UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date:		August 26, 2014

SUBJECT:	Thiabendazole: Human Health Risk Assessment for the Requested Increase in the Currently Registered Seed Treatment Use Rate on Soybeans and the New Section 3 Uses of Thiabendazole for Seed Treatment on Assorted Vegetables and Small Grains Including:  Vegetable, Root (Except Sugar Beet), Subgroup1B; Radish Tops; Onion, Bulb, Subgroup 3-07A; Brassica, Head and Stem, Subgroup 5A; Vegetable, Cucurbit Group 9; Alfalfa; Spinach; and a Number of Small Grains (Barley, Oats, Rye, and Triticale).

PC Code:  060101
DP Barcode:  416471
Decision No.:  476711
Registration No.:  100-889, 100-963
Petition No.:  3F8166
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  2670
TXR No.:  NA
CAS No.:  148-79-8
MRID No.:  NA
40 CFR:  180.242

FROM:	Jessica Kidwell, Risk Assessor
		Bonnie Cropp-Kohlligian, Dietary Exposure
		Abdallah Khasawinah, PhD., Toxicologist
		Susan Hummel, Chemist
		Kelly O'Rourke, Occupational/Residential Exposure Assessor
		Risk Assessment Branch 4
		Health Effects Division (7509P)

THROUGH:	Elissa Reaves, PhD, Branch Chief
		Risk Assessment Branch 4
		Health Effects Division (7509P)

TO:		Tony Kish/Rosemary Kearns, RM 22
		Fungicide Branch
      Registration Division (7505P)

	The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment for the proposed seed treatment use of thiabendazole on Alfalfa, Brassica, Bulb Vegetables, Cucurbits, Root Vegetables, Small Grain Cereals, Spinach and Soybeans. The product to be used is Mertect 34F, a 42.3% (4.1 lb ai/gal) flowable concentrate formulation (EPA Reg. No. 100-889). The uses are to be added to the Thiabendazole Technical label, as well (EPA Reg. No. 100-963.

1.0	Executive Summary	4
2.0	HED Recommendations	8
2.1	Data Deficiencies/Conditions of Registration	8
2.2	Tolerance Considerations	9
2.2.1	Enforcement Analytical Method	9
2.2.2	International Harmonization	9
2.2.3	Recommended Tolerances	9
2.2.4	Revisions to Petitioned-For Tolerances	11
2.3	Label Recommendations	12
2.3.1	Recommendations from Residue Reviews	12
2.3.2	Recommendations from Occupational Assessment	12
2.3.3	Recommendations from Residential Assessment	12
3.0	Introduction	12
3.1	Chemical Identity	12
3.2	Physical/Chemical Characteristics	13
3.3	Pesticide Use Pattern	13
3.4	Anticipated Exposure Pathways	14
3.5	Consideration of Environmental Justice	15
4.0	Hazard Characterization and Dose-Response Assessment	15
4.1	Toxicology Studies Available for Analysis	15
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	16
4.2.1	Dermal Absorption	16
4.3	Toxicological Effects	17
4.4	Safety factor for Infants and Children (FQPA Safety Factor)	18
4.4.1	Completeness of the Toxicology Database	19
4.4.2	Evidence of Neurotoxicity	19
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	19
4.4.4	Residual Uncertainty in the Exposure Database	19
4.5	Toxicity Endpoint and Point of Departure Selections	20
4.5.1	Dose-Response Assessment	20
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	21
4.5.3	Cancer Classification and Risk Assessment Recommendation	21
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	22
4.6	Endocrine Disruption	25
5.0	Dietary Exposure and Risk Assessment	26
5.1	Metabolite/Degradate Residue Profile	26
5.1.1	Summary of Plant and Animal Metabolism Studies	26
5.1.2	Summary of Environmental Degradation	26
5.1.3	Comparison of Metabolic Pathways	26
5.1.4	Residues of Concern Summary and Rationale	27
5.2	Food Residue Profile	28
5.3	Water Residue Profile	32
5.4	Dietary Risk Assessment	33
5.4.1	Description of Residue Data Used in Dietary Assessment	33
5.4.2	Percent Crop Treated Used in Dietary Assessment	34
5.4.3	Acute Dietary Risk Assessment	34
5.4.4	Chronic Dietary Risk Assessment	34
5.4.5	Cancer Dietary Risk Assessment	34
5.4.6	Summary Table	35
6.0	Aggregate Exposure/Risk Characterization	36
7.1	Acute Aggregate Risk	36
7.2	Short- and Intermediate-Term Aggregate Risk	36
7.3	Chronic Aggregate Risk	37
8.0	Cumulative Exposure/Risk Characterization	38
9.0	Occupational Exposure/Risk Characterization	38
9.1	Short- and Intermediate-Term Handler Risk	38
9.2	Short-/Intermediate Post-Application Risk	42
10.0	References	42
Appendix A.  Toxicology Profile and Executive Summaries	44
A.1	Toxicology Data Requirements	44
A.2	Toxicity Profiles	45
A.3	Hazard Identification and Endpoint Selection	51
A.4	Executive Summaries	57
Appendix B. Chemical Names and Structures	72
Appendix C.  Physical/Chemical Properties	73
Appendix D.  Studies Reviewed for Ethical Conduct	74

