mg/kg           |            |
+-----------+------------+------------+-----------------+------------+
| 81-2      | Acute      | 45404815   | LD~50~ =\>2000  | III        |
|           | Dermal     |            | mg/kg           |            |
+-----------+------------+------------+-----------------+------------+
| 81-3      | Acute      | 45404816   | LC~50~ =\>6.7   | IV         |
|           | Inhalation |            | mg/L            |            |
+-----------+------------+------------+-----------------+------------+
| 81-4      | Primary    | 45404817   | Not irritating  | IV         |
|           | Eye        |            |                 |            |
|           | Irritation |            |                 |            |
+-----------+------------+------------+-----------------+------------+
| 81-5      | Primary    | 45404818   | Not irritating  | IV         |
|           | Skin       |            |                 |            |
|           | Irritation |            |                 |            |
+-----------+------------+------------+-----------------+------------+
| 81-6      | Dermal     | 4          | Could not be    | n/a        |
|           | Sen        | 5404819^1^ | determined      |            |
|           | sitization |            |                 |            |
+-----------+------------+------------+-----------------+------------+

^1^ Unacceptable because the 5% concentration used for the challenge was
inadequate.

[]{#__RefHeading___Toc169599946 .anchor}**A.3 Executive Summaries**

**A.3.1 Subchronic Toxicity**

**870.3100 Oral Subchronic Toxicity - Rodent**

[Studies Selected:]{.underline} Co-critical studies: Chronic Toxicity
Dietary Study - Rats

Carcinogenicity Feeding Study - Rats

One-year Feeding Study -Dogs

[MRID No]{.underline}.: 45404827 (chronic rat)

45404828 (carcinogenicity rat)

45404826 (1-year dog)

[Dose and Endpoint for Establishing RfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid and hepatic toxicity seen in rats and dogs.
These studies are described (Guideline Numbers, MRID Numbers, Executive
Summaries and Dose and Endpoint for Establishing RfD) under their
appropriate sections; 870.4100a for chronic toxicity in rats, 870.4200a
for carcinogenicity study in rats and 870.4100b for the one-year feeding
study in dogs.

[Comments about Study/Endpoint/Margins of Exposure:]{.underline} In the
90-day dog study,

increased alkaline phosphatase activity and liver weights were seen in
both sexes, and these effects were also seen in the 1-year dog study.
The Committee determined that the NOAEL of 21.8 mg/kg/day from the
1-year dog study is appropriate for this risk assessment as discussed
under chronic RfD. The lower NOAEL (7.6 mg/kg/day) in the 90-day study
is an artifact of dose selection. This endpoint is appropriate for the
population (infants and children) and duration (1-30 days and 30-180
days) of concern, because there are no concerns that the effects will
worsen following longer treatment.

**870.31050 Oral Subchronic Toxicity - Nonrodent**

[Studies Selected:]{.underline} Co-critical studies: Chronic Toxicity
Dietary Study - Rats

Carcinogenicity Feeding Study - Rats

One-year Feeding Study -Dogs

[MRID No.]{.underline}: 45404827 (chronic rat)

45404828 (carcinogenicity rat)

45404826 (1-year dog)

[Dose and Endpoint for Establishing RfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid and hepatic toxicity seen in rats and dogs.
These studies are described (Guideline Numbers, MRID Numbers, Executive
Summaries and Dose and Endpoint for Establishing RfD) under their
appropriate sections; 870.4100a for chronic toxicity in rats, 870.4200a
for carcinogenicity study in rats and 870.4100b for the one-year feeding
study in dogs.

[Comments about Study/Endpoint/Margins of Exposure:]{.underline} In the
90-day dog study,

increased alkaline phosphatase activity and liver weights were seen in
both sexes, and these effects were also seen in the 1-year dog study.
The Committee determined that the NOAEL of 21.8 mg/kg/day from the
1-year dog study is appropriate for this risk assessment as discussed
under chronic RfD. The lower NOAEL (7.6 mg/kg/day) in the 90-day study
is an artifact of dose selection. This endpoint is appropriate for the
population (infants and children) and duration (1-30 days and 30-180
days) of concern, because there are no concerns that the effects will
worsen following longer treatment.

**870.3200 21-Day Dermal Toxicity -- Rat**

[Studies Selected]{.underline}: Co-critical studies: Chronic Toxicity
Dietary Study in Rats

Carcinogenicity Feeding Study in Rats

One-year Feeding Study in Dogs

[MRID No.]{.underline}: 45404827 (chronic rat)

45404828 (carcinogenicity rat)

45404826 (1-year dog)

[Dose and Endpoint for Establishing RfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid and hepatic toxicity seen in rats and dogs.
These studies are described (Guideline Numbers, MRID Numbers, Executive
Summaries and Dose and Endpoint for Establishing RfD) under their
appropriate sections; 870.4100a for chronic toxicity in rats, 870.4200a
for carcinogenicity study in rats and 870.4100b for the one-year feeding
study in dogs.

[Comments about Study/Endpoint/Uncertainty Factor:]{.underline} The
HIARC noted that neither dermal nor systemic toxicity was seen at the
Limit Dose (1000 mg/kg/day) in the 28-day dermal toxicity study (MRID
No. 45404824). The Committee, however, selected the oral NOAEL of 21.8
mg/kg/day because of the concerns for the decreases in the body weight
and body weight gains seen in the offsprings in the two-generation
reproduction and the developmental neurotoxicity studies. Additionally,
this dose would address the concerns for thyroid and hepatotoxicity seen
via the oral route in multiple species (mice, rats and dogs) after
various exposure durations (90-day, 1-year and 2-years). There are no
concerns that the effects will worsen following longer treatment.

**870.3250 Intermediate-Term Dermal Toxicity -- Dog**

[Studies Selected]{.underline}: Co-critical studies: Chronic Toxicity
Dietary Study in Rats

Carcinogenicity Feeding Study in Rats

One-year Feeding Study in Dogs

[MRID No.]{.underline}: 45404827 (chronic rat)

45404828 (carcinogenicity rat)

45404826 (1-year dog)

[Executive Summary]{.underline}: See 870.3200 21-Day Dermal Toxicity-
Rat, above.

**870.3465 90-Day Inhalation -- Rat**

[Studies Selected:]{.underline} Co-critical studies: Chronic Toxicity
Dietary Study in Rats

Carcinogenicity Feeding Study in Rats

One-year Feeding Study in Dogs

[MRID No.]{.underline}: 45404827 (chronic rat)

45404828 (carcinogenicity rat)

45404826 (1-year dog)

[Executive Summary]{.underline}: See 870.3100 Oral Subchronic Toxicity -
Rat, above.

[Dose and Endpoint for Establishing RfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid

and hepatic toxicity seen in rats and dogs.

[Comments about Study/Endpoint/Uncertainty Factor:]{.underline} The
HIARC selected the oral

NOAEL for this risk assessment due to the lack of a repeated dose
inhalation toxicity

study. There are no concerns that the effects will worsen following
longer treatment.

Absorption via inhalation is assumed to be equivalent to absorption via
the oral route.

