Document ID: EPA-HQ-OPP-2005-0145-0047
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-03-28T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

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

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc169599906"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc169599906 \h  3  

  HYPERLINK \l "_Toc169599907"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc169599907 \h  12  2

  HYPERLINK \l "_Toc169599908"  2.1	Proposed Use	  PAGEREF _Toc169599908
\h  12  2

  HYPERLINK \l "_Toc169599909"  2.2	Identification of Active Ingredient	
 PAGEREF _Toc169599909 \h  16  

  HYPERLINK \l "_Toc169599910"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc169599910 \h  16  6

  HYPERLINK \l "_Toc169599911"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc169599911 \h  16  6

  HYPERLINK \l "_Toc169599911"     3.1	   Hazard and Dose-Response
Characterization	  PAGEREF _Toc169599911 \h  16  

  HYPERLINK \l "_Toc169599911"     3.2	   Endocrine Disruption	 19

  HYPERLINK \l "_Toc169599912"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc169599912 \h  19  

  HYPERLINK \l "_Toc169599913"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc169599913 \h  19  

  HYPERLINK \l "_Toc169599914"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc169599914 \h  19  

  HYPERLINK \l "_Toc169599915"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc169599915 \h  19  

  HYPERLINK \l "_Toc169599916"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc169599916 \h  20  

  HYPERLINK \l "_Toc169599917"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc169599917 \h  20  

  HYPERLINK \l "_Toc169599918"  5.1.4	Analytical Methodology	  PAGEREF
_Toc169599918 \h  20  

  HYPERLINK \l "_Toc169599920"  5.1.5	Environmental Degradation	 
PAGEREF _Toc169599920 \h  21  

  HYPERLINK \l "_Toc169599920"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc169599920 \h  21  

  HYPERLINK \l "_Toc169599921"  5.1.7	 Drinking Water Residue Profile	 
PAGEREF _Toc169599921 \h  21  

  HYPERLINK \l "_Toc169599922"  5.1.8	Food Residue Profile	  PAGEREF
_Toc169599922 \h  22  

  HYPERLINK \l "_Toc169599923"  5.1.9	International Residue Limits	 
PAGEREF _Toc169599923 \h  23  

  HYPERLINK \l "_Toc169599924"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc169599924 \h  24  

  HYPERLINK \l "_Toc169599925"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc169599925 \h  24  

  HYPERLINK \l "_Toc169599926"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc169599926 \h  24  

  HYPERLINK \l "_Toc169599927"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc169599927 \h  25  

  HYPERLINK \l "_Toc169599928"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc169599928 \h  25  

  HYPERLINK \l "_Toc169599929"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc169599929 \h  26  

  HYPERLINK \l "_Toc169599930"  7.0	AGGREGATE RISK ASSESSMENT AND RISK
CHARACTERIZATION	  PAGEREF _Toc169599930 \h  26  

  HYPERLINK \l "_Toc169599931"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc169599931 \h  27  

  HYPERLINK \l "_Toc169599932"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc169599932 \h  27  

  HYPERLINK \l "_Toc169599932"  7.3	Intermediate/Long-Term Aggregate
Risk	  PAGEREF _Toc169599932 \h  27  

      HYPERLINK \l "_Toc169599933"  7.4	   Chronic Aggregate
Risk…………………………………………………….  
PAGEREF _Toc169599933 \h  27  

  HYPERLINK \l "_Toc169599934"  7.5	Cancer Aggregate Risk	  PAGEREF
_Toc169599934 \h  28  

  HYPERLINK \l "_Toc169599935"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc169599935 \h  28  

  HYPERLINK \l "_Toc169599936"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc169599936 \h  28  

  HYPERLINK \l "_Toc169599939"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc169599939 \h  33  

  HYPERLINK \l "_Toc169599940"  10.1	Toxicology	  PAGEREF _Toc169599940
\h  33  

  HYPERLINK \l "_Toc169599941"  10.2	Residue Chemistry	  PAGEREF
_Toc169599941 \h  33  

  HYPERLINK \l "_Toc169599942"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc169599942 \h  35  

  HYPERLINK \l "_Toc169599943"  Appendix A:  TOXICOLOGY ASSSESSMENT	 
PAGEREF _Toc169599943 \h  37  

  HYPERLINK \l "_Toc169599944"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc169599944 \h  37  

  HYPERLINK \l "_Toc169599945"  A.2	Toxicity Profiles	  PAGEREF
_Toc169599945 \h  38  

