Document ID: EPA-HQ-OPP-2007-0546-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-03T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 	August 29, 2007

MEMORANDUM

SUBJECT:	THIABENDAZOLE:  Final Threshold of Regulation Decision to
Support 			Proposed New Use as a Seed Treatment for Dry Pea.  

		Petition No: PP#1E6323.  D343139.

FROM:	Donna S. Davis, Chemist

		Reregistration Branch 1

		Health Effects Division (7509P)

			

THROUGH:	Michael S. Metzger, Chief

		Reregistration Branch 1

		Health Effects Division (7509P)

		Christina Swartz, Chief

		Registration Action Branch 2

		Health Effects Division (7509P)

TO:		Susan Stanton

		Barbara Madden

		Risk Integration, Minor Use, Emergency Response Branch

	            Registration Division (7505P)

Attached please find the final documentation to support a Threshold of
Regulation Decision for the proposed new use for thiabendazole as a seed
treatment for dry pea.  This memorandum supersedes the HED review of
June 7, 2007 entitled THIABENDAZOLE:  Revised Threshold of Regulation
Decision to Support Proposed New Use as a Seed Treatment for Dry Pea. 
(D340418, D. Davis).

1.0	Executive Summary

The Agency Threshold of Regulation Policy states that a use may be below
the threshold of regulation if the following two conditions are met. 
First, using a reliable and appropriately sensitive analytical method to
measure residues in the commodity, no resides are detected in the
commodity under the expected conditions of use.  Secondly, the estimated
potential risk of any theoretically possible residues in food is not of
concern.  

HED concludes that there are not likely to be detectable residues of
thiabendazole or its regulated metabolite, benzimidazole in/on dry pea
grown from treated seed, or in/on rotational crops as a result of use
under the conditions specified in this petition.

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 chemical.

The chronic dietary risk assessment conducted supports the TOR policy
requirement that the use of thiabendazole as a seed treatment in/on dry
pea poses minimal risk since the chronic risks were significantly below
the TOR policy threshold of 0.1% of the chronic population adjusted
dose.

Thiabendazole is 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.

Regulatory Recommendations

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

The petitioner must amend the label for the 30% FlC to include the
restriction “Do not feed vines or hay grown from treated seed to
livestock.”

The draft labeling contains a use on chick peas at 0.32 lb ai/100 lb
seed.  No data have been provided to support that use.  The petitioner
must either remove that use from the label or provide residue data
reflecting that use rate prior to registration of the higher application
rate on chick peas.

Provided the label revisions noted above are made, and further, provided
that there are no risk issues identified in the forthcoming occupational
risk assessment, HED concludes that the requested use of thiabendazole
as a seed treatment for use on dry pea is below the threshold of
regulation.  Therefore; while HED has determined that this is a food
use, consistent with the TOR policy, a tolerance is not required.  

2.0	Background

  SEQ CHAPTER \h \r 1 Thiabendazole [2-(4-thiazolyl) benzimidazole] is a
systemic benzimidazole fungicide used to control fruit and vegetable
diseases such as mold, rot, blight and stain.  

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of CA and ID and the U.S.A. Dry Pea and
Lentil Council has proposed, in PP#1E6323, the establishment of
permanent tolerances for residues of the fungicide thiabendazole
[2-(4-thiazolyl) benzimidazole], in/on “Peas (dry)” at 0.05 ppm
resulting from the use as a seed treatment.

In June of 2001, HED completed a human health risk assessment for the
active ingredient, thiabendazole for the Reregistration Eligibility
Decision (RED) document.  

In its review of this Section 3 request, HED has identified the proposed
seed treatment use of thiabendazole in/on dry pea as a use which may
meet the criteria developed under the Agency’s Threshold of Regulation
policy for a food use which does not require a tolerance.  In support of
that regulatory approach, this memorandum documents the likelihood of
detectable residues and the dietary risk likely to result from the
subject use of thiabendazole.  

3.0 	Threshold of Regulation Policy

In the Federal Register of October 27, 1999 (64 FR 57881), the EPA
announced its Threshold of Regulation (TOR) Policy.  This policy
recommended factors to consider and procedures to use when determining
whether a use of a pesticide in a location and manner that has the
possibility of resulting in residues in food is below the threshold of
regulation, that is, does not need a tolerance.  The policy stated that
a use may be below the threshold of regulation if the following two
conditions are met.  First, using a reliable and appropriately sensitive
analytical method to measure residues in the commodity, no resides are
detected in the commodity under the expected conditions of use. 
Secondly, the estimated potential risk of any theoretically possible
residues in food is not of concern.  