**A.3.2 Prenatal Developmental Toxicity**

**870.3700a Developmental Toxicity Study -- Rodent**

[Study Selected:]{.underline} Developmental Toxicity -- Rat

[MRID No.:]{.underline} 45404904

[Executive Summary:]{.underline} In a developmental toxicity study, BAS
510 F (94.4% ai, batch/lot \# N37) was administered to 25 female Wistar
rats/dose by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day
from days 6 through 19 of gestation. Due to the unscheduled death
(gavage error) of 3 animals each in the low- and high-dose groups, an
additional section with 6 animals (3 each low and high doses) was added
to guarantee at least 20 pregnant rats/group. On gestation day 20, dams
were sacrificed, subjected to gross necropsy, and all fetuses examined
externally. The total numbers of fetuses examined (number of litters)
was 319 (22), 246 (18), 333 (22), and 287 (21) for the 0, 100, 300, and
1000 mg/kg bw/day groups, respectively. Approximately one-half of the
fetuses were examined viscerally, and the other one-half of the fetuses
were examined for skeletal malformations/ variations. There were no
treatment-related effects in survival, clinical signs, body weight, food
consumption, or gross necropsy. Deaths of several maternal animals were
ascribed to gavage error.

**The maternal toxicity NOAEL is** ≥**1000 mg/kg bw/day, and the
maternal toxicity LOAEL could not be established.**

No treatment-related effects on pregnancy rates, number of corpora
lutea, pre- or post-implantation losses, resorptions/dam,
fetuses/litter, fetal body weights, or fetal sex ratios were observed in
the treated groups compared with the controls.

No treatment-related external, visceral, or skeletal
malformations/variations were observed in any groups. Most treated and
control litters contained fetuses with minor variations in skeletal
ossification.

**The developmental toxicity NOAEL is** ≥**1000 mg/kg bw/day, and the
developmental toxicity LOAEL could not be established.**

The developmental toxicity study in the rat is classified
**Acceptable/Guideline** and

satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in the rat.

**870.3700b Prenatal Developmental Toxicity Study -- Nonrodent**

[Study Selected:]{.underline} Developmental Toxicity -- Rabbit

[MRID No.:]{.underline} 45404905

[Executive Summary:]{.underline} In a developmental toxicity study, BAS
510 F (94.4% ai, batch \# N37) was administered to 25 Himalayan
rabbits/dose by gavage at dose levels of 0, 100, 300, or 1000 mg/kg
bw/day from gestation days (GDs) 7-28. On GD 29, does were sacrificed
and subjected to gross necropsy. All fetuses were examined for external,
visceral, and skeletal malformations/variations. The total numbers of
fetuses examined (number of litters) was 135 (23), 183 (24), 145 (22),
and 136 (21) for the 0, 100, 300, and 1000 mg/kg bw/day groups,
respectively.

No clinical signs related to dose were observed. However,
treatment-related maternal toxicity was observed in the high-dose group
as evidenced by an increased number of abortions and early delivery and
decreased food consumption. One high-dose doe delivered early, and 3
high-dose does aborted: two on GD 27 and one on GD 29. Statistically
significant decreases (p\<0.05; 0.01) were observed in mean absolute
body weights on GD 28 and 29 (95% of controls); mean corrected terminal
body weight (94% of controls); mean maternal body weight gains on GDs
7-9 (-22.9 g compared to -3.1 g) and GDs 21-23 (-10.3 g compared to 10.2
g); and mean corrected body weight change (-233.3 g vs. -125.3 g).
High-dose animals also consumed less food than the controls starting
with the commencement of treatment and continuing throughout the
treatment period (52-90% of controls; generally statistically
significant at p\<0.05; 0.01). Over the entire treatment interval of GD
7-28, the high-dose group consumed 26% less food than the controls
(p\<0.05; 0.01). Upon inspection of individual animal data, 4 does in
particular were affected: the doe that delivered early, two of the does
that aborted (on GD 27 or GD 29), and a fourth doe. These does started
to exhibit drastic decreases in food consumption accompanied by
decreases in body weight gain generally starting between GDs 14-16. The
other doe that aborted on GD 27 did not exhibit consistent decrements in
food consumption and body weight gain. Other findings noted in the
high-dose group and in the low- and mid-dose groups were not
definitively related to treatment.

**The maternal LOAEL is 1000 mg/kg bw/day based primarily on abortions
or early delivery. The maternal NOAEL is 300 mg/kg bw/day.**

Developmental toxicity was also evident in the high-dose group. As
discussed, one high dose doe delivered early, and 3 high-dose does
aborted: two on GD 27 and one on GD 29. No treatment-related,
statistically significant effects on pregnancy rates, number of corpora
lutea, pre- or postimplantation losses, resorptions/dam, fetuses/litter,
fetal body weights, or fetal sex ratios were observed in the treated
groups as compared with the controls. One control and one mid-dose
female had complete litter resorptions. No treatment-related external,
visceral, or skeletal malformations/variations were observed in any
groups. Most treated and control litters contained fetuses with minor
variations in skeletal ossification.

**The developmental LOAEL is 1000 mg/kg bw/day based on increased number
of abortions and early delivery. The developmental NOAEL is 300 mg/kg
bw/day.**

The developmental toxicity study in the rabbit is classified
**Acceptable/Guideline** and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in the rabbit.

**A.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects -- Rat**

[Study Selected]{.underline}: 2-Generation Reproduction Study - Rats

[MRID No.]{.underline}: 45404906

[Executive Summary]{.underline}: In a two-generation reproduction study,
BAS 510F (94.4% ai, batch #N 37) was administered to 25 Wistar
(Chbb=THOM(SPF)) rats/sex/dose in the diet at concentrations of 0, 100,
1000, or 10,000 ppm. One litter was produced in each generation.
Pre-mating doses for the treated F0 parental animals were 10.1, 101.2,
and 1034.5 mg/kg/day, respectively, for males and 10.7, 106.8, and
1062.0 mg/kg/day, respectively, for females. Premating doses for the
treated F1 parental animals were 12.3, 123.9, and 1295.4 mg/kg/day,
respectively, for males and 12.5, 124.7, and 1299.6 mg/kg/day,
respectively, for females. F0 and F1 parental animals were administered
test or control diet for at least 74 or 76 days, respectively, prior to
mating, throughout mating, gestation, and lactation, and until
sacrifice. All parental animals of both generations survived to
scheduled sacrifice. No treatment related clinical signs of toxicity
were observed in any animal during the study. Food consumption was not
affected by treatment with the test article in either sex of either
generation. Absolute body weights and body weight gains of the F0
animals were similar between the treated and control groups throughout
the study. For the treated F1 females, body weights and body weight
gains were similar to those of the control group throughout premating.
Absolute body weights of the high-dose F1 males were significantly
(91-94% of controls; p ≤ 0.05 or 0.01) less than the controls beginning
at week 1 of premating and continuing until termination. Weight gain by
the high-dose F1

males was significantly (p ≤ 0.01) less than that of the control group
during weeks 0-1 (89% of control), 3-4 (84% of control), and 13-14 (62%
of control), with pre-mating weight gain 93% of the controls and overall
weight gain 91% of the control level.

At necropsy, no treatment-related gross lesions were found in any animal
of either sex or generation. An increased incidence and severity of
centrilobular hepatocyte hypertrophy in many mid- and all high-dose
animals corresponded with increased liver weights only at the high dose.
Additionally in the high-dose groups, hepatocyte degeneration was
observed in three F0 males, one F0 female, and eight F1 males.