1.0	Executive Summary

Thiabendazole [2-(4-thiazolyl)benzimidazole] is a benzimidazole fungicide currently registered for use as a seed or seed piece treatment to dry pea, potato, sweet potato, soybean, and wheat.  It is also registered for use on mushrooms and is mostly used post-harvest as a dip or spray on citrus fruits, apples, pears, bananas, mangos, papaya, plantain, carrots, and potatoes.  The Thiabendazole Reregistration Eligibility Decision (RED) was issued October 2002.  A human health risk assessment was completed in June 2001 for the RED.

Tolerances for plant commodities are established under 40 CFR §180.242(a) and are expressed in terms of combined residues of thiabendazole and its metabolite benzimidazole (free and conjugated); tolerances range from 0.1 ppm for dry bean seed and soybean to 40.0 ppm for mushroom.  Tolerances for livestock commodities are established under 40 CFR §180.242(b) and are expressed in terms of combined residues of thiabendazole, 5-hydroxythiabendazole (free and conjugated), and benzimidazole.

Syngenta Crop Protection is requesting registration of new seed treatments uses on assorted vegetables and small grains (vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3-07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa; spinach (including baby); and small grains (wheat, barley, oats, rye, and triticale). Tolerances already exist for wheat grain and wheat processed commodities.  The product to be used is Mertect 34F, a 42.3% (4.1 lb ai/gal) flowable concentrate formulation (EPA Reg. No. 100-889).  The uses are to be added to the Thiabendazole Technical label, as well (EPA Reg. No. 100-963).   The 4.1 lb ai/gal Flowable Concentrate formulation is proposed for seed treatment use at 0.0 02  -  0.1 mg ai/seed, depending on the commodity.

Syngenta is also requesting an amendment to the registration for Mertect 34F, a 42.3% (4.1 lb ai/gal) flowable concentrate formulation (EPA Reg. No. 100-889), to increase the application rate for soybean seed treatment. This amendment is not a part of the petition; no increased tolerance is requested.

There is a potential for acute and chronic dietary exposure to thiabendazole. Based on the proposed use pattern, short-/intermediate-term durations of exposure are expected for occupational handlers. The proposed uses do not result in residential exposures, however, aggregate exposure was assessed using existing residential uses as antimicrobial ingredients in household items (e.g., paint and sponges).

Residue Chemistry

The nature of the residue in plants is understood based on acceptable plant metabolism studies conducted in wheat, soybean, and sugar beet.  The residues of concern in crops for purposes of tolerance enforcement and risk assessment are thiabendazole and its metabolite benzimidazole (free and conjugated). The nature of the residue in livestock is understood based on acceptable hen and goat metabolism studies. The residues of concern in livestock commodities are thiabendazole, 5-hydroxy-thiabendazole (free and conjugated), and benzimidazole. Based on the available confined rotational crop study, the residues of concern in rotated crops are the same as those in primary crops.

