Document ID: EPA-HQ-OPP-2007-0472-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-22T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)

EPA Registration Division contact: Shaja R. Brothers (703) 308-3194

 

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
petition documents.  In cases where the outline element does not apply
please insert “NA-Remove” and maintain the outline.  The comment
notes that appear on the left margin represent hidden typesetting codes
designed to expedite the processing of the Federal Register document. 
Please do not remove or alter these comment notes or change the margins,
font, or format in your document. Simply replace the instructions that
appear in italics and brackets, i.e., “[insert company name],” with
the information specific to your action.

TEMPLATE:

Interregional Research Project Number 4 (IR-4)

7E7213

	EPA has received a pesticide petition (7E7213) from (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 thiobencarb in or on the raw agricultural commodity
rice, wild at 0.2 parts per million (ppm).  EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408 (d)(2) of the FDDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
support 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 an acceptable study depicting the
metabolism of thiobencarb in rice.  On May 13, 1993 the Agency’s
Metabolism Committee determined that the current tolerance expression
for residues of thiobencarb and its metabolites containing the
chlorobenzyl and chlorophenyl moieties is appropriate  .

	2. Analytical method. Adequate methods are available for enforcement
and data collection purposes for both plant and animal commodities. 
Successful radiovalidation of the enforcement methods, using samples
from the metabolism studies, has also been conducted.  Residues of
thiobencarb are completely recovered using multiresidue method Section
302 (Luke method; Protocol D), and variably recovered using method
Section 304 (Mills, Onley, Gaither method; fatty food).

	3. Magnitude of residues. Magnitude of the residue in/on plants are
fulfilled for rice grain and straw.  Adequate field trial data,
following treatments according to the maximum registered use pattern,
have been submitted for rice grain and straw.

B. Toxicological Profile

	1. Acute toxicity.  Thiobencarb has been tested for acute toxicity by
the oral, dermal and inhalation routes of exposure.  The results
obtained in these studies satisfy the acute toxicity data requirements.

	2. Genotoxicty. Thiobencarb was evaluated in an Ames assay, and was
negative in tester strains TA100, TA98 and TA1537 at levels up to 50
g/plate, both with and without metabolic activation.  Thiobencarb was
negative in a dominant lethal assay in mice, administered at a single
oral dose of 600 mg/kg, and at an oral dose of 300 mg/kg for 5 days.  In
a clastogenicity test using human lymphocytes, thiobencarb (96.0% a.i.)
was tested at dose levels of 0, 5, 10, and 20 g/ml without S9 activation
and at dose levels of 0, 10, 20, and 40 g/ml with S9 activation. No
mutagenic activity was noted.  In a micronucleus test in mice,
thiobencarb (96.0% a.i.) was tested at dose levels of 0, 270, 540, and
1080 mg/kg in males and at dose levels of 0, 405, 810, and 1620 mg/kg in
females, as a single oral dose.

	3. Reproductive and developmental toxicity. In a multigeneration
reproduction study, Charles River CD rats received either 0, 2, 20, or
100 mg/kg/day Technical Bolero® (96.7% a.i.) by daily oral gavage in
0.5% CMC aqueous solution.  For reproductive toxicity, the NOEL was
equal to or greater than 100 mg/kg/day and the LOEL was greater than 100
mg/kg/day.

In a developmental toxicity study, albino rats of the Sim: (SD) FBR
(Sprague Dawley derived) strain received by oral gavage either 0, 5, 25,
or 150 mg/kg/day thiobencarb technical (97% a.i.) in Deionized
Water/CMC/Tween 80 on days 6 through 19 of gestation. Developmental
toxicity was noted as a slight increase in skeletal anomaly observations
at the high dose mostly related to reduced ossification and an increase
in runts in the high dose group. For developmental toxicity, the NOEL
was 25 mg/kg/day and the LOEL was 150 mg/kg/day based on increased
skeletal anomaly observations and an increase in the number of runts.

In another developmental toxicity study, New Zealand white rabbits
received 0, 20, 100, or 200 mg/kg/day technical thiobencarb (96.0% a.i,)
by oral gavage from days 6 through 18 of gestation. No developmental
toxicity was observed at dose levels tested. For developmental toxicity,
the NOEL was equal to or greater than 200 mg/kg/day and the LOEL was
greater than 200 mg/kg/day.

