Document ID: EPA-HQ-OPP-2007-0604-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-22T04:00Z

<Notice of Filing: PP#7E7230>

<EPA Registration Division contact: Barbara Madden, 703-305-6463>

 

<TEMPLATE:>

<Interregional Research Project Number 4 (IR-4)>

<7E7230>

<	EPA has received a pesticide petition (7E7230) from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Suite 201-W,
Princeton, NJ  08540 proposing, pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180 by establishing a tolerance for residues of
Dichlobenil, 2,6-dichlorobenzonitrile and its metabolite
2,6-dichlorobenzamide in or on the raw agricultural commodity rhubarb at
0.15 parts per million (ppm) and Caneberry, subgroup 13A and Wild
raspberry at  0.1 ppm and Bushberry, subgroup 13B; Aronia berry;
Bluberry, lowbush; Buffalo currant; Chilian guava; European barberry;
Highbush cranberry; Honeysuckle; Jostaberry; Juneberry; Lingonberry;
Native currant; Salal; and Sea buckthorn at 0.15 ppm.  EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of the FDDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition.  Additional data
may be needed before EPA rules on the petition.>

<A. Residue Chemistry>

<1. Plant metabolism. The qualitative nature of the residue in plants is
adequately understood based on acceptable plant metabolism studies.  The
major residue of concern is BAM, 2,6-dichlorobenzamide; the parent
compound, dichlobenil, was not detected.  The residues to be regulated
in plant commodities are dichlobenil and BAM.>

<	2. Analytical method. Dichlobenil and BAM are extracted with a
solution of ethyl acetate in hexane.  A cleanup system utilizes an
alumina column.  Detection and quantitation are achieved by a gas
chromatograph equipped with an electron capture detector.  The lowest
limit of method validation for dichlobenil and BAM is 0.05 and 0.01 ppm,
respectively.>

<3. Magnitude of residues. Field trials were conducted at 3 locations in
commercial growing areas of the United States, to evaluate the quantity
of dichlobenil and BAM residues in rhubarb.  The residue in all samples,
treated according to label directions, was less than the lowest level of
method validation.>

<B. Toxicological Profile>

<	1. Acute toxicity.  Acute toxicity studies on dichlobenil technical
indicate that the acute oral LD50 in rats is 4.25 g/kg, the acute dermal
LD50 in rabbits is >2g/kg and the acute inhalation LC50 in rats is >0.25
mg/l.  Dichlobenil technical is non-irritating to the eye and skin of
rabbits and it is not a dermal sensitizer in guinea pigs.>

<	2. Genotoxicty. Dichlobenil technical did not show any mutagenic
activity in the following:  Ames reverse mutation assay, B. subtilis REC
assay, L5178Y mouse lymphoma forward mutation assay, human lymphocyte
chromosome aberration assay, S. cerevisiae mitotic gene conversion
assay, mouse micronucleus and the BalbC/3T3 fibroblast transformation
assay.  It was equivocal in a DNA repair assay in human epithelial
cells.>

<	3. Reproductive and developmental toxicity. In a rat developmental
toxicity study, dichlobenil technical was administered by oral gavage to
pregnant Sprague-Dawley rats at dosage levels of 20, 60 and 180
mg/kg/day.  Maternal toxicity, as evidenced by a reduction in food
intake and body weight gain, was seen at 60 and 180 mg/kg/day.  There
were no developmental or teratogenic effects at any dosage level.  The
NOEL for maternal toxicity in rats is 20 mg/kg/day and the NOEL for
developmental toxicity is greater than 180 mg/kg/day.

Dichlobenil technical was also administered by oral gavage to pregnant
New Zealand White rabbits at dosage levels of 15, 45 and 135 mg/kg/day. 
Maternal toxicity, as evidenced by a reduction in food intake and body
weight gain from day 7 to 13, was seen at the high dosage level. 
Litters of three does show reduced fetal weight and an increased
incidence of developmental malformations that were attributed to severe
maternal toxicity.  The NOEL for maternal and developmental toxicity is
45 mg/kg/day.