**The parental systemic LOAEL is 10,000 ppm for males (1034.5-1295.4
mg/kg/day) based on decreased body weights and body weight gains of the
F1 males and hepatocyte degeneration in F0 and F1 males; the systemic
LOAEL was not identified for females. The parental systemic NOAELs are
1000 ppm for males (101.2-123.9 mg/kg/day) and 10,000 ppm for females
(1062.0-1299.6 mg/kg/day).**

No treatment-related differences in estrous cycle length and periodicity
were found in females of either generation. All control and almost all
treated F0 and F1 animals showed regular estrous cycles and became sperm
positive within a few days after pairing. No treatment-related
differences were observed in any sperm measures. No treatment related
lesions occurred in the reproductive tracts from males or females from
either generation. No differences in mating, fertility, or gestation
indices were seen between the treated and control groups of either
generation. The copulatory interval and gestation length of the treated
groups were comparable to the control groups in both generations.

**The reproductive toxicity NOAEL is** ≥**10,000 ppm (1034.5-1295.4
mg/kg/day for males and 1062.0-1299.6 mg/kg/day for females) and the
reproductive toxicity LOAEL was not identified.**

For the F1 litters, live birth, viability, and lactation indices, mean
litter sizes, and sex ratios were similar between the treated and
control groups. Pup survival in the high-dose F2 litters was decreased
during lactation days 0-4 as indicated by a significantly lower
viability index (86% vs 93% for controls; p ≤ 0.01). Post-implantation
loss was significantly (p≤0.05) greater for the high-dose F1 females,
resulting in a mean live litter size of 12.5 pups for the high-dose
group (n.s.) compared with 13.8 pups/litter for the control group. The
live birth index, the lactation index, and pup sex ratio were similar
between the treated and control groups. No treatment-related clinical
signs of toxicity were observed in the F1 or F2 pups during lactation.
For the F1 pups, no differences in the rate of sexual maturation were
noted between the treated and control groups. Pups from the high-dose
litters of both generations and mid-dose F2 male pups had significantly
reduced body weights and body weight gains during lactation as compared
with their respective control group. High-dose male and female F1 pups
had significantly (p ≤ 0.05) lower body weights on lactation day 21
compared with the controls due to consistently reduced body weight gains
(p ≤ 0.05 or 0.01; 89-93% of the control level) for all intervals after
lactation day 4. Body weights of the high-dose F2 male and female pups
were 86-90% (p ≤ 0.01) of the control levels on lactation days 14 and 21
due to consistently reduced body weight gains (p ≤ 0.05 or 0.01; 83-88%
of the control level) for all intervals after lactation day 4. In
addition, body weights were significantly (p ≤ 0.05) reduced for the
mid- and high-dose F2 males on lactation day 7 and the mid-dose F2 males
on day 21. Body weight gains by the mid-dose F2 males were 88-93% (p ≤
0.05 or 0.01) of the control levels during lactation days 4-21.

**The offspring toxicity LOAEL is 1000 ppm for males (101.2-123.9
mg/kg/day) based on decreased body weights and body weight gains by the
F2 male pups and 10,000 ppm for females (1062.0-1299.6 mg/kg/day) based
on decreased body weights and weight gains. The offspring toxicity NOAEL
is 100 ppm for males (10.1-12.3 mg/kg/day) and 1000 ppm for females
(106.8-124.7 mg/kg/day).**

This study is **Acceptable/Guideline** and satisfies the guideline
requirement for a two generation reproduction study (OPPTS 870.3800;
OECD 416) in rats.

**A.3.4 Chronic Toxicity**

**870.4100a**

[Study Selected]{.underline}: Chronic Toxicity - Rat

[MRID No.]{.underline} 45404827

[Executive Summary:]{.underline} In a chronic toxicity study BAS 510 F
(94.4% ai, lot no. N37, Toxbatch III) was administered to 20 Wistar
rats/sex/dose in the diet at concentrations of 0, 100, 500, 2500, or
15,000 ppm (equivalent to 0, 4.4, 21.9, 110.0, 739.0 mg/kg bw/day for
males and 0, 5.9, 30.0, 150.3, 1000.4 mg/kg bw/day for females,
respectively) for 24 months. Due to excessive body weight losses, both
15,000 ppm groups were sacrificed after 17 months and not further
analyzed.

At ≤2500 ppm, there were no statistically or biologically significant
differences from controls in clinical observations, survival rates, body
weights and weight gains, food consumption, food efficiency,
ophthalmoscopy, hematology, or urinalysis parameters. The most notable
clinical chemistry alteration was a dose-related increase in serum
gamma-glutamyl transferase (1.2-18X), which was seen in 2500 ppm males
throughout the study and in 2500 ppm females and 500 ppm males during
the first year. The increase in gamma-glutamyl transferase was
correlated with an increased incidence of centrilobular hypertrophy ppm
in both sexes, liver eosinophilic foci in males, and an 11% increase in
relative liver weight in females at 2500 ppm. Slight but non-significant
increases occurred at 2500 ppm in gross thyroid gland foci in males, and
in thyroid follicular cell diffuse hypertrophy and focal hyperplasia in
both sexes, and were correlated with a significant increase in absolute
thyroid weight in males (131% of controls, p ≤ 0.05).

**The LOAEL is 2500 ppm for both sexes of rats (110.0 and 150.3**

**mg/kg/day for males and females, respectively) under the conditions of
this study, based on thyroid toxicity (organ weight and microscopic
changes) that resulted indirectly from the liver adaptive response. The
NOAEL is 500 ppm (21.9 and 30.0 mg/kg/day for males and females,
respectively).**

At the doses tested, there was **not** a treatment related increase in
the incidence of any tumor type, or in the total number of tumors.
Thyroid follicular cell adenoma was seen in only treated animals (0/20,
0/20, 2/20, 1/20 in males and 0/20, 0/20, 1/20, 0/20 in females given 0,
100, 500, and 2500 ppm, respectively), but was within the range of the
testing laboratory's historical control values and near the mean of
0.8%. Dosing was considered adequate based on the liver and thyroid
toxicity seen in both sexes at 2500 ppm.

This chronic toxicity study in the rat is **Acceptable/Guideline**, and
satisfies the guideline requirement for a chronic oral study \[OPPTS
870.4100a; OECD 452\] in rats.

[Dose and Endpoint for Establishing cRfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid and hepatic toxicity seen in rats and dogs.

[Uncertainty Factor(s):]{.underline} 100X (10X for interspecies
extrapolation and 10X for intraspecies variation).

**870.4100b Chronic Toxicity -- Nonrodent**

[Study Selected]{.underline}: One-year Feeding Study - Dog

[MRID No.:]{.underline} 45404826

[Executive Summary:]{.underline} In a chronic toxicity study, BAS 510 F
(94.4% ai, batch/lot N 37) was administered to 5 beagle dogs/sex/dose in
the diet at dose levels of 0, 200, 800, 2000, or 20,000 ppm (equivalent
to 0, 5.5, 21.8, 57.4, and 544.0 mg/kg bw/day for males, and 0, 5.8,
22.1, 58.3, and 592.9 mg/kg bw/day for females) for 12 months.

