Document ID: EPA-HQ-OPP-2009-0910-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-09-03T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

July 8, 2010

MEMORANDUM

SUBJECT:	THIABENDAZOLE Human Health Risk Assessment for Seed Treatment
Use on Corn.  

PC Code:  060101	DP Barcode:  D378944

Decision No.:  407543	Registration No.:  100-RGLE

Petition No.:  0F7730	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical	Case No.:  2760

TXR No.:  NA	CAS No.:  148-79-8

MRID No.:  N/A	40 CFR §:  180.242, 180.2010

	

FROM:	Susan V. Hummel, Chemist

		Risk Assessment Branch 4

		Health Effects Division (7509P)

			

THROUGH:	Ray Kent, Branch Chief

		Risk Assessment Branch 4

		Health Effects Division (7509P)	

TO:		Janet Whitehurst/Tony Kish, PM 22

		Fungicide Branch, Registration Division (7505P)

Attached is HED’s risk assessment to support the proposed new use for
thiabendazole as a seed treatment for corn.   This assessment relies on
the toxicology assessment done by David Nixon for the thiabendazole RED
and updated by Sue Shallal, Ray Kent, and updated dermal absorption by
Jessica Ryman, the residue chemistry assessment by Susan Hummel, the
dietary exposure assessment by Thurston Morton, the residential exposure
assessment for antimicrobial uses by Timothy Leighton, and the
occupational exposure assessment by Rebecca Daiss.  1.0	Executive
Summary

In a Joint NAFTA Submission, Syngenta Crop Protection is requesting
registration of a new seed treatment product for use on corn, a 2.5
lb/gal flowable concentrate seed treatment (FS) formulation (Maxim®
Quattro Fungicide; EPA File Symbol 100-RGLE).  The product is a multiple
active ingredient (MAI) formulation containing thiabendazole as well as
fludioxonil, mefenoxam and azoxystrobin.  The FS formulation for use on
corn represents a new use for thiabendazole, but the three additional
active ingredients contained in the formulation are all registered for
seed treatment use on corn and have existing tolerances for corn.

For thiabendazole, Syngenta has submitted a petition, PP#0F7730, to
establish tolerances at the limits of quantitation for corn commodities
to support the proposed seed treatment use.  Syngenta proposes to amend
40 CFR 180.242 by establishing tolerances for the residues of
thiabendazole and its benzimidazole metabolites (free and conjugated)
resulting from the application of thiabendazole fungicide in or on a
number of corn commodities.

Hazard summary.  The target organs for thiabendazole toxicity are the
liver and thyroid. Effects to these organs were observed in multiple
studies and across species.  With respect to carcinogenicity,
thiabendazole is classified as “not likely to be carcinogenic to
humans at doses that do not alter rat thyroid hormone homeostasis”. 
There is no evidence of neurotoxicity in the existing database, and in
developmental and reproductive studies, effects to offspring are
observed only at doses toxic to the parents.  There are no effects seen
in the toxicity database that would be attributable to a single exposure
of thiabendazole.

HED is regulating chronic dietary risk with a chronic RfD at a dose
below which thyroid hormone balance is not impacted and consequently is
protective of potential carcinogenic effects.

Endpoints and points of departure for occupational and residential risk
assessment are based on oral studies in rats.

FQPA.  The database for thiabendazole is complete with the exception of
a developmental thyroid study.  The FQPA factor is 10x as a database
uncertainty factor for the missing thyroid study. Since the uncertainty
focuses on potential differences in sensitivity between adult rats and
developing rats, and since adult rats are known to be more sensitive
pharmacodynamically to thyroid toxicants than humans, the overall
composite uncertainty factor for risk assessment is 300x – 10x for
intraspecies variability among humans, 3x for interspecies
pharmacokinetic differences between humans and rats and the 10x database
uncertainty factor for the missing developmental thyroid study.

  

Residues in food.  HED concludes that there are not likely to be
detectable residues of thiabendazole or its regulated benzimidazole
metabolites (free and conjugated in field, sweet, or pop corn
commodities grown from treated seed, in the processed commodities of
field corn (meal and oil), or from rotational crops as a result of use
under the conditions specified under this action. The chronic dietary
risk assessment showed 1.4 % of the chronic population adjusted dose 
(cPAD) occupied for the U. S. Population.  The most highly exposed
subpopulation was all infants at 4.6 % cPAD.  

Residential Exposure.  There are no residential uses proposed in
connection with this petition.  However, there are registered
residential uses, i.e., antimicrobial use of thiabendazole in paint and
sponges, which may result in residential exposure.  These residential
uses have been assessed and aggregated with the food and water
exposures.  If we assume that 5% of the thiabendazole on sponges is
transferred to the surface each day, none of the aggregate exposures
represent risks of concern, as all MOEs are greater than the target MOE
of 300.

Aggregate Exposure.  Short- and Intermediate-term residential exposures
have been aggregated with the chronic dietary exposure.  No risks of
concern were found.

Occupational Exposure.  Margins of Exposure (MOEs) for commercial seed
treatment (Loader/Applicators, Sewers, Baggers and Multiple Activities)
were greater than the target of 100 for all exposure scenarios.   Also,
MOEs for planting treated seed were greater than the target of 100 for
all exposure scenarios.   

Use of Human Studies.  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 2.0,
have been determined to require a review of their ethical conduct.  Some
of these studies are also subject to review by the Human Studies Review
Board.  All of the studies used have received the appropriate review.