In a rat reproduction study, dichlobenil technical was fed to two
generations of male and female Sprague-Dawley rats at dietary
concentrations of 60, 350 and 2000 ppm.  Body weight gains were impaired
in males and females receiving 2000 ppm and males receiving 350 ppm. 
Mean pup weights were reduced at dosage levels of 350 and 2000 ppm.  No
effects were seen on reproductive parameters.  The NOEL for systemic and
developmental toxicity in rats is 60 ppm (3 mg/kg/day).  The NOEL for
reproductive toxicity is greater than 2000 ppm (100 mg/kg/day). >

<	4. Subchronic toxicity. In a dermal toxicity study dichlobenil
technical was applied to the backs of male and female rabbits for three
weeks (5 days/week) at dosages of 100, 300 and 1000 mg/kg/day.  No
treatment related effects were seen on body weights, food consumption,
organ weights, clinical chemistry or histopathology.  The NOEL for
subchronic dermal toxicity in rabbits is greater than 1000 mg/kg/day.>

<	5. Chronic toxicity. Dichlobenil technical was administered in
capsules to male and female Beagle dogs for one year at dosages of 1, 6
and 36 mg/kg/day.  Body weight gain was reduced in high dose males.  Mid
and high dose males had lower albumin, hemoglobin, packed red cell
volume and red blood cell count.  Male and female dogs in the mid and
high dose groups and low dose males had elevated serum cholesterol,
triglyceride, and phospholid concentrations in blood.  Mid and high dose
males and females and low dose females had increased liver weights,
while all treated females and high dose males had increased thyroid
weights.  Kidney weights were increased in high dose males and females
in the high dose group had reduced uterus and ovary weights.  High dose
male and female dogs exhibited liver cell hypertrophy and adrenal
cortical vacuolation.  At a dose level of 1 mg/kg/day, the only effects
seen were slightly higher blood triglyceride levels in males and
increased liver and thyroid weight in females.  Since there were no
histopathological lesions at this dosage level and no evidence of
functional impairment in any organ the no observable adverse effect
level (NOAEL) for chronic toxicity in dogs is 1 mg/kg/day.

Dichlobenil technical was fed to male and female Fischer 344 rats for
two years at dietary concentrations of 50, 400 or 3200 ppm.  Reduced
survival was seen in male rats given 3200 ppm.  A reduction in body
weight gain and food intake was seen in males and females at the high
dose level.  Histopathological effects were seen in kidneys of high dose
males and females and in livers of mid and high dose females.  There was
no treatment related increase in tumor incidence.  The NOEL for chronic
toxicity in rats was 50 ppm (2.5 mg/kg/day).

Two chronic feeding studies were conducted with Syrian hamsters.  In one
study dichlobenil technical was fed to male and female hamster for 88
and 80 weeks, respectively, at dietary concentrations of 26, 132 and 675
ppm.  Hamsters in the high dose group had slightly reduced body weight
gains.  High dose females had an increased incidence of adrenal cortical
hyperplasia and hepatocellular enlargement.  There was no increase in
tumor incidence resulting from dichlobenil administration.  The NOEL for
chronic toxicity in hamsters was 132 ppm.  In a second study,
dichlobenil technical was fed to male and female hamsters for 91 and 78
weeks, respectively, at dietary concentrations of 675, 1500 and 3375
ppm.  Reduced body weight gain was seen in all treated males and in high
dose female hamsters.  Microscopic evidence of liver toxicity was seen
in males and females given 1500 and 3375 ppm.  An increased incidence of
liver adenoma was seen in high dose males, which was considered to be
the result of liver toxicity.  The NOEL for chronic toxicity in hamsters
in this study was less than 675 ppm.>

<	6. Animal metabolism. Radiolabeled dichlobenil was administered to
both male and female Sprague-Dawley rats by either intravenous or oral
administration in single doses of 5 mg/kg. Urine and feces were
collected at various intervals after dosing.  Results from both routes
of administration were similar for both male and female rats.  That is,
seven days after IV administration, male rats had excreted 70.7% of the
dose in urine and 25.4% in feces.  In females, 65.1% and 30.9% of the
dose was excreted in urine and feces, respectively.  In rats
administered dichlobenil orally, males excreted 65.1% and 19.2% of the
dose in urine and feces whereas females excreted 64.9% and 20.7% of the
dose in urine and feces, respectively.  Although recoveries following IV
administration were higher than oral administration, absorption via
either route was deemed significant. The rate of urinary excretion was
rapid for both routes of administration with 95% of the dose excreted
within 24 hours.

Three bile-duct cannulated male rats were dosed orally with 5 mg/kg and
bile was collected at 2, 5 and 24 hours post administration.  For these
rats, 78.9% of the dose was recovered in bile and 19.8% recovered in
urine 24 hours after dosing again indicating extensive oral absorption.