Based on the results of these studies, thiobencarb is not considered to
be a

developmental toxicant in rats or rabbits.

	4. Subchronic toxicity. In a 21 day dermal study, Sprague-Dawley rats
received repeated dermal applications of Bolero® 8EC (85.2% a.i.) at
doses of 0, 40, 160, or 500 mg/kg, 5 days per week, over a 22-day
period. Thirty-six animals of each sex were used, 6 animals/sex/dose for
the 0, 40, 160 and 500 mg/kg dose plus an extra 6/sex/dose for the 0 and
500 mg/kg doses at recovery. There was a dose related increase in the
incidence of skin irritation in treated versus control rats of both
sexes. Six additional animals dosed with 0 and 500 mg/kg were held for 2
weeks following dosing as a recovery group. Reduced food intake with an
associated reduction in body weight gain was observed in the mid- and
high-dose groups. The reduction in body weight gain persisted in
high-dose males in the recovery group. Statistically significant
decreases in food efficiency were observed in mid-and high-dose males.
For dermal toxicity, a NOEL was not observed and the LOEL was less than
40 mg/kg/day based on the skin irritation observed. For systemic
toxicity, the NOEL was 40 mg/kg/day and the LOEL was 160 mg/kg/day based
on decreases in body weight gain and food consumption in males and
females, and statistically significant decreases in food efficiency in
males.

	5. Chronic toxicity. In a combined chronic toxicity/carcinogenicity
feeding study, Fischer 344 rats received 0, 20, 100 or 500 ppm
(approximately 0, 1, 5, and 25 mg/kg/day by standard conversion methods)
technical Bolero® (95.3% a.i. ) in the diet for 2 years. Systemic
toxicity was noted at 100 ppm and higher as decreased body weight gain,
food consumption and food efficiency. There was also an increase in
blood urea nitrogen. However, no evidence of carcinogenicity at the dose
levels tested was observed. For chronic toxicity, the NOEL was 1
mg/kg/day and the LOEL was 5 mg/kg/day based on decreased body weight
gains, food consumption, food efficiency and increased blood urea
nitrogen.

In a chronic oral toxicity study, Beagle dogs received 0, 1, 8, or 64
mg/kg/day of thiobencarb technical (Lot# SX-1381; Purity 96.3% a.i.) by
capsule for 52 weeks. Systemic toxicity was noted in the high dose males
as decreased body weight gains and increased absolute and relative
kidney and liver weights in high dose males and females. There were
decreases in serum albumin and protein in high dose males and females (a
slight effect was noted in mid dose males). In addition, there were
decreased erythrocyte counts and hemoglobin levels with a reduction in
hematocrit in high dose males and females along with decreases in
alanine aminotransferase and cholesterol levels in the high dose group.
For systemic toxicity, the NOEL was 8 mg/kg/day and the LOEL was 64
mg/kg/day based on increased liver and kidney weights, and decreased
hematological and clinical chemistry parameters. Based on biologically
significant depression in cholinesterase activity, for plasma
cholinesterase, the NOEL was 1 mg/kg/day and the LOEL was 8 mg/kg/day.
For erythrocyte cholinesterase, the NOEL was 8 mg/kg/day and the LOEL
was 64 mg/kg/day. For brain cholinesterase, the NOEL was equal to or
greater than 64 mg/kg/day and the LOEL was greater than 64 mg/kg/day.