Environmental Justice.  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 ).

Regulatory Recommendations

The following label revision should be addressed as part of the
regulatory action taken on this petition.

The registrant should revise the label to include the use rates in terms
of weight of product per weight of seed (e.g. g/100 kg seed).

Provided the label revision noted above is made, HED has no objections
to establishment of tolerances for residues of thiabendazole on corn
commodities under 40 CFR § 180.242 for the proposed use/limits of
thiabendazole on field, sweet, and popcorn forage, grain, and stover at
0.01 ppm, each.

Commodities	Proposed Tolerance

(ppm)

Corn, field, forage	0.01

Corn, field, grain	0.01

Corn, field, stover	0.01

Corn, pop, forage	0.01

Corn, pop, grain	0.01

Corn, pop, stover	0.01

Corn, sweet, forage	0.01

Corn, sweet, kernels plus cob with husks removed	0.01

Corn, sweet, stover	0.01

  

2.0	Background

(HED memo of 12/10/09, S. Hummel, D363974)

Syngenta has submitted a draft label (dated 3/17/09) and a description
of the proposed use for the 2.5 lb/gal FS formulation (Flowable
Concentrate for seed treatment), Maxim® Quattro Fungicide; EPA File
Symbol 100-RGLE.  The product is an MAI formulation that also contains
fludioxonil (0.31 lb/gal), mefenoxam (0.25 lb/gal), and azoxystrobin
(0.12 lb/gal).  

In their transmittal letter, Syngenta noted that two formulations are
intended to be supported:  a colorless formulation for use in Canada
(A14918E), and a formulation containing a small amount of dye (A14918D)
to be submitted in addition to the colorless formulation for use in the
U.S.

The proposed use directions for corn are summarized in Table 2.0.

Table 2.0.	Summary of Directions for Use of Thiabendazole.

Applic. Timing, Type, and Equip.	Formulation

[EPA File Symbol No.]	Applic. Rate 	Max. No. Applic. per Season	PHI

(days)	Use Directions and Limitations

From label	From transmittal letter

	Field corn, sweet corn, and pop corn (includes seed production)

Seed treatment,

Seed treatment application equipment	2.5 lb/gal FS

[100-RGLE]	0.05 mg ai/kernel

0.46 fl. oz. product/

80,000 kernel count 	0.020 lb ai/100 lb seed

[20 g ai/100 kg seed]	1	Not appli-cable	Application is to be made as a
water-based slurry maintained under constant agitation.  Treated sweet
corn should be planted and not carried over to the following year.  A
30-day pregrazing interval (PGI) is specified for corn forage.

The use rates on the draft labeling are expressed in terms of mg
ai/kernel and fl. oz. product/80,000 kernel count.  Syngenta has stated
that the intended use rate for thiabendazole is 20 g/100 kg seed. 
Because the product is proposed for use on three types of corn (field,
sweet, and pop corn) with varying average grain weights, we recommend
that the use rates in terms of weight of product per weight of seed
(e.g. g/100 kg seed) be included on the label.

Other uses registered for thiabendazole include agricultural treatments,
post-harvest treatments of fruit & vegetables using thiabendazole
treated washes or wax, and residential uses including treating paint and
sponges.

The chemical structure and nomenclature of thiabendazole and its
regulated metabolites are presented in Table 1, and the physicochemical
properties of the technical grade of thiabendazole are presented in
Table 2.  

Common name	5-hydroxy-thiabendazole

Chemical name	2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-ol) 

Table 2.	Physicochemical Properties of the Technical Grade Test
Compound: Thiabendazole. 

Parameter	Value	Reference

Melting point/range	304-305 °C	Thiabendazole RED 10/02

pH	5.16-5.97	Thiabendazole RED 10/02

Bulk Density	25-30 g/cc (tapped)	CSF for Reg. No 100-963

Water solubility	0.028-0.030 mg/mL at 25 °C	Thiabendazole RED 10/02

Solvent solubility	

acetone

benzene

chloroform

dimethylformamide

dimethyl sulfoxide

ethanol 

ethyl acetate

methanol		25 ºC

4.2 g/L

230 mg/L

80 mg/L

39 g/L

80 g/L

7.9 g/L

2.1 g/L (R.T.)

9.3 g/L	The Pesticide Manual, 8th edition

Vapor pressure	4 x 10 -9 mm Hg at 25 °C	Thiabendazole RED 10/02

Dissociation constant, pKa	Pka1 = 4.73; Pka2 = 12.00	Thiabendazole RED
10/02

Octanol/water partition coefficient	Log(KOW) = 240-285 at pH 7
Thiabendazole RED 10/02

UV/visible absorption spectrum	Neutral solution

32,170 L/mol*cm3 at 205.5 nm

Acidic solution

41,520 L/mol*cm3 at 303.5 nm

Neutral solution

40,553 L/mol*cm3 at 215.5 nm	MRID 462868011

1 Data were referenced in MRID 47705121. 

Hazard Characterization/Assessment

Hazard summary.  The primary target organs affected by thiabendazole in
multiple studies and across species are the liver and thyroid.  In rat
subchronic studies, oral administration of thiabendazole caused
increased liver and thyroid weights and increased incidence of hepatic
centrilobular hypertrophy and thyroid follicular cell hyperplasia and
hypertrophy in both sexes. 