Metabolism was also studied using single as well as multiple doses at
dosing levels of 3.75, 30 and 240 mg/kg administered orally.  There were
no significant sex-related differences.  Although some saturation
kinetics were evident at the high dose, there were no major differences
related to sex or dosing regimens.  These results indicate that
dichlobenil was readily absorbed and excreted by rats even at the
highest doses.

Nine metabolites were found in urine and four in feces.  Major
metabolites identified in both urine and feces and were comprised of
2,6-dichloro-3-hydroxybenzonitrile and its sulfate conjugate;
6-chloro-3-hydroxy-2-cysteinyl-benzonitrile; and
6-chloro-2-cysteinyl-benzonitrile.  Based on identified metabolites, two
metabolic pathways were postulated: (1) oxidation at the 3 or 4 position
of the phenyl ring followed by sulfation or glucuronidation of the
resulting hydroxyl group and (2) conjugation with gluthathione through
displacement of a chlorine atom.>

<	7. Metabolite toxicology. BAM was administered by oral gavage to
pregnant New Zealand White rabbits at dosage levels of 10, 30 and 90
mg/kg/day.  Maternal toxicity, in the form of mortality and reduced body
weight gain, was seen at 90 mg/kg/day.  No teratogenic or developmental
effects were seen.  The NOEL for maternal toxicity in rabbits was 30
mg/kg/day and the NOEL for developmental toxicity was greater than 90
mg/kg/day.

BAM was fed to three generations of male and female Sprague Dawley rats
at dietary concentrations of 60, 100 and 180 ppm.  No effects were seen
on parental body weight gain.  Pup weights were reduced in F1B, F3A and
F3B litters at a dose level of 180 ppm.  The NOEL for systemic and
reproductive toxicity was greater than 180 ppm (9 mg/kg/day) and the
NOEL for developmental toxicity was 100 ppm (5 mg/kg/day).

BAM was fed to male and female Beagle dogs for two years at dietary
concentrations of 60, 180 and 500 ppm.  Body weight gain was reduced and
the relative liver weight was elevated in high dose male dogs.  No
additional effects were seen.  The NOEL for chronic toxicity in dogs was
180 ppm (4.5 mg/kg/day.)

BAM was fed to male and female Sprague-Dawley rats at dietary
concentrations of 60, 100 180 and 500 ppm.  Body weight gain was reduced
in males and females at a dose level of 500 ppm, which was accompanied
by an occasional reduction in RBC level and hematocrit.  There was a
slight increase in the incidence of liver degeneration in high dose
females.  Occasional depressions in hematocrit, RBC levels or hemoglobin
levels were seen in males and females at a dose level of 180 ppm.  There
was a slight increase in the incidence of liver adenoma in female rats
given 500 ppm.  The NOEL for chronic toxicity in rats was 100 ppm (5
mg/kg/day).>

<	8. Endocrine disruption. There are no known reported adverse
reproductive or developmental effects in domestic animals or wildlife as
a result of exposure to this chemical or its metabolite.  

A standard battery of required toxicity tests have been conducted on
dichlobenil.  No effects were seen in the reproduction or teratology
studies to indicate that dichlobenil has an effect on the endocrine
system.  While dichlobenil administration to hamsters for 90 days at
dose levels of 16, 79 and 263 mg/kg/day (300, 1500 and 5000 ppm)
resulted in decreased prostate weight and prostate degeneration and
demineralization with a no observable effect level (NOEL) of 3 mg/kg/day
(60 ppm), no correlating effects were seen in 2 chronic hamster studies.
 In one chronic hamster feeding study, no prostate effects were seen in
male hamsters fed 3375 ppm for 91 weeks and in another study no prostate
effects were observed in male hamsters fed 675 ppm for 88 weeks. 
Furthermore, no similar effects were seen in rats or dogs fed
dichlobenil.  