Biologically and statistically significant increases in alkaline
phosphatase activities in the 2000-ppm males and in 20000 ppm males and
females reflected hepatic enzyme induction, which would be consistent
with the observed increases in triglyceride and cholesterol levels in
high-dose animals. Increased absolute hepatic weights in high-dose males
and females (130% and 142% of control, respectively) correlated with the
clinical chemistry data, and were attributed to a toxicological effect
of the compound. Although increased thyroid weights were observed at the
high-dose in males and females (154% and 142% of control, respectively),
the absence of additional clinical correlates precluded the
identification of the thyroid as a target organ.

**The LOAEL is 2000 ppm in beagle dogs (\~: 57.4 mg/kg/day; \~: 58.3
mg/kg/day), based on elevated ALP activities in the 2000-ppm males, and
elevated hepatic weights in the 2000-ppm males. The NOAEL is 800 ppm
(\~: 21.8 mg/kg/day; \~: 22.1 mg/kg/day).**

This chronic study (MRID 45404826) is **Acceptable/Guideline** and
satisfies the guideline requirement for a subchronic toxicity oral study
\[OPPTS 870.4100, OECD 452\] in the dog.

[Dose and Endpoint for Establishing cRfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid and hepatic toxicity seen in rats and dogs.

[Uncertainty Factor(s):]{.underline} 100X (10X for interspecies
extrapolation and 10X for intraspecies variation).

**A.3.5 Carcinogenicity**

**870.4200a Oncogenicity -- Rat**

[Study Selected]{.underline}: Carcinogenicity - Rat

[MRID No.:]{.underline} 45404828

[Executive Summary:]{.underline} In a carcinogenicity study BAS 510 F
(94.4% ai, lot no. N37, Toxbatch III) was administered to 50 Wistar
rats/sex/dose in the diet at concentrations of 0, 100, 500, 2500, or
15,000 ppm (equivalent to 0, 4.6, 23.0, 116.1, and 768.8 mg/kg bw/day
for males and 0, 6.0, 29.7, 155.6, and 1024.4 mg/kg bw/day for females)
for 24 months. The investigators determined that 15,000 ppm was causing
excessive weight loss in females and mortality in males and these groups
were sacrificed after approximately 17 months and not further analyzed.
No treatment-related effects were seen on clinical observations,
survival rates, food consumption, food efficiency, differential blood
count or morphology, or gross pathology. Body weights and body weight
gains differed consistently from the controls in 2500 ppm females,
starting on day 315 and persisting throughout the study (body weights,
84.1-95.3% of controls; overall weight gain, 75.8% of controls). The
incidence of liver centrilobular hypertrophy was elevated at 2500 ppm in
both sexes (p≤0.01). The incidence of liver eosinophilic foci was
increased slightly but not statistically significantly in 500 and 2500
ppm males, but was not seen in females. The incidences of thyroid
follicular cell diffuse hypertrophy and focal hyperplasia were increased
in both sexes at 2500 ppm, although the changes were statistically
significant in only males. The thyroid lesions (as well as thyroid
adenoma) caused a 17-18% increase in the absolute and relative thyroid
weight in 2500 ppm males. The liver and thyroid findings in this study,
as well as in two separate mechanistic studies conducted by the
registrant, are consistent with an adaptive response of the liver to a
xenobiotic that resulted in a secondary toxic effect on the thyroid.

**The LOAEL is 2500 ppm for both sexes of rats (116.1 and 155.6
mg/kg/day for males and females, respectively) under the conditions of
this study, based on the significant decrease in body weight gain in
females and the increased incidence of thyroid follicular cell
hyperplasia and hypertrophy in both sexes. The NOAEL is 500 ppm (23.0
and 29.7 mg/kg/day for males and females, respectively). At the doses
tested, there was a small but not statistically significant increase in
thyroid follicular cell adenoma in 2500 ppm males and females when
compared to controls.**

The incidence at 0, 100, 500, and 2500 ppm in males was 0/50, 0/50,
1/50, and

4/50, respectively and in females was 0/50, 1/50, 0/50, and 3/50,
respectively. The thyroid adenomas were supported by correlating thyroid
histological changes, and appeared to be a secondary effect of the
chronically induced liver metabolism. No dose-related increase was seen
for the number of animals with tumors (benign or malignant) or the total
number of primary neoplasms/group. Dosing was considered adequate based
on the body weight decreases in females and thyroid lesions in both
sexes at 2500 ppm.

This carcinogenicity study in the rat is **Acceptable/Guideline**, and
satisfies the guideline requirement for a carcinogenicity study \[OPPTS
870.4200; OECD 451\] in rats.

**870.4200b Oncogenicity -- Mouse**

[Study Selected]{.underline}: Carcinogenicity Study - Mouse

[MRID No]{.underline}.: 45404901

[Executive Summary:]{.underline} In a carcinogenicity study (MRID
45404901) BAS 510 F (94.4% ai, batch no.N37, Tox-batch III) was
administered to 50 C57BL/6 J Rj mice/dose in the diet at concentrations
of 0, 80, 400, 2000, or 8000 ppm (equivalent to 0, 13, 65, 331, and 1345
mg/kg bw/day for males and 0, 18, 90, 443, and 1804 mg/kg bw/day for
females) for 18 months. No treatment-related effects were seen in
clinical observations, survival rates, food consumption, food
efficiency, differential blood count or morphology, or gross pathology.
Body weights of males were statistically decreased occasionally at 400
ppm (≥92% of controls) and for most time points at 2000 ppm (≥92% of
controls) and 8000 ppm (≥89% of controls). Overall body weight gains of
males at 80, 400, 2000, and 8000 ppm were 94.0, 86.5, 82.0, and 75.9%,
respectively, of controls, (p ≤0.05 or 0.01 at ≥400 ppm). Body weights
of all groups of females were within 8% of controls throughout the
study, but the weight gains at 8000 ppm were consistently lower than for
the controls or other dose groups starting on day 315, and their overall
weight gain was 79.5% of controls (compared to gains of 92-99% of
controls for the other dose groups; no dose-response). A dose-related

increase in liver weights was seen in both males and females. The
absolute liver weight was increased 16% in 8000 ppm males and 8-11% in
2000 and 8000 ppm females, and the relative (to body) liver weight was
increased at ≥400 ppm in males (5-28%) and at ≥2000 ppm in females
(8-18%). The liver weights were correlated with an increased incidence
(p≤0.01) of minimal or slight liver peripheral hypertrophy at 8000 ppm
in both sexes and in 2000 ppm females. The liver effects are consistent
with an adaptive response of the liver to a xenobiotic toxicant.

**The LOAEL is 2000 ppm for males (331 mg/kg/day) and 8000 ppm for**

**females (1804 mg/kg/day) under the conditions of this study, based on
the**

**significant decreases in body weight and body weight gains. The NOAEL
is**

**400 ppm for males (65 mg/kg/day ) and 2000 ppm for females (443**

**mg/kg/day).**

This disagrees with the investigators' conclusion that the LOAEL for
males is 400 ppm based on lower body weights and weight gains (reviewer
considers the change too small) and that the LOAEL for females is 2000
ppm based on liver effects (reviewer considers these to be a
non-specific adaptive response and not appropriate as the basis for a
LOAEL). At the doses tested, there was **not** a treatment related
increase in the incidence of any tumor type, or in the total number of
tumors. Dosing was considered adequate based on the body weight and
weight gain decreases seen in males at ≥2000 ppm and in females at 8000
ppm.