The Office of Pesticide Programs (OPP) has developed a draft Standard
Operating Procedure (SOP) for the implementation of the Threshold of
Regulation Policy.  That SOP provides additional guidance on determining
if a food use might fall under the scope of the TOR policy. 
Additionally, the implementation guidance directs HED to conduct dietary
risk assessments to determine if the subject food use poses minimal
risk.  The SOP defines minimal risk as acute and chronic dietary risks
which are equal to, or less than 0.1% of both the acute and chronic
population adjusted doses.

  TC \l1 "2.0	Ingredient Profile 4.0	“No Detectable Residues”
Determination 

Thiabendazole.  Petition for the Establishment of a Permanent Tolerance
for Use on Dry Pea.  Summary of Analytical Chemistry and Residue Data. 
PP#1E6323.   D. Davis, 10/11/06, D315435

Proposed Use

IR-4 is requesting establishment of a tolerance for residues of
thiabendazole in/on dry pea to support the use of thiabendazole as a
single seed treatment application of the 30% flowable concentrate (FlC)
formulation at 0.075 lbs ai/100 lbs seed.  The proposed use directions
for dry pea are summarized in Table 4.1, below.  

Table 4.1  Summary of Directions for Use of Thiabendazole on Dry Pea.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 	Max. No. Applic. per Season	Max. Seasonal
Applic. Rate	PHI

(days)	Use Directions and Limitations

Dry pea (including field pea), pigeon pea, chickpea and lentil

Seed application	30% FlC

[7501-134]	0.075 lb ai/100 lb seed	1	0.075 lb ai/100 lb seed	Not
applicable	Applications are to be made as a spray mist or slurry
treatment maintained under constant agitation.  Treated seed is to be
planted as late in the spring as possible.

The proposed label states that treated seed must be colored with an
approved dye, cannot be used for food, feed, or oil purposes, and must
bear the following labeling:  “This seed is treated with Thiabendazole
at the manufacturer’s recommended rate.  Not for human or animal
consumption.  Do not use treated seed for food, feed, or oil
purposes.”  The product is not to be tank mixed with any pesticide
unless adequate physical compatibility and phytotoxicity tests have been
completed and proved to be satisfactory.  No rotational crop
restrictions are specified.

The submitted data reflect residues of thiabendazole in/on dry pea seed
following seed treatment according to the proposed use pattern.

The proposed use on dry pea includes field pea.  The petitioner must
amend the label for the 30% FlC to include the restriction “Do not
feed vines or hay grown from treated seed to livestock.  Additionally,
the draft labeling contains a use on chick peas at 0.32 lb ai/100 lb
seed.  No data have been provided to support that use.  The petitioner
must either remove that use from the label or provide residue data
reflecting that use rate prior to registration of the higher application
rate on chick peas.

Residue Chemistry Data

Crop Field Trial DER for Dry Pea.  MRID 454282-01, D. Davis,
45428201.der

IR-4 submitted field trial data for thiabendazole on dry pea.  A total
of five field trials were conducted in Zone 11 (2 trials in ID and 3
trials in WA) during the 1996 growing season.  Thiabendazole (30% FlC
formulation) was formulated with water and seed dye and applied to dry
pea seed at a seed treatment facility, at a nominal rate of 0.075 lb
ai/100 lb seed.  Treated seed was planted within 10 days of seed
treatment, and samples of dry pea were collected from the field trial
sites at maturity, 83-90 days after planting. 

Samples of dry pea were analyzed for residues of thiabendazole per se
using an HPLC/FLD method.  The lower limit of the method validation
(LLMV) was 0.05 ppm; the LOD was not reported, however sufficient sample
chromatograms were provided to allow the reviewer to estimate the method
limit of detection (LOD) at <0.02 ppm.  This method was adequately
validated and determined appropriate for use as a data collection method
based on acceptable concurrent recovery data.

The maximum storage interval for dry pea samples from harvest to
analysis was 856 days (28.2 months).  To support sample storage
conditions and intervals, the petitioner conducted a concurrent storage
stability study which indicated that residues of thiabendazole in/on dry
pea were stable for up to 857 days of frozen storage.

Duplicate samples were analyzed for residues of thiabendazole at each of
the five field trial locations.  Residues of thiabendazole were less
than the method LOD of 0.02 ppm in all ten field trial samples. 