In prenatal developmental toxicity studies in rats, rabbits, and mice
and in the two-generation reproduction study in rats, effects in the
fetuses or neonates occurred at or above doses that caused maternal or
parental toxicity.  The available database indicates that thiabendazole
is not neurotoxic. There is no other evidence in the database that would
suggest a requirement for a developmental neurotoxicity study with
thiabendazole; however, the thyroid effects to adult animals indicate
the need for a developmental thyroid study in rats to assess potential
effects on developing offspring.

The acceptable genetic toxicology studies on thiabendazole indicate that
it is nongenotoxic/mutagenic in in vivo and in vitro assays. Review of
literature studies indicated that thiabendazole has weak aneugenic
activity in both somatic and germinal cells.  In a chronic rat study,
thiabendazole induced thyroid tumors in males only and thiabendazole did
not induce tumors in mice. Thiabendazole has been classified “not
likely to be carcinogenic to humans at doses that do not alter rat
thyroid hormone homeostasis”.

There are no toxic affects attributable to a single dose of
thiabendazole. In acute studies, thiabendazole has low acute toxicity
via the oral and dermal routes (Category III). It is not an eye or
dermal irritant nor a dermal sensitizer. 

 1% of the dose) of free 5-hydroxythiabendazole were present in urine
from rats from all dose groups.

Endpoints/points of departure for risk assessment. As there are no toxic
affects attributable to a single dose of thiabendazole, an acute dietary
point of departure and endpoint of concern was not identified for
females ages 13 to 49 or for the general population.  The chronic
reference dose (cRfD) for all populations of 0.1 mg/kg/day is based on a
NOAEL of 10 mg/kg/day from a rat chronic toxicity/carcinogenicity study.
 Dermal and inhalation endpoints and PODs are based on oral studies
(Table 3).  The absorption factor for inhalation risk is 100% and the
dermal absorption factor based on recently submitted studies is 0.5%, a
marked change from the previously used DAF of 60%.

FQPA Factor

The FQPA SF was retained at 10x as a database uncertainty factor since a
developmental thyroid study is required. Pending the outcome of the
comparative thyroid toxicity study, there is uncertainty with respect to
the effect of thiabendazole in developing offspring and an uncertainty
factor of 10x is warranted.  An interspecies scaling factor of 3x,
lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a
thyroid hormone) at a higher rate than humans), an intraspecies
variability factor of 10X, and a database uncertainty factor of 10x for
lack of a developmental thyroid study was applied, are combined for a
total uncertainty factor of 300x.  



Table 3.  Summary of Toxicological Doses and Endpoints for Thiabendazole
 

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Factors	Level of Concern
for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(general population including females 13 – 49 years)	No effect
attributable to a single dose seen in the database

Chronic Dietary	NOAEL =

10mg/kg/day	UFA = 3x

UFH = 10x

FQPA = UFDB = 10x	cRfD =

0.033 mg/kg/day

cPAD =

0.033 mg/kg/day	2-Year Feed/chronic Carcinogenicity in the Rat

LOAEL = 30 mg/kg/day based on decreased body weight gains and liver
hypertrophy

Incidental Oral (ST/IT)	NOAEL= 10mg/kg/day	UFA= 30x

UFH=10x

FQPA = UFDB = 10x	LOC for MOE = 300	Developmental Toxicity study - rat.

LOAEL = 40 mg/kg/day based on decreases in fetal body weight

Dermal Short-Term (1-30 days) DAF = 0.5%	NOAEL= 10mg/kg/day	UFA= 3x

UFH=10

FQPA = UFDB = 10x	Occupational & Residential LOC for MOE = 300
Developmental Toxicity study - rat.

LOAEL = 40 mg/kg/day based on decreases in fetal body weight

Inhalation Short-Term (1-30 days) 	NOAEL= 10mg/kg/day	UFA= 3x

UFH=10x

FQPA = UFDB = 10x

	Occupational LOC for MOE = 300	Developmental Toxicity study - rat.

LOAEL = 40 mg/kg/day based on decreases in fetal body weight

Dermal Intermediate Term (1-6 mos) DAF = 0.5%*	NOAEL= 10mg/kg/day	UFA=
3x

UFH=10x

FQPA = UFDB = 10x

	Occupational LOC for MOE = 300	Subchronic oral toxicity study – rat

LOAEL = 40 mg/kg/day based on reduced body weight gains and
histopathological changes in the bone marrow, liver and thyroid

Inhalation Intermediate Term (1-6 mos)	NOAEL= 10mg/kg/day	UFA= 3x

UFH=10x

FQPA = UFDB = 10x

	Occupational 

LOC for MOE = 300	Subchronic oral toxicity study – rat

LOAEL = 40 mg/kg/day based on reduced body weight gains and
histopathological changes in the bone marrow, liver and thyroid

Cancer (all routes)	Not likely to be carcinogenic to humans at doses
that do not alter rat thyroid hormone homeostasis

NOAEL = no observed adverse effect  level   LOAEL = lowest observed
adverse effect level  MOE = margin of exposure

LOC = level of concern  DAF = dermal absorption factor, UFA = 3x =
interspecies scaling factor, reduced from 10x for toxicokinetic reasons,
UFH = 10x = intraspecies variability, UFDB = 10x =  database uncertainty
factor for lack of a developmental thyroid study.  The FQPA safety
factor includes the 10x database uncertainty factor.

* DAF has been revised from 60% to 0.5% based on submitted dermal
absorption studies (MRIDs 47705131, 47705102, 47705101, 47705106).