This carcinogenicity study in the mouse is **Acceptable/Guideline**, and
satisfies

the guideline requirement for a carcinogenicity study \[OPPTS 870.4200;
OECD

451\] in mice.

[Discussion of Tumor Data:]{.underline} No treatment-related increase in
tumor incidence was

found in this carcinogenicity study.

[Adequacy of the Dose Levels Tested:]{.underline} Dosing was adequate
based on the lack of

an increase in tumors at the highest dose tested of 1345 and 1804
mg/kg/day in

males and females, respectively.

[Dose and Endpoint for Establishing cRfD:]{.underline} NOAEL = 21.8
mg/kg/day based on thyroid and hepatic toxicity seen in rats and dogs.

[Uncertainty Factor(s):]{.underline} 100X (10X for interspecies
extrapolation and 10X for intraspecies variation).

**870.4300 Chronic/Oncogenicity**

[Study Selected]{.underline}: Carcinogenicity Study - Rat

[MRID No.]{.underline} 45404827

[Executive Summary:]{.underline} See chronic toxicity -- rat, above.

Discussion of Tumor Data: See comments for combined chronic rat and

carcinogenicity rat studies.

Adequacy of Dose Levels Tested: See comments for combined chronic rat
and

carcinogenicity rat studies.

**A.3.6 Mutagenicity**

**870.5100 Mutagenicty -- Bacterial;** *Salmonella/Escheichia/*Mammalian
Activation Gene Mutation

[MRID No.:]{.underline} 45404913

[Executive Summary:]{.underline} In repeat reverse gene mutation assays
in bacteria (MRID 45404913), strains TA98, TA100, TA1535 and TA1537 of
*S. typhimurium* and strain WP2(uvrA) of *E. coli* were exposed to BAS
510 F (95.3% ai, Batch No.: N 26) in DMSO, initially at concentrations
of 22, 110, 550, 2750 or 5500 g/plate, with and with mammalian metabolic
activation (S9-mix), using a standard plate assay (EXPERIMENT 1). The
same five strains were exposed to the test material in a repeat assay at
concentrations of 20, 100, 500, 2500 or 5000 g/plate in the presence and
absence of S9-mix using a preincubation assay (EXPERIMENT 2). The
S9-fraction was obtained from Aroclor 1254 induced male Sprague-Dawley
rat liver. BAS 510 F was tested up to and beyond a limit concentration
of 5000 g/plate. Precipitation was seen at concentrations of 500 g/plate
and higher and weak cytotoxicity was evident at concentrations of 2500
g/plate and higher in the *S. typhimurium* strains. There was no
increase in the number of revertants per plate over the solvent control
value in any bacterial strain at any BAS 510 F concentration in either
assay, with or without S9-mix. The solvent and positive control values
were appropriate for the respective strains and within the testing
laboratory's historical control ranges. **There was no evidence of
induced mutant colonies over background.**

This study is classified as **Acceptable/Guideline**. It satisfies the
Test Guideline OPPTS 870.5100; OECD 471 requirements for *in vitro*
mutagenicity (bacterial reverse gene mutation) data.

**870.5300 Mutagenicty -- Bacterial;** Mammalian Cells in Culture Gene
Mutation Assay in Chinese Hamster CHO Cells

[MRID No.:]{.underline} 45404914

[Executive Summary:]{.underline} In repeat mammalian cell gene mutation
assays at the hypoxanthine-guanine phosphoribosyl transferase (HPRT)
locus (MRID 45404914), Chinese hamster CHO-K1 cells cultured *in vitro*
were exposed initially for four hours to BAS 510 F (94.4% ai, Batch No.:
N 37) in DMSO at concentrations of 15.625, 31.25, 62.5, 125, 250 or 500
:g/mL in the presence and absence of mammalian metabolic activation
(S9-mix). Subsequently, a second experiment was conducted using test
material concentrations of 10.24, 25.6, 64, 160, 400 or 1000 g/mL

with and without S9-mix with a repeat of the nonactivated test at
concentrations of 3.125, 6.25, 12.5, 25, 50 or 100 g/mL. The S9-fraction
was obtained from Aroclor 1254 induced male Sprague-Dawley rat liver.
BAS 510 F was tested up to cytotoxic and precipitating concentrations.
In the preliminary cytotoxicity assay without S9-mix, the relative
cloning efficiency was reduced to approximately 10% at test material
concentrations of 500 g/mL and higher and a precipitate was seen in the
culture medium at concentrations of 50 g/mL and higher. In the presence
of S9-mix the relative cloning efficiency was below 10% at
concentrations of 500 g/mL and higher. Results of the mutation assays
were not affected by pH or osmolality changes. The mutant frequency of
all BAS 510 F treated cultures was within the testing laboratory's

historical solvent control ranges in both assays, with and without
S9-mix. Excessive

cytotoxicity occurred in the absence of S9-mix in the second mutation
assay necessitating a repeat at lower doses. The solvent and positive
controls induced the appropriate responses within the testing
laboratory's historical control ranges. **There was no evidence of
induced mutant colonies over background.**

This study is classified as **Acceptable/Guideline**. It satisfies the
guideline requirement for Test Guideline OPPTS 870.5300, OECD 476 for
*in vitro* mutagenicity (mammalian forward gene mutation) data.

**870.5375 Mutagenicty -- Structural Chromosomal Aberrations;** *In
vitro* Chromosomal Aberration

[MRID No.:]{.underline} 45404915

[Executive Summary:]{.underline} In repeat mammalian cell cytogenetics
assays (chromosomal aberrations) (MRID 45404915), Chinese hamster V79
cell cultures were exposed to BAS 510 F (94.4% ai, batch \# N 37) in
DMSO in two independent assays. In the first assay, cells were exposed
to the test material for four hours at concentrations of 0, 20.0, 100.0
or 500.0 g/mL with and without metabolic activation and the cells
harvested 14 hours after termination of treatment. In the second
cytogenetic assay, cells were exposed to the test material for 18 hours
at concentrations of 0, 31.25, 62.5 or 125.0 g/mL in the absence of
S9-mix and harvested immediately after exposure. Cells were also exposed
to 0 or 125 g/mL of test material for 28 hours in the absence of S9-mix
and harvested immediately after exposure. Cells were exposed to test
material concentrations of 0, 125.0, 250.0 or 500.0 g/mL for four hours
in the presence of

S9-mix and harvested 24 hours after termination of exposure. BAS 510 F
was tested up to precipitating concentrations. A preliminary
cytotoxicity test at concentrations up to 3500 g/mL showed precipitation
at BAS 510 F concentrations of 100 g/mL and higher. Little or no
cytotoxicity, as evaluated by mitotic index and cell morphology changes,
was seen with or without S9-mix. The test material did not change the pH
or osmolality of the treatment medium. Both structural and numerical
aberrations were recorded. There were no statistically significant
increases in the percentage of metaphases with structural aberrations or
numerical aberrations, either including or excluding gaps, at any test
material concentration or exposure/harvest time scenario. The types and
frequencies of aberrations in test material treated cells were similar
to those of the solvent controls. The solvent and positive controls
induced the appropriate responses within the testing laboratory's
historical control ranges. **There was no evidence of chromosomal
aberration induction over background.**

This study is classified as **Acceptable/Guideline**. It satisfies the
guideline requirement for an *in vitro* mammalian cytogenetics
(chromosomal aberrations) assay in Chinese hamster V79 cells; OPPTS
870.5375; OECD 473.