A standard battery of required toxicity tests have been conducted on the
dichlobenil metabolite, BAM.  No effects were seen in the reproduction
or teratology studies to indicate that BAM has an effect on the
endocrine system.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Based on dietary, drinking water, and
non-occupational exposure assessments, there is reasonable certainty of
no harm to the US population, any population subgroup, or infants and
children from chronic exposure to dichlobenil.  The tolerance expression
for dichlobenil includes both parent compound (2,6-dichlorobenzonitrile
or dichlobenil) and a metabolite (2,6-dichlorobenzamide or BAM). 
Dichlobenil residues are not found on food, whereas they may occur in
surface and ground water.  BAM residues are found on food commodities
treated with dichlobenil and also in water.>

<	i. Food. Tier 1 chronic dietary exposure estimates to BAM were based
on: (1) tolerance level residues for all current and proposed crops, (2)
default processing factors, (3) assumption of 100% crop treated, and (4)
consumption data from the 1994 through 1998 USDA Continuing Survey of
Food Intake by Individuals (CSFII).  Estimates of dietary exposure were
calculated using Exponent’s Dietary Exposure Evaluation Module –
Food Consumption Intake Database (DEEM-FCID)( software.  Chronic dietary
exposure is estimated for the U.S. Population to be 0.000841 mg/kg/day,
which corresponds to 5.6% of the chronic reference dose (RfD) of 0.015
mg/kg/day.  The highest chronic dietary exposure (0.006236 mg/kg/day)
was estimated for children 1-2 years of age.  This exposure corresponds
to 41.6% of the cPAD.  These chronic dietary exposure estimates indicate
reasonable certainty of no harm for all population subgroups.  The
chronic dietary results for the U.S. Population and select
subpopulations are summarized in the table below.  An acute dietary
assessment was not conducted for BAM because EPA has concluded that
there is no acute toxicological endpoint of concern for BAM.

	It is important to remember that this assessment is quite conservative
because it includes tolerance level residues in all current and proposed
crops and the assumption of 100% crop treated for all crops.  Actual
exposures are likely to be considerably less than those estimated here.>

<	ii. Drinking Water. Balu, et al. (2006) reports ground water
monitoring results from 25 wells located in major dichlobenil use areas.
 109 samples were collected and analyzed for dichlobenil. 
Concentrations of DCB and BAM were well below the level of concern. 
Surface water monitoring data for dichlobenil and BAM are not available.
 Therefore, it was necessary to estimate concentrations using FIRST. 
According to the Casoron 4G label, dichlobenil is applied to a variety
of food crops and non-food crops (i.e., woody ornamentals and
shelterbelts, hybrid cottonwood and poplar plantations, and various
non-crop areas).  For food crops, the maximum single application rate is
6 lb ai/A, with just one application per season, and the product
granules are to be completely incorporated into the surface through
watering-in.  For woody ornamentals and cottonwood/poplar plantations,
the maximum single application rate is 8 lb ai/A, with just one
application per season, and the product granules are to be completely
incorporated into the surface through watering-in.  Finally, for
non-crop areas, the maximum single application rate is 10 lb ai/A for
nutsedge control, and the product granules are to be incorporated to a
depth of 4-6 inches.

For the maximum estimated peak dichlobenil residue in surface water (673
ppb), the acute exposure is therefore estimated to be 0.0224 mg/kg/d
with a corresponding margin of exposure (MOE) of 2,000.  Since the MOE
is greater than 100, it can be concluded that acute exposures to
dichlobenil in drinking water will be associated with a reasonable
certainty of no harm.

For the maximum estimated chronic dichlobenil concentration in surface
water of 5.3 ppb, the exposure for children is estimated to be 0.00053
mg/kg/d, which corresponds to 4.1% of the RfD.  Thus, there is
reasonable certainty of no harm resulting from the chronic consumption
of water containing dichlobenil residues.

The calculated DWLOCs for chronic exposure for adult males, adult
females and toddlers were estimated to be 496 ppb, 439 ppb and 88 ppb,
respectively.   As a comparison, the annual average concentration of BAM
measured in any well in the ground water monitoring study (Balu, et al.,
2006) was 10.4 ppb.  For BAM, the DWLOCs are greater than the DWEC, and
therefore there is reasonable certainty that no harm will result from
combined dietary (food and water) exposure to BAM resulting from the use
of dichlobenil on all registered and proposed crops.>

<	2. Non-dietary exposure. The only source of non-dietary exposure to
dichlobenil for consideration under FQPA is in the use of CASORON® 2G
in residential areas.  The 2G granular formulation of dichlobenil is
used by homeowners in landscape areas and around buildings and
structures.  Residential exposure to dichlobenil is possible through
homeowner application of CASORON® 2G granular.  However, foliar
residues are not anticipated.  CASORON is not applied directly to lawns
and it will not adhere to foliage of ornamental plants.  In addition,
CASORON is typically applied during the winter season when there is less
potential for contact with outdoor areas.  This implies that handler
exposure is by far the greatest contributor to residential non-dietary
exposure