Developmental Thyroid Study

There is evidence of thyroid toxicity following subchronic and chronic
exposures to rats characterized as histopathological changes in the
thyroid in multiple studies in rats.  Disruption of thyroid homeostasis
is the initial, critical effect that may lead to adverse effects on the
developing nervous system.   

Normally, if a neurodevelopmental concern is raised by existing data on
a pesticide, a rat developmental neurotoxicity (DNT) study is requested.
 However, a DNT study is not required for thiabendazole since this study
would not address thyroid toxicity concerns. Thus, in lieu of the rat
DNT study, a special study is needed to further evaluate the hormonal
responses associated with the developing fetal nervous system.  OPP has
developed guidance for thyroid assays in pregnant animals, fetuses and
postnatal animals, and adult animals. The guidance is not intended to be
prescriptive. The Agency recognizes that registrants may chose to
propose an alternative approach that adequately addresses the issue of
disruption of thyroid hormone homeostasis during development. 
Registrants are encouraged to consult with the Agency during development
of any alternative study protocol or the implementation of the guidance.
 

Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Thiabendazole is not among the group of 58 pesticide active ingredients
on the initial list to be screened under the EDSP.  Under FFDCA sec.
408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:    HYPERLINK
"http://www.epa.gov/endo/" http://www.epa.gov/endo/ .

Neurotoxicity

There is no indication of neurotoxicity in the existing toxicity
database.  However, acute and subchronic neurotoxicity studies are
required , under 40 CFR Part 158 as part of the new data requirements
for registration of a pesticide.  See GLN 870.6100. 

Immunotoxicity

There are no indications in the available studies that organs associated
with immune function, such as the thymus and spleen, are affected by
thiabendazole.  There are no effects seen on the developing immune
system in the existing studies.  An immunotoxicity study is required,
however, under 40 CFR Part 158 as a part of the new data requirements
for registration of a pesticide (food and non-food uses).  See GLN
870.7800.

  TC "2.0	Ingredient Profile" \l 1  4.0	Dietary and Drinking Water
Exposure Assessment

(HED memo of 12/10/09, S. Hummel, D363974)

(HED memo of 11/22/09, T. Morton, D371327)

Enforcement analytical method:  Adequate analytical methodology is
available for data collection and enforcing tolerances of residues of
thiabendazole per se.  PAM Vol. II lists four spectrophotofluorometric
methods (Methods I, A, B, and C) for determining residues of
thiabendazole per se in or on plant commodities.  In all of the methods,
residues are extracted with ethyl acetate, and the extracts are purified
by washing with dilute NaOH and/or HCl.  The LODs range from 0.05-0.1
ppm.

In addition, an HPLC method with fluorescence detection (FLD) is
available for the enforcement of tolerances for residues of free and
conjugated benzimidazole.  This method is listed in the U.S. EPA Index
of Residue Analytical Methods under thiabendazole as Study No. 93020
(MRID 43328302).  The reported LOQ is 0.1 ppm, and the LOD is 0.05 ppm
in wheat grain, straw, and processed wheat commodities.

The FDA PESTDATA database (June 2005) indicates that thiabendazole is
completely recovered using FDA Multiresidue methods 302 and 404, and is
not recovered through method 303.  Thiabendazole was not tested through
method 304.  Data remain outstanding concerning recovery of the
metabolites 5-hydroxy-thiabendazole and benzimidazole through FDA
Multiresidue Protocols as indicated in the Thiabendazole RED. 

Analytical Methods for Data Collection 

Syngenta Crop Protection, Inc. has submitted an LC/MS/MS method,
GRM040.01A, for the determination of residues of thiabendazole and
benzimidazole in crop matrices.  The method was used for data collection
in the submitted U.S. and Canadian corn field trials and the corn
processing study.    The method LOQ is 0.01 ppm, and the LOD is 0.004
ppm.  The registrant adequately explained how the LOQ and LOD were
determined.

Residue Levels

Adequate crop field trial data from the U.S. and Canada have been
submitted to support the proposed seed treatment use on corn.  Residues
of thiabendazole and benzimidazole were below the method LOQ of 0.01 ppm
in all samples of field corn forage, grain, and stover; sweet corn
kernel + cob with husk removed (K+CWHR), and stover; and pop corn grain
and stover from the U.S. field trials, and were non-detectable in all
samples of field corn forage, grain, and stover and sweet corn K+CWHR
and forage from the Canadian field trials.  Although no data were
provided for residues of benzimidazole in the U.S. trials, HED does not
expect detectable residues of benzimidazole in field, sweet, or pop corn
grown from thiabendazole-treated seed.  The available metabolism studies
for thiabendazole in three diverse crops (wheat, soybean, and sugar
beets) indicated that residues of benzimidazole were consistently lower
than residues of the parent compound, thiabendazole in all crop
matrices.  No additional data on residues of benzimidazole in field,
sweet, or pop corn grown from treated seed are required to support the
requested use.  Based on examination of the data, including close
examination of the raw data and chromatograms, HED concludes that there
are not likely to be detectable residues of thiabendazole or its
regulated metabolite, benzimidazole, in field, sweet, or pop corn
commodities grown from seed treated according to the proposed use
pattern.

An adequate field corn processing study was submitted reflecting
analysis of meal, flour, grits, starch, and refined oil (wet and dry
milled) processed from field corn grain grown from seed treated at 5x
the proposed seed treatment rate for corn.  Residues of thiabendazole
were non-quantifiable in corn grain and all processed commodities. 
Therefore, HED concludes that there are not likely to be detectable
residues of thiabendazole or its regulated metabolite, benzimidazole, in
the processed commodities of corn:  meal or wet- or dry-milled refined
oil.