  HYPERLINK \l "_Toc169599946"  A.3	Executive Summaries	  PAGEREF
_Toc169599946 \h  38  

  HYPERLINK \l "_Toc169599943"  Appendix B:  REFERENCES (in MRID Order)
57 

  HYPERLINK \l "_Toc169599943"  Appendix C:  REVIEW OF HUMAN RESEARCH	59

 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 
 SEQ CHAPTER \h \r 1 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, 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, 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

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

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

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

Boscalid is registered to BASF Corporation for use on food/feed crops as
two water-dispersible granular (WDG) formulations, a   SEQ CHAPTER \h \r
1 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)   SEQ CHAPTER
\h \r 1 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

 tc \l2 "4.3 Water Exposure/Risk Pathway   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

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,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
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: 

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.

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 greens, subgroup 5B	18.0

Vegetable, cucurbit, group 9, except cucumber	1.6

Vegetable, fruiting, group 8	1.2

Vegetable, root, subgroup 1A, except sugar beet, garden beet, radish,
and turnip	1.0

Belgian endive	16

1   Proposed tolerance

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). 

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 2.1.	Summary of Directions for Use of Boscalid.

Applic. Timing, Type, and Equip. 1	Formulation 2

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations 3

Berry Group

Broadcast foliar applications during fruiting; ground or aerial
equipment	70% WDG 4

[7969-197]

25.2% WDG

[7969-199]	0.36-0.39	4	1.40-1.45	0	For aerial applications, use a
minimum of 5 gal/A

The minimum RTI is 7 days.

Cucurbit Vegetables

Broadcast foliar applications from flowering to fruiting; ground or
aerial equipment	70% WDG 5

[7969-197]

25.2% WDG

[7969-199]	0.28-0.29	4	1.14-1.17	0	For aerial applications, use a
minimum of 5 gal/A The minimum RTI is 7 days.

Fruiting Vegetables

Broadcast foliar applications during crop development and fruiting;
ground or aerial equipment	70% WDG

[7969-197]	0.15	6	0.92	0	For aerial applications, use a minimum of 5
gal/A. The minimum RTI is 7 days.

0.54

(tomato only)	2	1.09

(tomato only)

Grape

Broadcast foliar applications during fruit development; ground or aerial
equipment	70% WDG

[7969-197]

25.2% WDG

[7969-199]	0.35-0.36	3	1.09	14	For aerial applications, use a minimum of
10 gal/A.

The minimum RTI is 10 days

Spearmint and Peppermint 6

Broadcast foliar applications during crop development; ground or aerial
equipment 	No labeled uses	0.40	4	1.60	14	None

Brassica Leafy Vegetables (leafy greens)

Broadcast foliar applications; ground or aerial equipment	70% WDG 5

[7969-197]	0.39	2	0.79	14	The minimum RTI is 7 days.

For aerial applications, use a minimum of 5 gal/A

Root Vegetables (carrot, ginseng, horseradish, skirret)

Broadcast foliar applications; ground or aerial equipment	70% WDG 5

[7969-197]	0.20	5	0.98	0	The minimum RTI is 7 days.

For aerial applications, use a minimum of 5 gal/A

Do not use on sugar beets, garden beets, turnips, and radishes

25.2% WDG is labeled only for use on carrots

	25.2% WDG

[7969-199]	0.17	6	0.99

Stone Fruits

Broadcast foliar applications from pink bud through fruit development;
ground or aerial equipment	70% WDG 4

[7969-197]

25.2% WDG

[7969-199]	0.22-0.23	5	1.14-1.16	0	The minimum RTI is 7 days.

For aerial applications, use a minimum of 10 gal/A

Sunflowers

Broadcast foliar applications during plant growth; ground or aerial
equipment	70% WDG 5

[7969-197]	0.39	2	0.79	21	The minimum RTI is 7 days.

For aerial applications, use a minimum of 5 gal/A

Endive

Manual7 Spray application to roots	25.2% WDG [7969-199]	0.022 lbs ai/875
lbs roots	2	0.044 lbs ai/875 lbs roots	20	The minimum RTI is 11 days. 
Apply prior to cold storage and prior to forcing

Cotton

Foliar broadcast applied during boll development	70% WD [7969-197]
0.39-0.48	2	0.80-0.88	11-39	RTI varied from 5 – 9 days

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:

Prior to Cold Storage

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

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.