Applicator Exposures

Granular formulations of dichlobenil are intended for the home use
market.  Residential dichlobenil products are intended for the control
of annual and certain perennial grassy and broadleaved weeds around
established ornamental trees and shrubs, fruit trees, nut trees and
berries, and in non-crop areas (i.e., around buildings and fences). 
Dichlobenil is not applied to turf.  Dichlobenil granular products are
applied by shaking uniformly over the soil area to be treated at rates
of 2 to 3 tablespoons per 10 square feet.  This corresponds to a maximum
application rate of 6 pounds active ingredient per acre for a 2%
product:

3 T	=	1.125 oz	(	43560 ft²	(	1 lb	(	2%	=	6 lb ai

10 ft²

10 ft²

A

16 oz

A

For residents applying a granular product with a shaker can, the
Residential SOPs (EPA, 1997) provide unit exposure estimates of 430
mg/lb ai for dermal exposures and 467 µg/lb ai for inhalation
exposures.  Results from a radiolabeled in vitro study indicate that
0.99% of dichlobenil (applied to excised skin in an aqueous slurry of a
6.75% product) was absorbed within 24 hours, as defined by OECD
Guideline 428.  Applications of granular products by residents are
assumed to cover 1000 ft2 (EPA, 2001). Since the product is applied just
once per year, handler exposures are expected to be short-term only. 
The short-term toxicity endpoint (45 mg/kg/d) for dichlobenil is from a
developmental toxicity study, so the population of interest is adult
females, who are assumed to have a body weight of 60 kg.  Using these
assumptions, the total applicator exposure is estimated to be 0.0108
mg/kg/d.  The associated MOE of 4,100 indicates a reasonable certainty
of no harm for residents applying dichlobenil granular products.

Postapplication Exposures

Granular dichlobenil products are applied only in small areas (e.g.,
under trees or ornamentals where weed control is desired, and in
non-crop areas around buildings, etc.).  Applications are typically made
between late fall (after a killing frost) and mid-winter or in early
spring.  These granular products are fully watered in (¼ to ½ half
inch deep) upon application.  Furthermore, dichlobenil is not applied to
turf.  Due to the use pattern for dichlobenil products, the potential
for postapplication exposures to children is very low.  Since
applications are made only once a year at times when there is minimal
potential contact with outdoor area, any postapplication exposures are
expected to be quite low and would be of short-term duration only.  For
dichlobenil, the short-term toxicity endpoint is from a developmental
toxicity study.  Since there is no short-term toxicity endpoint
appropriate for children (i.e., the population most likely to experience
postapplication exposures), it is inappropriate to estimate MOEs for
this population.  Consequently, postapplication exposures are not
estimated for children.

Aggregate (Water + Application) Exposures

As calculated in the previous section, the short-term dichlobenil
drinking water exposure is estimated using the peak dichlobenil residue
in surface water (673 ppb) to be:

Exposure (mg/kg/d) = 0.673 mg/L ( 2 L/day / 60 kg = 0.0224 mg/kg/d.

Applicator exposures were estimated above to be 0.0108 mg/kg/d. 
Therefore, the maximum total short-term dichlobenil exposure (i.e.,
drinking water and application exposures) would be 0.0322 mg/kg/d.  The
associated MOE of 1,350 indicates a reasonable certainty of no harm for
short-term aggregate (water + application) exposures to dichlobenil.>

<D. Cumulative Effects>

<	EPA has not made a common mechanism of toxicity finding as to
dichlobenil and any other substances and dichlobenil does not appear to
produce a metabolite produced by other registered substances.>

<E. Safety Determination>

<	1. U.S. population. Dichlobenil residues are not present in food,
therefore the worst-case chronic residue exposure is due to the BAM
metabolite in food and water.  Based on the toxicology database and
available information on anticipated residues, chronic dietary exposure
to the U.S. population (total) was 5.6% of the cPAD.>

<	2. Infants and children. Dichlobenil residues are not present in food,
therefore the worst-case chronic residue exposure is due to the BAM
metabolite in food and water.  Most sensitive group was children 1-2
years of age with a chronic dietary exposure of 41.6%.>

<F. International Tolerances>

<	Maximum residue limits are established in the EU on vegetables, grain,
fruit at 0.05 to 0.2 mg/kg; in Canada on fruit at 0.1 mg/kg. No Codex
MRLs have been established for residues of dichlobenil.  Therefore,
there are no questions with respect to compatibility of U.S. tolerances
with Codex MRLs.>