The available and submitted storage stability data are adequate to
support the storage durations and conditions of samples from the corn
crop field trial and processing studies.

Because HED has determined that the proposed seed treatment use on corn
will not result in detectable residues in corn commodities including
livestock feed stuffs, no data pertaining to livestock enforcement
methods, storage stability data, or feeding studies are required to
support this petition.

International Harmonization. Codex has not established maximum residue
limits (MRLs) in any corn commodities.  Therefore there are no Codex
harmonization issues with this petition.  PMRA in Canada is concurrently
reviewing proposed MRLs for corn commodities to be established at 0.01
ppm.  The Canadian residue definition is thiabendazole
(2-(4-thiazolyl)-1H-benzimidazole), while the US residue definition also
includes benzimidazole.   There are no harmonization issues with
Canadian MRLs for corn commodities, since non-detectable residues are
expected.

Conclusions:  Based on examination of the submitted data HED concludes
that there are not likely to be detectable residues of thiabendazole or
its regulated metabolite benzimidazole in field, sweet, or pop corn
commodities grown from treated commodities, in the processed commodities
of field corn (meal and oil), or from rotational crops as a result of
use under the conditions specified under this action.  Therefore, HED
concludes that the proposed tolerances of 0.1 ppm for residues of
thiabendazole or its regulated metabolite benzimidazole in field, sweet,
or pop corn commodities are appropriate.

5.0	Dietary Endpoints

(HED memo of 08/29/07, D. Davis, D343139).

Acute Dietary Endpoint

There was no endpoint in the toxicology database that attributable to a
single dose of thiabendazole, and that an acute risk assessment was not
required for this chemical.  

Chronic Dietary Endpoint

The chronic dietary endpoint decisions made at the June 1 and June 17,
1999 HIARC meetings and used in the most recent thiabendazole risk
assessments remain unchanged.

Endpoint Summary for Dietary Exposure

Thiabendazole toxicological doses and endpoints for dietary risk
assessment purposes are summarized in Table 3.0, above.  

6.0	Dietary Risk 

(HED memo of 12/10/09, T.  Morton, D379937).

(BEAD memo of 11/5/09, A. Grube, D371171)

Acute Dietary Exposure and Risk Assessment

HED has determined that there are no effects seen in the toxicity
database that would be attributable to a single exposure of
thiabendazole; therefore, an acute dietary risk assessment is not
required for this pesticide.

Chronic Dietary Exposure and Risk Assessment

 (ver. 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.
 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.

The dietary exposure assessment conducted for this petition updates the
anticipated residues used in the RED, as 5 years have passed since that
assessment.  All current tolerances plus residues of thiabendazole and
it regulated metabolite in/on corn were included in the analyses. 
Updated percent crop treated and PDP monitoring data from the past five
years were used when available and appropriate for the assessment.  A
chronic dietary assessment was conducted that included anticipated
residues of thiabendazole and its regulated metabolites on corn at the
proposed tolerance level of 0.01 ppm.

Dietary (food plus water) exposure and risks from the proposed use of
thiabendazole as a seed treatment in/on corn, including all existing
tolerances for thiabendazole are summarized in Table 6.0, below.

Table 6.0.  Summary of Dietary (Food and Water) Exposure and Risk for
Thiabendazole (all registered uses plus the proposed use on corn)

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary	Cancer

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

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	N/A	0.000451	1.4

All Infants (< 1 year old)

0.001527	4.6	N/A	N/A

Children 1-2 years old

0.001536	4.7

Children 3-5 years old

0.001252	3.8

Children 6-12 years old

0.000671	2.0

Youth 13-19 years old

0.000289	<1

Adults 20-49 years old

0.000308	<1

Adults 50+ years old

0.000331	1.0

Females 13-49 years old

0.000333	1.0

Cancer Dietary Exposure and Risk Assessment

Thiabendazole has been classified as “not likely to be carcinogenic to
humans at doses that do not alter rat thyroid hormone homeostasis”. 
HED is currently regulating chronic dietary risk with a chronic RfD that
reflects a dose level below dose levels at which thyroid hormone balance
is impacted and consequently is also being protective of potential
carcinogenic effects.  Therefore, a cancer dietary assessment was not
performed.

Conclusions

The chronic dietary risk assessment conducted to support this petition
shows chronic risks were below 1% of the chronic population adjusted
dose for the General U.S. Population, and 1.5% of the chronic population
adjusted dose for the most highly exposed subpopulation, all infants.

Drinking water

(EFED memo of 10/13/09, James K. Wolf, D363978). 

Drinking water was directly included in the Dietary Exposure Analysis. 
A Tier 2 drinking water assessment was conducted for thiabendazole in
surface water and Tier 1 in ground water for the proposed new seed
treatment product on corn.   The annual mean concentration of  0.0000048
ppm was used in the chronic dietary exposure analysis.   Drinking water
concentrations from ground water sources were estimated, but were lower
than that estimated concentration from surface water, so the estimated
concentration from surface water sources was used in the dietary
exposure analysis.