No data were provided on residues of benzimidazole, a regulated
metabolite of thiabendazole in/on dry pea grown from treated seed. 
However, HED notes that in three diverse crops, wheat, soybean and sugar
beets, residues of benzimidazole were consistently less than residues of
the parent compound, thiabendazole.  Since the proposed use is for a
seed treatment application, and since residues of parent compound were
below the limit of detection, HED concludes that residues of
benzimidazole are not likely to be detectable in dried peas grown from
thiabendazole treated seed.

Although no data were submitted reflecting residues of thiabendazole
in/on field pea vine and forage, these data will not be required if the
petitioner revises the proposed use pattern to include a restriction
against the feeding of pea vines and hay to livestock. 

Residues in the Primary Crop

HED concludes that the analytical method used to determine residues of
thiabendazole is sufficiently sensitive and has been adequately
validated for the purpose of making a threshold of regulation
determination.  Based on the data summarized above, HED concludes that
there are not likely to be detectable residues of thiabendazole or its
regulated metabolite, benzimidazole in/on dry pea grown from seed
treated under the proposed use conditions stated in the subject
petition.

Processed Commodities

The TOR implementation SOP directs HED to determine if there are likely
to be residues in processed commodities derived from the subject raw
agricultural commodity (RAC).  Since there are no processed commodities
associated with dry pea in which residues could concentrate, detectable
residues are not expected in processed commodities.

Rotational Crop Residues

The TOR SOP directs HED to determine if there are likely to be
detectable residues in rotational crops as a result of the proposed use.
 Given that this use is for a seed treatment as opposed to a soil-type
application, and further given that there are no detectable residues in
the primary crop grown from treated seed, HED concludes that it is
unlikely that there will be detectable residues of thiabendazole and its
regulated metabolite, benzimidazole in/on rotational crops as a result
of the requested seed treatment use in/on dry pea. 

Conclusion

HED concludes that there are not likely to be detectable residues of
thiabendazole or its regulated metabolite, benzimidazole in/on dry pea
grown from treated seed, or from rotational crops as a result of use
under the conditions specified in this petition.  Therefore; HED
concludes that the proposed use of thiabendazole as a seed treatment
satisfies the first condition that there be no detectable residues in
order to be regulated under the TOR policy. 

 

5.0	Dietary Endpoints

Revised Acute Dietary Endpoint

THIABENDAZOLE – Revised Acute Dietary Endpoint Selection; TXR 0054506;
1/23/07; D. Davis

On October 23, 2006, the thiabendazole risk assessment team met with HED
senior leadership to reevaluate the existing toxicology database with
respect to the acute dietary endpoints selected for risk assessment. 
The senior leadership team considered the previous report of the HIARC
(7/21/1999, P. Gaunt) as well as study DERs and concluded that,
consistent with current HED policy, reduced fetal weights/decreased
maternal body weights were not effects that were likely to occur after a
single dose of a pesticide; therefore, these endpoints were not
appropriate for acute dietary risk assessments for the general
population or for females 13+.  The senior leadership group reviewed the
toxicology database to determine if there were endpoints appropriate for
acute risk assessment.  The group gave careful consideration to the
reproductive and developmental effects noted in the database and in
literature citations; however, concluded that those effects were only
observed at very high doses and were not appropriate for risk assessment
at the exposures expected for thiabendazole.

The senior leadership group concluded that there was no endpoint in the
toxicology database that was attributable to a single dose of
thiabendazole, and that an acute risk assessment was not required for
this chemical.  This finding supersedes the endpoint selection decisions
made at the June 1 and June 17, 1999 HIARC meetings documented in the P.
Gaunt memorandum dated 7/21/06 with respect to acute dietary risk
assessments.

Chronic Dietary Endpoint

The chronic dietary endpoint decisions made at the June 1 and June 17,
1999 HIARC meetings documented in the P. Gaunt memorandum dated 7/21/06
and used in the most recent thiabendazole risk assessment of June 2001
remain unchanged.

Cancer

Thiabendazole is 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.  A separate risk assessment for cancer is not
required.

 

FQPA SF

As noted in the June 2001 risk assessment, the FQPA safety factor for
thiabendazole was reduced to 1X.  The toxicology database for
thiabendazole is considered complete.  Further, the data submitted to
the Agency, as well as those from published literature, demonstrate no
increased susceptibility in rats, rabbits, or mice to in utero and/or
early postnatal exposure to thiabendazole.  In the prenatal
developmental toxicity studies in rats, rabbits, and mice and in the
two-generations reproduction study in rats, developmental effects in the
fetuses or neonates occurred at or above doses that caused maternal or
parental toxicity.  A developmental neurotoxicity study with
thiabendazole is not required.  Finally, there are no residual
uncertainties in the exposure data that would result in an underestimate
of risk.