2.2	Identification of Active Ingredient

Common name	Boscalid

Company experimental name	BAS 510 F

IUPAC name	2-chloro-N-(4'-chlorobiphenyl-2-yl)-nicotinamide

CAS name	3-pyridinecorboxamide,
2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl

CAS registry number	188425-85-6

End-use product (EP)	70% WDG (Endura® Fungicide; EPA Reg. No. 7969-197)

25.2% WDG (Pristine® Fungicide; EPA Reg. No. 7969-199), which also
contains 12.8% pyraclostrobin.

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 45404804-45404809

pH	Does not dissociate in water. 

	Relative Density (20ºC)	1.381g/cm3

	Water solubility (20ºC)	4.64 mg/L at pH 6

	Solvent solubility (g/100 mL at 20ºC)	acetone	16-20	ethyl 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 constant, pKa	None

	Octanol/water partition coefficient, Log(KOW)	2.96 

	UV/visible absorption spectrum	UV molecular extinction(e[lmol-1cm-1]):
3.15 x104 at 228 nm; 1.53 x103 at 290 nm

	

3.0	HAZARD CHARACTERIZATION  TC \l1 "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 Toxicological Dose and Endpoints of Boscalid for
Use in Risk Assessments. 

Exposure Scenario	Dose Used in Risk Assessment, UFa	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Acute Dietary	No appropriate endpoint identified	NA	NA

Chronic Dietary (All populations)	NOAEL = 21.8 mg/kg/day

UF = 100

Chronic RfD = 0.218 mg/kg/day	FQPA SF = 1X

cPAD = chronic RfD 

               FQPA SF

= 0.218 mg/kg/day

	Chronic rat, carcinogenicity rat and 1-year dog studies

LOAEL = 57-58 mg/kg/day based    on liver and thyroid effects

Incidental Oral 

Short- and Intermediate- Term Residential Only	NOAEL = 21.8 mg/kg/day

	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Chronic rat, carcinogenicity rat and
1-year dog studies

LOAEL = 57-58 mg/kg/day based on liver and thyroid effects

Dermal

(All Durations)	Oral study NOAELb=21.8 mg/kg/day

(dermal absorption rate = 15%)	Occupational LOCc for MOE = 100 	Chronic
rat, carcinogenicity rat and 1-year dog studies

LOAELd = 57-58 mg/kg/day based on liver and thyroid effects

Inhalation

(All Durations)

	Oral study NOAEL= 21.8 mg/kg/day

(inhalation absorption rate = 100%)	Occupational LOC for MOE = 100
Chronic rat, carcinogenicity rat and 1-year dog studies

LOAEL = 57-58 mg/kg/day based on liver and thyroid effects 

Cancer (oral, dermal, inhalation)	Classification: “Suggestive evidence
of carcinogenicity, 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.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

5.1	Pesticide Metabolism and Environmental Degradation

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).

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).

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).

5.1.4	Analytical Methodology	

Plants

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.  

 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

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).

  TC \l3 "5.1.4	Analytical Methodology 

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.   

  TC \l3 "5.1.5	Environmental Degradation 

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.”
  

 tc \l2 "4.3 Water Exposure/Risk Pathway   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.

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: 

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.

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.

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.

5.2	Dietary Exposure and Risk

™ 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).

 TC \l2 "5.2  Dietary Exposure and Risk 

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.    

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 (mg/kg/day)	% aPAD*

General U.S. Population	0.020914	10

All Infants (< 1 year old)	0.048451	22

Children 1-2 years old	0.069579	32

Children 3-5 years old	0.048713	22

Children 6-12 years old	0.025284	12

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 old	0.016094	7

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.    
 

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 Do Not Concentrate in Processed Commodity	Adj.

#1	Tolerance Level Adequate to Cover Slight Concentration

(processing factor)	Adj.

#1	Separate Tolerance Established	Adj.

#1

Apple Juice	1.0	Wheat Germ (1.2x)	1.0	Grape, Raisin	1.0

Plum - Prune	1.0	Wheat Bran (1.2x)	1.0	Peanut Oil	1.0

Rice Bran	1.0	Tomato Paste (1.1x)	1.0

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. 

 

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.

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.

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.   

7.2	Short-Term Aggregate Risk  TC \l2 "5.2  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 + water	

Dermal	

MOE Aggregate

	

NOAEL	

EXP	

LOC	

MOE	

NOAEL	

EXP	

LOC	

MOE	

U.S Population	

21.8	

0.020914	

100	

1000	

21.8	

0.0008	

100	

27000	

960

	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.  