7.0	Residential Exposure and Risk

(AD memo of 6/23/10, T. Leighton, D379421)

There are several thiabendazole uses which may result in residential
exposures – exposures to adults and/or children in residential
settings.   Two antimicrobial exposure scenarios have been assessed for
residential exposures.  The two uses include treated paint and
impregnated sponges.  Other antimicrobial uses of thiabendazole are not
expected to cause exposure in residential settings.  These uses are use
on carpet backing, canvas textiles, wallboard and ceiling tiles,
polyurethane foam, plastics and rubber, paper, and coatings and filters
used in HVAC systems.  These additional uses are not expected to result
in exposures in residential settings because there is no direct contact
to the treated articles, the vapor pressure of thiabendazole is very
low, and the unlikelihood that the treated plastics and rubbers would be
used in toys.

Residential exposure and risk to residential handlers of
thiabendazole-treated paints, using  brush/roller application and
airless sprayer application was assessed.  This exposure is expected to
be short-term in duration.  The dermal MOEs of 17,000 and 6,800 for
brush/roller application and airless sprayer application, respectively,
are not of concern.  The inhalation MOEs of 70,000 and 3,200 for
brush/roller and for airless sprayer applications, respectively, are
also not of concern, since these MOEs are much greater than the target
MOE of 100.

Thiabendazole treated sponges are limited to 600 ppm thiabendazole on a
sponge.  Various residue amounts may be transferred from the sponge to
food contact surfaces, such as countertops and utensils/glassware, and
then to food and subsequently ingested.  A screening-level assessment
was conducted by assuming exposures would be similar to a hard surface
sanitizer.  If we assume that all of the thiabendazole leaches out of
the sponge in a single day, and a new sponge is used every day, then
there may be risks of concern to children.  But if we use the more
realistic assumption that 5% of the thiabendazole is leached out of the
sponge each day, there are no risks of concern (i.e., the exposure  is 
<10 percent cPAD ).

8.0	Aggregate Exposure and Risk Assessment

The FPQA requires that food and water exposures be aggregated or added
to residential exposures.  In the table below, the chronic food and
water exposure is aggregated with the short term exposure for
residential handlers/painters.  In the second table below, the chronic
food/water exposure is aggregated with short/intermediate term exposure
to thiabendazole from treated sponges, since it is unlikely that a
person would consume all of the thiabendazole in a treated sponge each
day, and would continue to do so for a long period of time.

Short- and Intermediate-Term Aggregate Risk

To assess short- and intermediate-term aggregate risk likely to result
from the new and existing thiabendazole uses, HED combined average food
and water exposure values with estimates of residential exposure for
both adult painters and adult females and small children exposed to
surfaces cleaned with treated sponges.  



Table 8.1.  Short- and Intermediate- Term Aggregate Risk Calculations  -
Residential Painter LOC =300

Population Subgroup	Average

Food & Water Exposure

mg/kg/day	Residential Exposure1

mg/kg/day	Aggregate MOE

(food and

residential)2

U.S. Population	0.000451	0.0046	2000

Youth 13-19 yrs	0.000289

2000

Adults 20-49 yrs	0.000308

2000

Adults 50+ yrs	0.000331

2000

Females 13-49 yrs	0.000333

2000

1 Residential Exposure = [Dermal exposure + Inhalation Exposure].  

2 Aggregate MOE = [NOAEL (10 mg/kg/day (Avg Food & Water Exposure
+ Residential Exposure)]

Table 8.2.  Short- and Intermediate- Term Aggregate Risk Calculations  -
LOC =300

Population Subgroup	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure1

mg/kg/day	Aggregate MOE

(food and

residential)2

Fraction of Thiabendazole Transferred Daily From Sponge to Surface =
100%

Children 3-5	0.001252	0.08	120

Females 13-49 yrs	0.000333	0.02	500

Fraction of Thiabendazole Transferred From Sponge to Surface = 5%

Children 3-5	0.001252	0.004	2300

Females 13-49 yrs	0.000333	0.001	4500

1 Residential Exposure = [Dermal exposure + Inhalation Exposure].  

2 Aggregate MOE = [NOAEL (10 mg/kg/day (Avg Food & Water Exposure
+ Residential Exposure)]

A potential risk of concern would be the use of thiabendazole treated
sponges, if the Agency assumes that 100% of the thiabendazole on a
treated sponge is transferred to surfaces each day. Since this is a very
unrealistic assumption, a second aggregate assessment was conducted
assuming that 5% of the thiabendazole on sponges is transferred to the
surface each day. With this assumption, none of the aggregate exposures
represent risks of concern, as all MOEs are greater than the target MOE
of 300.

9.0	Occupational Exposure and Risk

(HED memo of 7/8/10, B. Daiss, D379423)

Toxicological endpoints were selected for occupational exposure via
dermal and inhalation exposure pathways.  Short and intermediate-term
exposures are expected based on use patterns and label provisions. 
Short-term dermal and inhalation exposure endpoints were selected from
an oral developmental toxicity study in rats.  Intermediate-term dermal
and inhalation endpoints were selected from a subchronic oral toxicity
study in rats.  The NOAEL is 10 mg/kg/day for inhalation and dermal,
both short and intermediate term.   A dermal absorption factor of 0.5%
was used in the assessment.  The level of concern (LOC) or target margin
of exposure (MOE) for occupational exposure is 100 (10x for interspecies
extrapolation, 10x for intraspecies variation).  

9.1 Occupational Handlers Exposure and Risk Estimates

Exposure Scenarios

Occupational handler (seed treatment) and post-application (seed
planting) exposure scenarios are assessed for the risk assessment of the
proposed new use on corn seed.  There is potential for short- and
intermediate-term occupational exposure to thiabendazole during mixing,
loading, application, and post-application activities.  Chronic exposure
is not expected for the proposed use patterns.  