	6. Animal metabolism. In a general metabolism study, the disposition
and metabolism of [Phenyl-U-14C]-thiobencarb was investigated in male
and female Sprague-Dawley rats at a single low oral dose (30 mg/kg),
repeated low oral doses (30 mg/kg x 14 days), and a single high dose
(300 mg/kg). Thiobencarb was rapidly absorbed after oral administration
as judged by the rate of excretion. No significant sex-related or dose
group differences in absorption were noted. Excretion was relatively
rapid at all doses tested, with a majority of radioactivity eliminated
in the urine and feces by 48 hours. The extent of excretion was
completed by 72 hours at the 300 mg/kg dose, but the mechanism
responsible for this delay was not identified. No significant sex- or
dose-related differences in urinary or fecal excretion of thiobencarb
derived radioactivity were noted. Repeated low oral dosing did not
affect elimination of thiobencarb in either male or female rats. Fecal
elimination of [Phenyl-U-14C]-thiobencarb derived radioactivity was a
minor route of excretion, and for urine, no significant sex- or
dose-related differences in amount of radioactivity excreted by this
route were observed. Residual levels of thiobencarb derived
radioactivity were also minor (less than 0.5% of an administered dose).
Urinary and fecal metabolites of [Phenyl-U-14C]-Thiobencarb were
isolated and identified by HPLC, TLC, and mass spectral analysis. The
major metabolite detected was the glycine conjugate 4-chlorohippuric
acid, comprising between 74-81% of an administered dose in urine. Other
metabolites detected included 4-chlorobenzyl methyl sulfoxide and
-sulfone, des-ethyl thiobencarb, and 4-chlorobenzoic acid, each
representing less than 10% of an administered dose of thiobencarb. A
single high or repeated low oral dose did not significantly affect the
urinary or fecal metabolite profile for thiobencarb in male or female
rats.

	7. Metabolite toxicology. NA

	8. Endocrine disruption. EPA is required to develop a screening program
to determine whether certain substances (including all pesticides and
inerts) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or such other endocrine
effect..." The Agency is currently working with interested stakeholders,
including other government agencies, public interest groups, industry
and research scientists in developing a screening and testing program
and a priority setting scheme to implement this program.

C. Aggregate Exposure

	1. Dietary exposure. Dietary exposure (food and drinking water sources)
is expected to occur over an acute through chronic period. To assess the
acute dietary risk, EPA calculates a margin of exposure (MOE), which is
the ratio of the NOEL to exposure. To assess chronic risk, EPA
calculated the percent of the reference dose [RfD] (i.e. % RfD)
occupied.

	i. Food. The MOE (margin of exposure) is calculated by dividing the
acute dietary NOEL (i.e. mg/kg/day) by the high-end exposure. High-end
exposure represents exposure of the pesticide to 99.5% of the targeted
population. Because the endpoint of concern for acute dietary risk
assessment is a developmental toxicity effect, the only subgroup of
concern is females (13+ years). Generally, acute aggregated MOEs greater
than 100 tend to cause no dietary concern when the data are compared to
a toxicological endpoint from an animal study (such is the case for
thiobencarb). Since the only subgroup of concern is females (13+) and
represents an MOE = 8928,the Agency is not concerned with acute dietary
risks from exposure to thiobencarb residues in food.

The chronic analysis for thiobencarb is a worst case estimate of dietary
exposure with all residues at tolerance level and 100 percent of the
commodities assumed to be treated with thiobencarb. Thus, the actual %
RfD is considered < 42.9%.

	ii. Drinking Food. Acute drinking water exposure was calculated using
the

following formula:

Exposure (mg/kg/day) = (ppb thiobencarb in the water
consumed)(10-6)(33.3)

Thus, drinking water exposure = 3.33 x 10-6 mg/kg/day and a resulting
MOE >

10,000. Therefore, there is no concern with acute drinking water risks
from

exposure to thiobencarb residues in drinking water.

A drinking water exposure estimate of 0.1 g/L (i.e. 2.86 x 10-6
mg/kg/day) was used to assess chronic exposure as was performed for
acute drinking water. As was noted previously in the acute drinking
water exposure assessment, data from the California surface water
monitoring study indicated thiobencarb residues were not above the a
limit of detection of 0.1 g/L. Thus, high end drinking water exposure
was utilized for the chronic drinking water risk assessment and
corresponds to a %RfD = 0.29.

	2. Non-dietary exposure. Thiobencarb is not available for use in a
residential setting. Thus, no non-occupational exposure to thiobencarb
is expected.

