Document ID: EPA-HQ-OPP-2007-0546-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-03T04:00Z

SEQ CHAPTER \h \r 1 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF              

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES 

MEMORANDUM

DATE:  	24- MAY-2007  

SUBJECT:	Thiabendazole Acute and Chronic Dietary Exposure and Risk
Assessments to Support a Threshold of Regulation Decision for the Use of
Thiabendazole as a Seed Treatment on Dry Pea.

PC Code:  060101			Decision Number:  330771

D339855

REVIEWER:	Donna S. Davis, Chemist

Reregistration Branch 1/Health Effects Division (7509P)

THROUGH:	Sheila Piper, Chemist

Dietary Exposure Science Advisory Council (DESAC)

Health Effects Division (7509P)

		Toiya Goodlow, Chemist

Michael S. Metzger, Chief

Reregistration Branch 1/Health Effects Division (7509P)

Christina Swartz, Chief

Registration Action Branch 2/ Health Effects Division (7509P)

TO:		Barbara Madden

		Stacey Groce/Dan Rosenblatt

		Risk Integration, Minor Use, Emergency Response Branch

	            Registration Division (7505P)

Executive Summary

As required by the draft Standard Operating Procedure (SOP) for the
implementation of the Threshold of Regulation (TOR) Policy, dietary risk
assessments are required to 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). 

The acute and chronic dietary risk assessments conducted support the TOR
policy requirement that the use of thiabendazole as a seed treatment
in/on dry pea poses minimal risk, as both acute and chronic risks were
significantly below the TOR policy threshold of 0.1% of the acute and
chronic population adjusted doses.

Thiabendazole is classified as “not likely to be carcinogenic to
humans at doses that do not alter rat thyroid hormone homeostasis”;
therefore, quantification of human cancer risk is not required and a
cancer dietary assessment was not performed.

I.	Introduction

In the Federal Register of October 27, 1999 (64 FR 57881), the EPA
announced its Threshold of Regulation (TOR) Policy.  This policy
established 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.  The policy stated that a use may be below the threshold of
regulation if, in addition to other criteria, 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 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.

HED is currently reviewing a Section 3 request for the use thiabendazole
as a seed treatment for dry pea.  HED believes that this use may be a
candidate for a threshold of regulation approach.  In support of that
regulatory approach, this memorandum documents the dietary exposure and
risk assessments that were conducted to determine if the use of
thiabendazole as a seed treatment for dry pea poses minimal risk as
defined in the TOR SOP.  

II.	Residue Information

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.  Further, the residue data
were supported by adequate storage stability data.

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; 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.

As directed by the TOR SOP, only residues of thiabendazole in/on dry pea
were included in the analyses. Acute and chronic assessments were
conducted that included residues of thiabendazole on dry pea at ½ the
limit of detection (LOD), which is 0.01 ppm.

DEEM-FCID™ Program and Consumption Information

Thiabendazole TOR acute and chronic dietary exposure assessments were
conducted using the Dietary Exposure Evaluation Model software with the
Food Commodity Intake Database DEEM-FCID™,Version 2.03 which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

IV.	Toxicological Information

The thiabendazole toxicological doses and endpoints for dietary risk
assessment purposes are summarized in the table below.  



Table 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

(females 13 – 49 years)	NOAEL = 150 mg/kg/day	UFA = 10

UFH = 10	aRfD =

1.5 mg/kg/day

aPAD =

1.5 mg/kg/day	Developmental Study in the Rabbit

LOAEL = 600 mg/kg/day based on increase in total number of resorptions

Acute Dietary

(general population)	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”

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  RfD = reference dose.  

V.	Results/Discussion 

Acute Dietary Exposure and Risk Assessment

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
females 13 – 49 years of age, the subpopulation of concern for this
risk assessment.    The estimated acute risk for females 13 – 49 years
of age is significantly below the TOR maximum risk level of 0.1% of the
aPAD.  The output from the acute dietary exposure and risk assessment is
included as Attachment 1 of this review and the results are summarized
in Table 2, below.   

Chronic Dietary Exposure and Risk Assessment

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.  The output from the chronic dietary exposure and risk assessment
is included as Attachment 2 of this review and the results are
summarized in Table 2, below. 

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 2.  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	N/A	0.000000	<0.01

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	0.000000	<0.01

VI.	Conclusions

The acute and chronic dietary risk assessments conducted support the TOR
policy requirement that the use of thiabendazole as a seed treatment
in/on dry pea poses minimal risk, as both acute and chronic risks were
significantly below the TOR policy threshold of 0.1% of the acute and
chronic population adjusted doses.