The term “handler” applies to individuals who mix, load, and apply
the pesticide product. Handler exposure scenarios evaluated for this
assessment are based on information provided in the Science Advisory
Council for Exposure (Expo SAC) Standard Operating Procedures for Seed
Treatment (SOP No. 14) dated May 1, 2003 and ExpoSAC SOP No. 15, Amount
of Seed Treated or Planted Per Day dated March 2, 2004.  Seed treatment
exposure scenarios evaluated for this assessment are as follows:

	-	Loading/Applying - Flowable concentrate for Seed treatment
applications (single layer clothing with gloves).

	-	Sewing - Flowable concentrate for Seed treatment applications (single
layer clothing with no gloves/ “Baseline”).

	-	Bagging - Flowable concentrate for Seed treatment applications
(single layer clothing with no gloves/ “Baseline”).

	-	Multiple Activities - Flowable concentrate for Seed treatment
applications (single layer clothing with gloves). 

Maximum application rates for all of the exposure scenarios assessed are
based on information provided in the thiabendazole label for the
proposed new use.  The maximum application rate for thiabendazole is
0.05 mg ai/kernel. The unit exposures are based on SOP 14.  The amount
of seed treated per day at commercial facilities is based on SOP 15.  

Exposure Assumptions

	•	Average body weight of an adult handler is 60 kg.

	•	Exposure duration is short-term and intermediate-term for all
workers assessed.  

	•	The maximum label application rate is 0.05 mg ai/kernel.  

	•	Maximum seeds per pound estimates based on SOP 15 are:

1360 seeds/lb for field corn

5000 seeds/lb for sweet corn 

	•	Amount treated per day during commercial seed treatment based on
SOP 15 are: 

	-  	550000 lbs/day for field corn

	- 	194000 lbs/day for sweet corn.

•	PPE assumptions based on SOP 14 are:

	-	Single layer with gloves for loader/applicator and multiple activity
scenarios

	-	Single layer no gloves for sewer and bagger activities.	

			

Handler Risks		

Margins of Exposure (MOEs) for commercial seed treatment
(Loader/Applicators, Sewers, Baggers and Multiple Activities) were
greater than the target of 100 for all exposure scenarios.   Summaries
of the risks for seed treatment are presented in Table 9.1.  

Table 9.1. Estimated Thiabendazole Exposure & MOEs for Short- and
Intermediate-Term Occupational Handler Exposure for Seed Treatment  with
Flowable Concentrate Formulation - Dermal and Inhalation LOC/MOE = 300 

PPEa	Dermal.b (mg/lb ai)	Inhal.b   (ug/lb ai)	Crop	App. Rate

(lb ai/lb seed) c	Amnt. Treatedd

(lbs. day)	Dermal

Dosee (mg/kg)	Inhal.

Dosef

(mg/kg)	Combined

Doseg

(mg/kg)	Agg

M0Eh

Loader/Applicator 

Single Layer gloves	0.023	0.34	Field Corn	0.00015	550000	0.00016	0.0005
0.0006	16000

	Sweet Corn	0.00056	194000	0.00021 	0.0006	0.0008	12000

Sewer

Single Layer no gloves	0.0062	0.23	Field Corn	0.00015	550000	0.00004
0.0003	0.0004	27000

	Sweet Corn	0.00056	194000	0.00006	0.0004	0.0005	21000

Bagger

Single Layer  no gloves	0.0091	0.16	Field Corn	0.000153	550000	0.00006
0.0002	0.0003	35000

	Sweet Corn	0.00056	194000	0.00008	0.0003	0.0004	27000

Multiple Activities

Single Layer gloves	0.042	1.6	Field Corn	0.000153	550000	0.00029	0.0022
0.0025	4000

	Sweet Corn	0.00056	194000	0.00038	0.0029	0.0033	3000

a. PPE (Personal Protection Equipment) – PPE assumptions based on SOP
14

b. Commercial seed treatment dermal and inhalation unit exposure
estimates reported in SOP 14.

c. Application rates based on label rate and SOP 15 maximum seed/lb
estimates e.g., Sweet Corn AR = 0.05 mg ai/kernel x 0.001 g/mg x 0.0022
lb/g x 5000 kernals/lb.  

d. Amount/Seed treated values are based on SOP 15

e. Dermal dose (mg/kg/event) = [unit dermal exposure (mg/lb ai) * dermal
absorption (0.005) * application rate (lb ai/lb seed) * Amount treated /
body weight (60 kg)].

f. Inhalation dose (mg/kg/event) = [unit exposure (kg/lb ai) * (1mg/1000
kg) conversion * appl. rate (lb ai/lbs seed) * Amount treated / body
weight (60 kg)].

g. Combined event dose = dermal dose + inhalation dose.

h. MOE = NOAEL (10 mg/kg/d)/combined dose.  UF = 300.	

	

9.2 Post-Application (Seed Planting) Exposure and Risk Estimates

Exposure Scenarios

Post-application exposure involving Commercial Seed treatment using
thiabendazole consists of a “Planting Treated Seed” activity. 
HED’s SOP 14 is the data source for this “planting scenario”
(which includes exposure to pesticide treated seed during both the
loading of hoppers and driving the equipment).  The post-application
exposure scenario evaluated for this assessment is:

	-	Seed Planting - Flowable concentrate for Seed treatment applications
{single layer clothing with gloves).

Exposure Assumptions

	•	Average body weight is 60 kg.