Occupational exposure:

Granular Formulations: The risks resulting from intermediate-term
exposures to the granular formulation are overestimated due to the use
of the 60.2 percent dermal absorption value for the granular scenarios.
In general, dermal absorption of granular formulations has been found to
be significantly lower than for liquid formulations. Therefore, the
Agency has determined that risks to handlers of granular formulations
will be adequately mitigated with the addition of personal protective
equipment.

Liquid Formulations: The risks resulting from intermediate term
exposures to persons handling liquid formulations are overestimated due
to limitations with the hazard identification and the dose-response
assessment for the intermediate-term endpoint, particularly in light of
the absence of serious effects to these target organs in either the
subchronic neurotoxicity or rat chronic feeding study, which suggest the
lack of a deleterious response to thiobencarb by the kidney and/or
liver. The risks to handlers using liquid formulations will be
adequately mitigated with the used of engineering controls and personal
protective equipment.

Post-Application Workers

The short-term endpoint (25 mg/kg/day) was used for the risk assessment,
since it is not anticipated that intermediate-term exposures (i.e., 7
days or more of exposure) are likely to occur for post-application
workers for these crops in early-stage development. It is assumed in the
surrogate assessment that dermal absorption would be significantly lower
that the 60.2 percent used in the handler assessment, since dermal
exposure would be to dry residues.

The surrogate post-application risk assessment indicated that at all
application rates (i.e., 4 pounds active ingredient per acre), risks
would be acceptable to post-application workers entering treated areas
to perform tasks, such as scouting, thinning, or hoeing, provided entry
is postponed for 24 hours following application.

D. Cumulative Effects

	Thiobencarb is structurally similar to thiocarbamate pesticides.
Further, other pesticides may have common toxicity endpoints with
thiobencarb. However, the Agency has not made a determination whether
thiobencarb and any other pesticides have a common mode of toxicity and
require a cumulative risk assessment. If required, cumulative exposure
and risks will be assessed when methodologies for determining common
mode of toxicity and for performing cumulative risk assessment are
finalized.

E. Safety Determination

	1. U.S. population. The tolerance for thiobencarb meets the safety

standards under the FQPA amendments to Section 408 (b)(2)(D) for the
general population. In reaching this determination, available 
information on the aggregate exposures (both acute and chronic) from
non-occupational sources, food and drinking water, as well as the
possibility of cumulative effects from thiobencarb and other chemicals
with a similar mechanism of toxicity have been considered.

Since there are no residential or lawn uses of thiobencarb, no dermal or
inhalation

exposure is expected in and around the home. No acute toxicity endpoints
of concern have been identified for thiobencarb.

In assessing chronic dietary risk , EPA estimates that thiobencarb
residues in food

sources account for < 42.9 percent (%) of the RfD, and includes the
highest-at-risk

subgroup, non-nursing infants. In drinking water thiobencarb residues
account for 0.29 percent (%) of the RfD. Thus, the aggregate exposures
from all sources of thiobencarb (in this case, only dietary and drinking
water exposures are relevant) account for 43.2 percent (%) of the RfD.

	2. Infants and children. The tolerance for thiobencarb meets the safety
standard under the FQPA amendment to section 408(b)(2)(C) for infants
and children. The safety determination for infants and children
considers the factors noted above for the general population, but also
takes into account the possibility of increased dietary exposure due to
the specific consumption patterns of infants and children, as well as
the possibility of increased susceptibility to toxic effects of
thiobencarb residues in this population subgroup.

Based on current data requirements, thiobencarb has a complete data base
for

developmental and reproductive toxicity. In the developmental studies,
effects were seen in the fetuses only at the same or higher dose levels
than effects on the mothers. In the reproduction study, no effects on
reproductive performance were seen. It is unlikely that there is
additional risk concern for immature or developing organisms. Therefore,
an additional uncertainty factor is not warranted for assessing the
risks of thiobencarb. Thiobencarb residues in the diet of infants and
children account for 42.9 percent of the RfD (29.5 for children 1-5) and
residues in drinking water account for 0.29 percent of the RfD. Thus the
aggregate exposure from all sources of thiobencarb account for 43.2
percent of the RfD for infants and children. Aggregate risks for infants
and children resulting from uses of thiobencarb are not of concern.

F. International Tolerances

	There are presently no existing Codex maximum residue limits for
thiobencarb.