7.4	Chronic Aggregate Risk  TC \l2 "5.4  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.

7.5	Cancer Aggregate Risk  TC \l2 "5.5  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.    
 

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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

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

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  Proposed New Occupational Uses of Boscalid

Crop	

Product,

Formulation	

Treatment Type	

Application Equipment	

Maximum Application Rate	

Amount Handled Per Day

Belgian endive roots	Pristine®,

DF

EPA Reg. No. 7969-199

25.2% Boscalid	Roots placed into cold storage	T-Jet or similar
mechanical spray equipment attached to a conveyor belt	1.4 oz in 2-2.5
gallons water to 850 lb of roots

(0.000026 lb ai/lb of endive root)	200,000 lb/day

Roots packaged in forcing trays

0.4 oz in 3 qt water per 12 ft2 forcing trays

(0.00063 lb ai/ft2 forcing tray)	2400 ft2 of forcing tray

Non-Occupational/Residential Exposure

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

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 9.0.b.  Handler Exposures and Risks from Post-Harvest
Applications to Boscalid

Exposure Scenario	Crop or Target	Application Ratea	Baseline Dermal Unit
Exposureb mg/lb ai	Baseline Inhalation Unit Exposurec mg/lb ai	Amount
Treated Dailyd	Baseline Daily Dermal Dosee mg/kg/day	Baseline Daily
Inhalation Dosef mg/kg/day	Combined Daily Doseg (mg/kg/day) 	Total MOEh 

Mixing/Loading Dry Flowables For T-jet or Similar Mechanical Spray
Equipment Attached To A Conveyor Belt

	Belgian endive roots (prior to cold storage)	0.000025

lb ai/root	0.066	0.00077	200,000 lb root	0.00073	0.000057	0.00080	27,000

	Belgian endive roots (in forcing trays)	0.00063

lb ai/sq ft forcing tray	0.066	0.00077	2,400 

sq ft	0.00021	0.000017	0.00023	94,000

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 ft2 of forcing tray

0.1 oz/10 ft2  * 1 lb/16 oz = 6.3e-4 lbs ai/ft2 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. 

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

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 

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

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.

Table 9.0.c. Post-application Exposures and Risks for Boscalid on
Belgian Endive Root

Fruit	Appl. Ratea

	Transfer Co-efficient

(cm2/hr)	Default Transferable Residuec

(day 0)	Conversion Factord (mg/lb)	Dermal Absorptione (%)	Exposure Timef

(hours)	Absorbed Dermal Doseg (mg/kg/

day)	Dermal MOEh

Belgian endive root prior to cold storage	4.7e-8

(lb ai/cm2 root)	1,500	20%	4.5E+05	15%	8	1.1E-01	200

a.	Application rate = lb ai/cm2 of root

b.	Transfer coefficient = 1,500 cm2/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@ 20o 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.

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

10.1	Toxicology

None.

10.2	Residue Chemistry

For Endive:

If IR-4 wants to continue with this Section 3 registration, then 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.

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 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:

Prior to Cold Storage

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

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.  

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.

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.

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.

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 --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.

Appendix A:  TOXICOLOGY ASSSESSMENT

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.

 TC \l2 "A.1  Toxicology Data Requirements  

Table A.1  Toxicology Data Requirements for Boscalid

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

no	yes

yes

yes

yes

-

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes	yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

-

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no

no

no

no	-

-

-

-

A.2	Toxicity Profiles

Table A.2  Acute Toxicity of Boscalid

Guideline

 No.	

Study Type	

MRID #(S).	

Results	

Toxicity Category

81-1	

Acute Oral	

45404814	

LD50 =>5,000 mg/kg	

IV

81-2	

Acute Dermal	

45404815	

LD50 =>2000 mg/kg	

III

81-3	

Acute Inhalation 	

45404816	

LC50 =>6.7 mg/L	

IV

81-4	

Primary Eye  Irritation	

45404817	

Not irritating	

IV

81-5

 	

Primary Skin Irritation	

45404818	

Not irritating	

IV

81-6	

Dermal Sensitization	

454048191	

Could not be determined	

n/a

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

A.3	Executive Summaries

A.3.1	Subchronic Toxicity

870.3100		Oral Subchronic Toxicity - Rodent 

Studies Selected: Co-critical studies: Chronic Toxicity Dietary Study -
Rats

		                                   Carcinogenicity Feeding Study -
Rats

				           One-year Feeding Study -Dogs

MRID No.: 45404827 (chronic rat)