**870.5395 Mutagenicty -- *In Vivo* Cytogenetics;** *In vivo* Mammalian
Cytogenetics - Micronucleus Assay in Mouse Bone Marrow Cells

[MRID No.:]{.underline} 45404916

[Executive Summary:]{.underline} In a mouse bone marrow micronucleus
assay, 5 NMRI male mice/dose were treated via two intraperitoneal
injections 24 hours apart with BAS 510 F (94.4% ai, batch \# N 37) at
doses of 0, 500, 1000 or 2000 mg/kg bw. Bone marrow cells were harvested
24 hours after the second treatment. The vehicle was 0.5% carboxymethyl
cellulose. There were signs of toxicity during the study. A preliminary
toxicity test with two i.p. injections of 2000 mg/kg test material in
male and female mice showed squatting posture, piloerection and poor
general state but no mortality. No sex differences were seen, therefore,
males only were used in the micronucleus assay. In the micronucleus
assay, the same clinical signs seen in the preliminary toxicity test
were seen during the first four hours following both the first and
second injections. All mice in the low dose group appeared normal 24
hours after each injection while all mice in the mid- and high-dose
groups showed squatting posture at this time after the first injection
and piloerection at this time after the second injection. The
frequencies of micronucleated PCEs in the 500, 1000 and 2000 mg/kg
groups were 1.4‰, 1.3‰ and 1.2‰, respectively, compared to the solvent
control value of 1.2‰. There were no statistically significant
differences between groups. Likewise, there were no statistically
significant differences between groups in the frequency of

micronucleated NCEs. Of the micronuclei that were observed in PCEs,
virtually all were small micronuclei. The PCE/NCE ratios indicated no
bone marrow cytotoxicity. BAS 510 F was tested to a toxic limit dose.
The solvent and positive controls (cyclophosphamide and vincristine
sulfate) induced the appropriate responses within the testing
laboratory's historical control ranges. **There was no statistically
significant increase in the frequency of micronucleated polychromatic
erythrocytes in bone marrow after any dose.**

This study is classified as **Acceptable/Guideline**. It satisfies the
guideline requirement for Test Guideline OPPTS 870.5395; OECD 474 for
*in vivo* cytogenetic mutagenicity data.

**870.5550 Mutagenicty -- Other;** Unscheduled DNA Synthesis in Primary
Rat

Hepatocytes/Mammalian Cell Cultures

[MRID No.:]{.underline} 45404917

[Executive Summary:]{.underline} In repeat unscheduled DNA synthesis
assays, primary rat hepatocyte cultures were exposed to BAS 510 F (94.4%
ai, Batch \# N 37) in DMSO at concentrations of 0, 5, 10, 50, 100, 250,
500, 750, and 1000 g/mL for 18 - 20 hours in the first UDS experiment.
Due to excess cytotoxicity, the first experiment was repeated at BAS 510
F concentrations of 0, 0.5, 1.0, 5.0, 10.0, 50.0, 100.0, 250.0, and
500.0 g/mL for 18 -- 20 hours. A second experiment was conducted at BAS
51 F concentrations of 1.563, 3.125, 6.250, 12.500, 25.000, and 50.000
g/mL for 18 - 20 hours. BAS 510 F was tested up to cytotoxic
concentrations. An upper dose of 500 g/mL was chosen for the first UDS
experiment based on results of a preliminary cytotoxicity test using
lactate dehydrogenase activity and lactate concentration as the measure
of cytotoxicity. A precipitate was seen in the culture medium at test
material concentrations of 50 g/mL and higher. The test material did not
change the pH or osmolality of the culture medium. Cytotoxicity was
greater than expected in the initial experiment and the cells were not
evaluated for UDS. In the repeat first experiment, BAS 510 F
concentrations of 1, 5, 10 and 50 g/mL were evaluated for UDS.
Concentrations of 100 - 500 g/mL were excessively cytotoxic and were not
evaluated. There was no evidence of induced UDS (all net nuclear grain
counts were well below zero) or any increase in the number of cells in
repair (net nuclear grain counts ≥ 5) compared to the solvent control in
the first experiment. BAS 510 F concentrations of 6.25, 12.50, 25.00 and
50.00 μg/mL were evaluated in the second UDS experiment. The results
confirmed those of the first experiment, with no induction of UDS (all
net nuclear grain counts were well below zero) or increases in the
percentage of cells in repair. The mean net nuclear grain counts were
-5.74 ± 4.44 and 29.01 ± 15.00 for the solvent and positive controls,
respectively, in the first experiment. Comparable values in the second
experiment were -4.40 ± 3.62 and 10.24 ± 10.45 for the solvent and
positive controls, respectively. The control values were within the
testing laboratory's historical control ranges. **There was no evidence
that unscheduled DNA synthesis, as determined by radioactive tracer
procedures \[nuclear silver grain counts\] was induced.**

This study is classified as **Acceptable/Guideline**. It satisfies the
guideline requirement for Test Guideline OPPTS 870.5550; OECD 482/486
for other genotoxic mutagenicity data.

**A.3.7 Neurotoxicity**

**870.6200a Acute Neurotoxcity Screening Battery - Rat**

[Study Selected]{.underline}: Acute neurotoxicity - Rat

[MRID No.:]{.underline} 45404820

[Executive Summary:]{.underline} In an acute neurotoxicity study, groups
of 10 male and 10 female 49-day old Wistar rats were given a single oral
dose of BAS 510 F (96.3% ai, batch N 46) in 0.5% carboxymethyl cellulose
at doses of 0, 500, 1000 or 2000 mg/kg bw and

observed for 14 days. Neurobehavioral assessment (functional
observational battery and motor activity testing) was performed in 10
animals/sex/group on days -7, 0, 7 and 14. Cholinesterase activities
were not measured. At study termination, 5 animals/sex/group were
euthanized and perfused *in situ* for neuropathological examination. Of
the perfused animals, 5 animals/sex in the control and 2000 mg/kg bw
groups were subjected to histopathological evaluation of brain and
peripheral nervous system tissues.

There were no effects on mortality, body weight, motor activity, or
clinical signs outside of the FOB. During the FOB, piloerection was
observed in 2 female rats in the 2000 mg/kg dose group on day 0. No
other FOB findings in either sex in any dose group were considered
treatment-related. There were no gross organ lesions and no
microscopically observed lesions of the brain or peripheral nervous
system tissues. Although the NOAEL for systemic effects in this study is
1000 mg/kg bw, in the absence of clinical signs related to neurotoxicity
and in the absence of lesions of the brain or peripheral nervous system,
the NOAEL for acute neurotoxicity is 2000 mg/kg bw.