Endpoint Summary for TOR Determination

Thiabendazole toxicological doses and endpoints for dietary risk
assessment purposes are summarized in Table 5.1, below.  



Table 5.1.  Summary of Thiabendazole Dietary Endpoints

Exposure Scenario	Point of Departure	Uncertainty/

FQPA Factor	RfD, PAD, Level of Concern	Study and Toxic Effects

Acute Dietary

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

Chronic Dietary	NOAEL =

10 mg/kg/day	UFA = 10

UFH = 10	cRfD =

0.1 mg/kg/day

cPAD =

0.1 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

Cancer	Classified as “not likely to be carcinogenic to humans at doses
that do not alter rat thyroid hormone homeostasis”

6.0	Dietary Risk 

Thiabendazole Dietary Exposure and Risk Assessments to Support a
Threshold of Regulation Decision for the Use of Thiabendazole as a Seed
Treatment on Dry Pea.  D339855, D. Davis

As recommended by the draft Standard Operating Procedure (SOP) for the
implementation of the Threshold of Regulation Policy, dietary risk
assessments should demonstrate that the use poses minimal risk, a level
defined in the SOP as risks less than 0.1% of both the acute population
adjusted dose (aPAD) and chronic population adjusted dose (cPAD). 

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 needed
for this chemical.

Chronic Dietary Exposure and Risk Assessment

EM-FCID™,Version 2.03 which incorporates consumption data from
USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII),
1994-1996 and 1998.  

As recommended by the TOR SOP, only residues of thiabendazole in/on dry
pea were included in the analyses.  A chronic dietary assessment was
conducted that included residues of thiabendazole on dry pea at ½ the
limit of detection (LOD), which is 0.01 ppm.

Dietary exposure and risks from the proposed use of thiabendazole as a
seed treatment in/on dry pea are summarized in Table 6.1, below.

Assuming a theoretical potential residue of 0.01 ppm in/on dry pea with
100% crop treated resulted in an exposure value of “0.000000” for
the general population and for all subpopulations of concern.  The
estimated chronic risk for the U.S. population and all subpopulations of
concern is significantly below the TOR maximum risk level of 0.1% of the
cPAD.  

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.

Table 6.1.  Summary of Dietary (Food Only) Exposure and Risk for
Thiabendazole

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	No acute risk	0.000000	<0.01	Not required

All Infants (< 1 year old)

0.000000	<0.01	N/A	N/A

Children 1-2 years old

0.000000	<0.01

Children 3-5 years old

0.000000	<0.01

Children 6-12 years old

0.000000	<0.01

Youth 13-19 years old

0.000000	<0.01

Adults 20-49 years old

0.000000	<0.01

Adults 50+ years old

0.000000	<0.01

Females 13-49 years old

0.000000	<0.01

Conclusions

The chronic dietary risk assessment shows that the use of thiabendazole
as a seed treatment in/on dry pea poses minimal risk, since the chronic
risks were significantly below 0.1% of the chronic population adjusted
dose.

7.0	Occupational Exposure and Risk

Occupational Exposure and Risk will be addressed in a separate
forthcoming memorandum.

8.0	Regulatory Recommendations

The Threshold of Regulation decision presented in this document pertains
to dry pea (including field pea), pigeon pea, chickpea, and lentil.  The
commodity definition in for regulatory purposes is “pea, dry, pigeon
pea, chickpea, lentil”.

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

The petitioner must amend the label for the 30% FlC to include the
restriction “Do not feed vines or hay grown from treated seed to
livestock.”

The draft labeling contains a use on chick peas at 0.32 lb ai/100 lb
seed.  No data have been provided to support that use.  The petitioner
must either remove that use from the label or provide residue data
reflecting that use rate prior to registration of the higher application
rate on chick peas.

Provided the label revisions noted above are made, and further, provided
that there are no risk issues identified in the forthcoming occupational
risk assessment, HED concludes that the requested use of thiabendazole
as a seed treatment for use on dry pea is below the level of regulatory
concern.  Therefore; while HED has determined that this is a food use,
consistent with the TOR policy, a tolerance is not required.  

Thiabendazole             Revised Threshold of Regulation Decision to
Support New Use on Dry Pea               D343139

 

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