VII.	List of Attachments

Attachment 1.  Acute Dietary Assessment Dry Pea Only 

Attachment 2.  Chronic Dietary Assessment Dry Pea Only

Attachment 1.  Acute Dietary Assessment – Dry Pea Only

U.S. Environmental Protection Agency                                
Ver. 2.02

DEEM-FCID Acute analysis for THIABENDAZOLE

Residue file name: C:\Documents and Settings\ddavis05\DEEM
files\thiabend dry pea only.R98

Analysis Date 05-15-2007             Residue file dated:
05-15-2007/07:43:14/8

Reference dose: aRfD = 1.5 mg/kg bw/day  NOEL = 150 mg/kg bw/day

Comment: Cancer POD is 10 mg/kg/day

------------------------------------------------------------------------
--------

  EPA    Crop                                   Def Res     Adj.Factors 
 Comment

  Code    Grp  Food Name                         (ppm)       #1    #2   

-------- ---- -------------------------------  ----------  ------ ------
 -------

06032560 6C   Pea, dry                           0.010000   1.000  1.000
 1/2 es

          Full comment: 1/2 estimated LOD; 100% CT

06032561 6C   Pea, dry-babyfood                  0.010000   1.000  1.000
 1/2 es

          Full comment: 1/2 estimated LOD; 100% CT

U.S. Environmental Protection Agency                                 
Ver. 2.02

DEEM-FCID ACUTE Analysis for THIABENDAZOLE                      
(1994-98 data)

Residue file: thiabend dry pea only.R98           Adjustment factor #2
NOT used.

Analysis Date: 05-15-2007/07:44:08    Residue file dated:
05-15-2007/07:43:14/8

NOEL (Acute) = 150.000000 mg/kg body-wt/day

Daily totals for food and foodform consumption used.

Run Comment: "Cancer POD is 10 mg/kg/day"

========================================================================
=======

Summary calculations (per capita):

      95th Percentile             99th Percentile             99.9th
Percentile

 Exposure  % aRfD     MOE    Exposure  % aRfD     MOE    Exposure  %
aRfD     MOE  

---------- ------- -------- ---------- ------- -------- ----------
------- --------

Females 13-50 yrs:

  0.000000   0.00 >1000000    0.000000    0.00 >1000000    0.000007  
0.00 >1000000  

Attachment 2.  Chronic Dietary Assessment Dry Pea Only

U.S. Environmental Protection Agency                                
Ver. 2.00

DEEM-FCID Chronic analysis for THIABENDAZOLE                     
1994-98 data

Residue file: C:\Documents and Settings\ddavis05\DEEM files\thiabend dry
pea only.R98

                                                           Adjust. #2
NOT used

Analysis Date 05-15-2007             Residue file dated:
05-15-2007/07:43:14/8

Reference dose (RfD) = 0.1 mg/kg bw/day

------------------------------------------------------------------------
--------

Food Crop                                       Residue      
Adj.Factors      Comment

EPA Code  Grp  Food Name                          (ppm)       

                                                             #1        
#2 

-------- ---- -------------------------------   ---------- ------    
------   -------

06032560 6C   Pea, dry                           0.010000   1.000     
1.000   1/2 es

  Full comment: 1/2 estimated LOD; 100% CT

06032561 6C   Pea, dry-babyfood                  0.010000   1.000     
1.000   1/2 es

  Full comment: 1/2 estimated LOD; 100% CT

U.S. Environmental Protection Agency                                
Ver. 2.00

DEEM-FCID Chronic analysis for THIABENDAZOLE                    (1994-98
data)

Residue file name: C:\Documents and Settings\ddavis05\DEEM
files\thiabend dry pea only.R98

                                                 Adjustment factor #2
NOT used.

Analysis Date 05-15-2007/07:45:11     Residue file dated:
05-15-2007/07:43:14/8

Reference dose (RfD, Chronic) = .1 mg/kg bw/day

========================================================================
=======

                    Total exposure by population subgroup

------------------------------------------------------------------------
-------

                                                    Total Exposure

                                        
-----------------------------------

          Population                         mg/kg             Percent
of   

           Subgroup                       body wt/day             Rfd   
   

--------------------------------------   -------------      
---------------

U.S. Population (total)                     0.000000                
0.0%

All infants (< 1 year)                      0.000000                
0.0%

Children 1-2 yrs                            0.000000                
0.0%

Children 3-5 yrs                            0.000000                
0.0%

Children 6-12 yrs                           0.000000                
0.0%

Youth 13-19 yrs                             0.000000                
0.0%

Adults 20-49 yrs                            0.000000                
0.0%

Adults 50+ yrs                              0.000000                
0.0%

Females 13-49 yrs                           0.000000                
0.0%

------------------------------------------------------------------------
-------

Thiabendazole	      Dietary Exposure and Risk Assessment	               
D339855	

PC Code:  060101	    	

________________________________________________________________________
______________

Page   PAGE  1  of   NUMPAGES  8 

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