**Based on the effects seen in this study, the systemic LOAEL for BAS
510 F was 2000 mg/kg bw (based on piloerection in females), with a NOAEL
of 1000 mg/kg bw. The neurotoxicity LOAEL was \>2000 mg/kg bw and the
NOAEL was 2000 mg/kg bw.**

This neurotoxicity study is classified as **Acceptable/Guideline** and
satisfies the

guideline requirement for an acute neurotoxicity study in rats
(870.6200; OECD 424).

**870.6200b Subchronic Neurotoxcity Screening Battery - Rat**

[Study Selected]{.underline}: Subchronic neurotoxicity - Rat

[MRID No.:]{.underline} 45404825

[Executive Summary:]{.underline} In a subchronic neurotoxicity study
(MRID 45404825), groups of 10 male and 10 female 49-day old Chbb. THOM
(SPF) Wistar rats were administered BAS 510 F (96.3% ai, batch \# N 46)
in the diet at dose levels of 0, 150, 1500 or 15000 ppm (equivalent ot
0, 10.5, 103.1 or 1050.0 mg/kg bw/day for males and 0, 12.7, 124.5 or
1272.5 mg/kg bw/day for females) for 3 months. Neurobehavioral
assessment (functional observational battery \[FOB\] and motor activity
testing) was performed in 10 animals/sex/group on days -7, 22, 50 and
85. Cholinesterease activities were not measured. At study termination,
5 animals/sex in the control and high-dose groups were subjected to *in
situ* perfusion and neuropathological examination of brain and nervous
system tissues.

No deaths occurred and there were not treatment-related clinical signs
or effects on body weight and food consumption. FOB and motor activity
testing revealed no treatmentrelated effects. Brain weights were
comparable to controls and there were no gross or histopahtologic
findings that could be attributed to treatment with BAS 510 F.

**A LOAEL was not attained in this study. The NOAEL for BAS 510 F is
15000 ppm in the diet (1050.0 mg/kg in male rats and 1272.5 mg/kg in
female rats) based on the absence of treatment-related systemic effects;
absence of effects in the FOB and motor activity tests; and the absence
of histopathological lesions in the brain and nervous system tissues.**

The study is classified as **Acceptable/Guideline** and satisfies the
guideline requirement for a subchronic neurotoxicity study in rats
(870.6200b; OECD 424).

**870.6300 Developmental Neurotoxicity - Rat**

[Study Selected]{.underline}: Developmental Neurotoxicity - Rat

[MRID No.:]{.underline} 45404907

[Executive Summary:]{.underline} In a developmental neurotoxicity study
(MRID 45404907) BAS 510 F (96.3% ai, N46) was administered to 35 female
Crl: WI (GLX/BRL/HAN) IGS BR (Wistar) rats per dose in the diet at dose
levels of 0, 100, 1000 or 10000 ppm \[0, 14, 147 and 1442 mg/kg/day,
average\] from gestation day (GD) 6 through lactation day (LD) 21. On
postnatal day (PND) 4, litters were standardized to 8 pups or
more/litter. Offspring from culled litters (1 male or female pup/litter)
were assigned to subgroups for further examination \[brain weights,
neuropathology (I,III), learning and memory (IV, V), motor activity
(II), and auditory startle response (III)\] no later than one day before
examinations commenced. Pups were weaned on postnatal day 21, after
which time maternal animals were killed.

No mortalities, significant treatment-related clinical signs or open
field observations, changes in body weight or food consumption, or
changes in the duration of gestation, numbers of litters, or
intercurrent deaths were noted in maternal animals. The high dose

(1442 mg/kg/day) exceeded the limit dose for this study.

**A maternal LOAEL was not observed. The maternal NOAEL is 10000 \[1442
mg/kg/day\].**

In pups, no treatment effects on litter size or viability during
lactation were seen. In high dose pups prior to weaning, there were
significant decreases in body weight in males (96-14%; PND 4-12) and in
females (96-16%; PND 1-21). In 1000 ppm pups, body weight gains were
reduced 21% (PND 1-4), and body weights were significantly decreased in
males (8%) and females (9%) on PND 4, but recovered by day 11. No
effects on post-weaning body weights, or the day of pre-putial
separation or vaginal opening were found. In the FOB, increased head
shaking among high dose male pups on PND 4, and slightly increased signs
of increased activity or urination, or irregular respiration were seen
amount high dose pups. No consistent effects on motor activity were
seen. Based on additional submitted data (MRID 45800101) that lead to
removal of data from one low dose male rat, and analysis of historical
control data, additional statistical analyses by EPA, and latency data,
it is concluded that no consistent effects on startle reflex amplitude
or latency were found. No effects on learning and memory performance
were seen, but reported data were somewhat limited. Both sexes of PND 11
pups in the 10000 ppm group showed statistically significant decreases
in body weight (9%) and brain weight (6-7%). No changes in microscopic
pathology were found. Significant decreases in brain length (3%) in high
dose males on PND 11 were found. While significant decreases in the
right hippocampus (8%) of high dose females on PND 11 were noted, and
left hippocampus measures in this group showed a similar, but
non-significant 6% decrease, additional data on the mid and low dose
females lead to the conclusion that these changes were not consistent or
dose dependent.

**The offspring LOAEL is 1000 ppm \[147 mg/kg/day\], based on decreased
body weights (8-9%) on PND 4 and decreased body weight gain (21%) on
PNDs 1-4.**

**The offspring NOAEL is 100 ppm \[14 mg/kg/day\].**

This study is classified **acceptable/non-guideline** but does not
satisfy the guideline requirement for a developmental neurotoxicity
study in rats (OPPTS 870.6300, 83-6); OECD 426. The bases for rating
this study as non-guideline are the lack of positive control data, and
limited data on the learning and memory test. This study can be
re-classified if these deficiencies are adequately addressed.

**A.3.8 Metabolism**

**870.7485 Metabolism -- Rat**

**870.7600 Dermal Absorption -- Rat**

Study Selected: Rodent *In vivo* Dermal Penetration Study - Rat

MRID No.: 45404920

Executive Summary: In a dermal penetration study, \[14C\]-BAS 510 F
(diphenyl label; Lot/Batch no. 641-2017; \>95% radiochemical purity) in
distilled water was applied to the shaved dorsal surface (-10 cm^2^) of
male rats (four/group) at nominal doses of 0.01, 0.10, or 1.0 mg/cm^2^
for periods of 1, 4, 10, or 24 hours. At the low dose two groups were
washed at 10 hours and sacrificed at 24 and 72 hours. At the
intermediate and high-dose one group at each dose was washed at 10 hours
and sacrificed at 72 hours.

The percent of the dose absorbed increased with duration of exposure to
24 hours but

decreased with increasing dose. This latter pattern is indicative of
approaching saturation of absorption. However, since the quantity
absorbed increased with each dose, one cannot determine directly if
saturation was reached at the high dose. By plotting the quantity
absorbed by dose with time, it was determined that the absorption from
the washed skin at the high dose continued at the same rate as before
washing. This showed that absorption was saturated at the high dose.
Test material remaining in the washed skin decreased significantly in
the animals that were washed at 10 hours and then sacrificed at 24 or 72
hours.