	•	Amount of seed planted per day is based on SOP 15 is 3000 lb/day
for both field and sweet corn.  

	

Post-Application Risks

Margins of Exposure (MOEs) for planting treated seed were greater than
the target of 100 for all exposure scenarios.   Summaries of the risks
for seed treatment are presented in Table 7.2.  

Table 9.2. Estimated Thiabendazole Exposure & MOEs for Short- and
Intermediate-Term Occupational Handler Exposure for Planting Treated
Seed  - Dermal and Inhalation LOC/MOE = 300 

PPEa	Dermal.b (mg/lb ai)	Inhal.b   (ug/lb ai)	Crop	App. Rate

(lb ai/lb seed) c	Amnt. Treatedd

(lbs. day)	Dermal

Dosee (mg/kg)	Inhal.

Dosef

(mg/kg)	Combined

Doseg

(mg/kg)	Agg

M0Eh

Loader/Applicator

Single Layer  gloves	0.25	3.4	Field Corn	0.000153	3000	0.00001	0.00003
0.00004	280000

	Sweet Corn	0.00056	3000	0.00004	0.0001	0.0001	77000

a. PPE (Personal Protection Equipment) – PPE assumptions based on SOP
14

b. Commercial seed treatment dermal and inhalation unit exposure
estimates reported in SOP 14.

c. Application rates based on label rate and SOP 15 maximum seed/lb
estimates e.g., Sweet Corn AR = 0.05 mg ai/kernel x 0.001 g/mg x 0.0022
lb/g x 5000 kernals/lb.  

d. Amount/Seed treated values are based on SOP 15

e. Dermal dose (mg/kg/event) = [unit dermal exposure (mg/lb ai) * dermal
absorption (0.005) * application rate (lb ai/lb seed) * Amount treated /
body weight (60 kg)].

f. Inhalation dose (mg/kg/event) = [unit exposure (kg/lb ai) * (1mg/1000
kg) conversion * appl. rate (lb ai/lbs seed) * Amount treated / body
weight (60 kg)].

g. Combined event dose = dermal dose + inhalation dose.

h. MOE = NOAEL (10 mg/kg/d) / combined dose.  UF = 300.	

Cumulative Exposure

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether
to establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the 

cumulative effects of a particular pesticide's residues and “other
substances that have a common mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether
thiabendazole has a common mechanism of toxicity with other substances. 
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 thiabendazole and any other
substances and, thiabendazole does not appear to produce a toxic
metabolite produced by other substances which have tolerances in the U.
S.  For the purposes of this tolerance reassessment action, therefore,
EPA has not assumed that thiabendazole 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 OPP 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/fedrgstr/EPA_PEST/2002/January/Day_16/"
http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/ .

11.0	Regulatory Recommendations

HED concludes that the proposed tolerances of 0.01 ppm for residues of
thiabendazole or its regulated metabolite benzimidazole in field, sweet,
or pop corn commodities grown from treated commodities are supported, a
safety finding can be made, and the proposed tolerances can be
established. No changes in commodity terminology are needed.

The following label changes and data are required as conditions of
registration.

The registrant should revise the label to include the use rates in terms
of weight of product per weight of seed (e.g. g/100 kg seed).

Neurotoxicity Screening Battery (GLN 870.6100) is required as a
condition of registration.

An immunotoxicity study (GLN 870.7800) is required as a condition of
registration.

A Developmental Thyroid Study (Special Study) is required as a condition
of registration.

Data remain outstanding concerning recovery of the metabolites
5-hydroxy-thiabendazole and benzimidazole through FDA Multiresidue
Protocols as indicated in the Thiabendazole RED.  (GLN 860.1360)

References

AD memo of 6/23/10, T. Leighton, Thiabendazole:  Antimicrobial
Residential Uses for Consideration in the Aggregate Assessment to be
Developed by USEPA/OPP/HED.  D379421.

Hazard Science Policy Council, Interim Guidance of 11/1/05, Thyroid
Disrupting Pesticides:  Use of Rat Thyroid Data and Application of
Uncertainty Factors for RfD Derivation

HED memo of 7/8/10, B. Daiss, “Thiabendazole: Occupational Exposure
Assessment for the Use of Thiabendazole as a Seed Treatment for Corn.”
 D379423. 

HED memo of 12/10/09, S. Hummel, “Thiabendazole.  Evaluation of
Residue Chemistry Data to Support a Threshold of Regulation Decision for
a Section 3 Registration for Seed Treatment Use on Corn.  Summary of
Analytical Chemistry and Residue Data”. D363974.

HED memo of 7/8/10, T.  Morton, “Thiabendazole.  Chronic Aggregate
Dietary Exposure and Risk Assessment for the Section 3 Registration
Request for Use of Thiabendazole as a Seed Treatment on Corn”. 
D379937.

HED memo of 08/29/07, D. Davis, “THIABENDAZOLE:  Final Threshold of
Regulation Decision to Support Proposed New Use as a Seed Treatment for
Dry Pea”. D343139. 

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EFED memo of 10/13/09, James K. Wolf , “Drinking Water Assessment for
Maxim® Quatro fungicide (EPA Reg. No. 100-RGLE)) a new fungicide for
field corn, sweet corn, and pop corn”. 

D363978.

Appendix I 	STUDIES REVIEWED FOR ETHICAL CONDUCT

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database,
Version 1.1.  Task Force members Health Canada, U.S. Environmental
Protection Agency, and the National Agricultural Chemicals Association,
released February, 1995. 

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