	       45404828 (carcinogenicity rat)

                   45404826 (1-year dog)

Dose and Endpoint for Establishing RfD: 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: 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: Co-critical studies: Chronic Toxicity Dietary Study -
Rats

		                                   Carcinogenicity Feeding Study -
Rats

				           One-year Feeding Study -Dogs

MRID No.: 45404827 (chronic rat)

	       45404828 (carcinogenicity rat)

                   45404826 (1-year dog)

Dose and Endpoint for Establishing RfD: 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: 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: Co-critical studies: Chronic Toxicity Dietary Study in
Rats

		                           	Carcinogenicity Feeding Study in Rats

					One-year Feeding Study in Dogs

MRID No.: 45404827 (chronic rat)

	      45404828 (carcinogenicity rat)

               45404826 (1-year dog)

Dose and Endpoint for Establishing RfD: 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: 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: Co-critical studies: Chronic Toxicity Dietary Study in
Rats

		                           	Carcinogenicity Feeding Study in Rats

					One-year Feeding Study in Dogs

MRID No.: 45404827 (chronic rat)

	       45404828 (carcinogenicity rat)

                   45404826 (1-year dog)

Executive Summary:	See 870.3200 21-Day Dermal Toxicity- Rat, above. 

870.3465		90-Day Inhalation – Rat

Studies Selected: Co-critical studies: Chronic Toxicity Dietary Study in
Rats

		                            Carcinogenicity Feeding Study in Rats

					 One-year Feeding Study in Dogs

MRID No.: 45404827 (chronic rat)

	       45404828 (carcinogenicity rat)

                   45404826 (1-year dog)

Executive Summary:	See 870.3100 Oral Subchronic Toxicity  - Rat, above. 

Dose and Endpoint for Establishing RfD: NOAEL = 21.8 mg/kg/day based on
thyroid

and hepatic toxicity seen in rats and dogs.

Comments about Study/Endpoint/Uncertainty Factor: 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:  Developmental Toxicity – Rat

MRID No.: 45404904

Executive Summary:  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.

≥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.

≥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:  Developmental Toxicity – Rabbit

MRID No.: 45404905

Executive Summary:  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:   2-Generation Reproduction Study - Rats

MRID No.: 45404906

Executive Summary:  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.

≤ 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:  Chronic Toxicity - Rat

MRID No. 45404827

Executive Summary:  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.

≤ 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: NOAEL = 21.8 mg/kg/day based on
thyroid and hepatic toxicity seen in rats and dogs.

Uncertainty Factor(s): 100X (10X for interspecies extrapolation and 10X
for intraspecies variation).

870.4100b 	Chronic Toxicity – Nonrodent

Study Selected:   One-year Feeding Study - Dog

MRID No.: 45404826

Executive Summary:  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: NOAEL = 21.8 mg/kg/day based on
thyroid and hepatic toxicity seen in rats and dogs.

Uncertainty Factor(s): 100X (10X for interspecies extrapolation and 10X
for intraspecies variation).

 

A.3.5	Carcinogenicity

870.4200a 	Oncogenicity – Rat

Study Selected:   Carcinogenicity - Rat

MRID No.: 45404828

≤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:  Carcinogenicity Study - Mouse

MRID No.: 45404901

≥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: No treatment-related increase in tumor
incidence was

found in this carcinogenicity study.

Adequacy of the Dose Levels Tested: 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: NOAEL = 21.8 mg/kg/day based on
thyroid and hepatic toxicity seen in rats and dogs.

 

Uncertainty Factor(s): 100X (10X for interspecies extrapolation and 10X
for intraspecies variation).

870.4300		Chronic/Oncogenicity

Study Selected:  Carcinogenicity Study - Rat

MRID No. 45404827

Executive Summary:  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.:  45404913

Executive Summary:  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.:  45404914

Executive Summary:  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.:  45404915

Executive Summary:  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.:  45404916

Executive Summary:  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.:  45404917

Executive Summary:  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:  Acute neurotoxicity - Rat

MRID No.:  45404820

Executive Summary:  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:  Subchronic neurotoxicity - Rat

MRID No.:  45404825

Executive Summary:  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:  Developmental Neurotoxicity - Rat

MRID No.:  45404907

Executive Summary:  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 cm2) of
male rats (four/group) at nominal doses of 0.01, 0.10, or 1.0 mg/cm2 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.

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ऀl 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

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