This dermal penetration study (MRID 45404920) in rats is
**Acceptable/Guideline** and satisfies the requirements for a Dermal
Penetration Study \[OPPTS 870.7600 (§85-13)\].

**Appendix B: REFERENCES** (in MRID order)

45404814 Wienmann, C.; Hellwig, J. (1998) BAS 510 F: Acute Oral Toxicity
in Rats: Final Report: Lab Project Number: 10A0179/971052: 2000/1018715:
1998/10643. Unpublished study prepared by BASF Aktiengesellschaft. 25 p.

45404815 Wienmann, C.; Hellwig, J. (1998) BAS 510 F Acute Dermal
Toxicity in Rats: Final Report: Lab Project Number: 11A0179/971053:
2000/1018711: 1998/10642. Unpublished study prepared by BASF
Aktiengesellshaft. 25 p.

45404816 Gamer, A.; Hoffman, H. (1998) BAS 510 F: Acute Inhalation
Toxicity Study in Wistar Rats 4 Hour Dust Exposure: Final Report: Lab
Project Number: 13I0179/977011: 1998/10803. Unpublished study prepared
by BASF Aktiengesellschaft. 24 p.

45404817 Wiemann, C.; Hellwig, J. (1998) Study on the Acute Eye
Irritation of BAS 510 F in the Rabbit: Final Report: Lab Project Number:
13A0179/972090: 2000/1018713: 1998/10641. Unpublished study prepared by
BASF Aktiengesellschaft. 20 p.

45404818 Wiemann, C.; Hellwig, J. (1998) Study on the Acute Dermal
Irritation/Corrosion of BAS 510 F in the Rabbit: Final Report: Lab
Project Number: 14H0179/972089: 1998/10640: 2000/1018712. Unpublished
study prepared by BASF Aktiengesellschaft. 20 p.

45404819 Wiemann, C.; Hellwig, J. (1998) BAS 510 F: Maximization Test in
Guinea Pigs: Final Report: Lab Project Number: 30H0179/972091:
2000/1018714: 1998/10638. Unpublished study prepared by BASF
Aktiengesellschaft. 53 p.

45404820 Mellert, W.; Kaufmann, W.; Hildebrand, B. (2000) BAS 510 F:
Acute Oral Neurotoxicity Study in Wistar Rats: Final Report: Lab Project
Number: 20C0179/97144: 2000/1018638. Unpublished study prepared by BASF
Aktiengesellschaft. 383 p.

45404825 Mellert, W.; Kaufmann, W.; van Ravenzwaay, B. (2001) BAS 510 F:
Subchronic Oral Neurotoxicity Study in Wistar Rats Administration in the
Diet for 3 Months: Lab Project Number: 50C0179/97148: 2001/1000113.
Unpublished study prepared by BASF Aktiengesellschaft. 455 p.

45404826 Wiemann, C.; Deckardt, K.; Kaufmann, W. et al. (2000) BAS 510
F: Chronic Oral Toxicity Study in Beagle Dogs Administration in the Diet
for 12 Months: Final Report: Lab Project Number: 33D0179/97118:
200/1016881. Unpublished study prepared by BASF Aktiengesellschaft. 779
p.

45404827 Mellert, W.; Deckardt, K.; Kaufmann, W. (2001) BAS 510 F:
Chronic Toxicity Study in Wistar Rats Administration in the Diet for 24
Months: Final Report: Lab Project Number: 82C0179/97091: 2001/1000114.
Unpublished study prepared by BASF AKtiengesellschaft. 1288 p.

45404828 Mellert, W.; Deckardt, K.; Kaufmann, W. et al. (2001) BAS 510
F: Carcinogenicity Study in Wistar Rats Administration in the Diet for
24 Months: Final Report: Lab Project Number: 82C0179/97090:
2001/1000115. Unpublished study prepared by BASF Aktiengesellschaft.
1352 p.

45404901 Mellert, W.; Deckardt, K.; Kuttler, K.; et al. (2001) BAS 510 F
Carcinogenicty Study in C57BL Mice Administration in the Diet for 18
Months: Final Report: Lab Project Number: 76C0179/97103: 2001/1000116.
Unpublished study prepared by BASF Aktiengesellschaft. 931 p.

45404904 Schilling, K. (2000) BAS 510 F-Prenatal Developmental Toxicity
Study in Wistar Rats Oral Administration (Gavage): Final Report: Lab
Project Number: 30R0179/97140: 2000/1015001. Unpublished study prepared
by BASF Aktiengesellschaft. 290 p.

45404905 Schilling, K.; Hellwig, J. (2000) BAS 510 F-Prenatal
Developmental Toxicity Study in Himalayan Rabbits Oral Administration
(Gavage): Final Report: Lab Project Number: 40R0179/97127: 2000/1013425.
Unpublished study prepared by BASF Aktiengesellschaft. 267 p.

45404906 Schilling, K.; Gembardt, C.; van Ravenzwaay, B. (2001) BAS 510
F Two Generation Toxicity Study in Wistar Rats Continuous Dietary
Administration: Final Report: Lab Project Number: 70R0179/97136:
2001/1000117. Unpublished study prepared by BASF Aktiengesellschaft. 924
p.

45404907 Schilling, K.; Kaufmann, W.; van Ravenzwaay, B. et al. (2001)
BAS 510 F Developmental Neurotoxicity Study in Wistar Rats
Administration in the Diet: Final Report: Lab Project Number:
67R0179/97167: 2001/1000118. Unpublished study prepared by BASF
Aktiengesellschaft. 621 p.

45404913 Engelhardt, G.; Hoffmann, H. (1998) Salmonella Typhimurium/
Escherichia Coli Reverse Mutation (Standard Plate Test and Preincubation
Test) with BAS 510 F: Final Report: Lab Project Number: 40M0179/974089:
1998/11440. Unpublished study prepared by BASF Aktiengesellschaft. 55 p.

45404914 Engelhardt, G.; Hoffmann, H. (2000) In Vitro Gene Mutation Test
with BAS 510 F in CHO Cells (HPRT Locus Assay): Final Report: Lab
Project Number: 50M0179/974097: 2000/1000180. Unpublished study prepared
by BASF Aktiengesellschaft. 56 p.

45404915 Engelhardt, G.; Hoffmann, H. (1999) In Vitro Chromosome
Aberration Assay with BAS 510 F in V79 Cells: Final Report: Lab Project
Number: 32M0179/974076: 1999/10978. Unpublished study prepared by BASF
Aktiengesellschaft. 84 p.

45404916 Engelhardt, G.; Hoffmann, H. (1999) Cytogenetic Study In Vivo
with BAS 510 F in the Mouse Micronucleus Test After Two Intraperitoneal
Administrations: Lab Project Number: 26M0179/974095: 1999/11048.
Unpublished study prepared by BASF Aktiengesellschaft. 52 p.

45404917 Engelhardt, G.; Hoffmann, H. (2000) In Vitro Unscheduled DNA
Synthesis (UDS) Assay with BAS 510 F in Primary Rat Hepatocytes: Final
Report: Lab Project Number: 81M0179/974096: 2000/1011413. Unpublished
study prepared by BASF Aktiengesellschaft. 45 p.

**Appendix C: REVIEW OF HUMAN RESEARCH**

No MRID - PHED Surrogate Exposure Guide