Hazard Identification

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. Subsequent to the RED, two mutagenicity studies, an immunotoxicity study, and a neurotoxicity screening battery have been submitted to satisfy the new data requirements. In 2013, HED Hazard and Science Policy Council (HASPOC) concluded that a developmental thyroid toxicity study is required, but waived the requirement for a 28-day inhalation toxicity study (TXR No. 0056686).

In subchronic and chronic oral studies, the thyroid and liver (centrilobular hypertrophy) are the primary target organs of thiabendazole toxicity. Thiabendazole produced a treatment-related increase in absolute and relative liver weights in both sexes in a chronic dog study. Other treatment related effects reported were histopathological changes in kidneys (hyperplasia of transitional epithelium, tubular degeneration) and spleen (congested and pigmented) in rats.  Additional toxic effects observed in these studies included decreases in body weight, and/or food consumption. The available database indicates that thiabendazole is not neurotoxic. No systemic or dermal effects were seen at the limit dose (1000 mg/kg/day) in a 21-day dermal toxicity study in rats. There was no evidence of increased qualitative or quantitative susceptibility in the developmental rat, mouse or rabbit studies or the 2-generation reproduction study in rats. 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. In an immunotoxicity study thiabendazole produced significant decreased spleen activity at the highest dose tested (1027 mg/kg/day) which also produced systemic toxicity of significant increased liver weight.

Thiabendazole has been classified by the HED Cancer Assessment Review Committee (CARC) as "Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower than those which could cause a disturbance of this hormonal balance" (TXR 0050554). A quantification of cancer risk is not required since the NOAEL (10 mg/kg/day) for non-cancer risk assessment is not expected to alter thyroid hormone homeostasis or result in thyroid tumor formation.

Thiabendazole showed no significant toxicity in a battery of acute toxicity tests (Toxicity Category IV for acute oral and dermal toxicity and dermal irritation, a Toxicity Category III for acute inhalation and eye irritation) and is not a sensitizer.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. Acute and chronic reference doses (RfDs) were selected for assessment of food and drinking water exposures. An acute RfD for the general population was selected from an acute neurotoxicity study (ACN) study with an acute point of departure (POD) of 50 mg/kg/day based on decreases in Functional Observational Battery (FOB) parameters and decreased motor activity at the LOAEL of 200 mg/kg/day. For the acute dietary endpoint, the total UF is 1000 (an interspecies extrapolation factor of 10X, an intraspecies variability factor of 10X, an FQPA database uncertainty factor of 10X for lack of a developmental thyroid study).

A chronic RfD for the general population was selected from a 2-year chronic/carcinogenicity study in rats with a POD of 10 mg/kg/day (NOAEL) based on histopathological changes in the liver and thyroid at the LOAEL of 30 mg/kg/day. This chronic endpoint is supported by the endpoint from a subchronic rat oral toxicity study of 10 mg/kg/day based on reduced body weight and histopathological changes in the bone marrow, liver and thyroid at the LOAEL of 40 mg/kg/day. 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 the chronic dietary risk assessment is 300X (10X for intraspecies variability among humans, 3X for interspecies pharmacokinetic differences between humans and rats and the 10X FQPA database uncertainty factor for the missing developmental thyroid study).

Toxicological endpoints for incidental oral exposure, short-/intermediate-term dermal and
short-/intermediate-term inhalation exposures were selected from a subchronic oral toxicity study in rats with a POD of 10 mg/kg/day (NOAEL) based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid at the LOAEL of 40 mg/kg/day. A dermal absorption factor of 0.5% was selected from a combination of in vivo and in vitro dermal absorption studies.  An uncertainty factor of 300X was applied to these endpoints (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 an FQPA database uncertainty factor of 10X for lack of a developmental thyroid study was applied).

Dietary Exposure Assessment

 For the probabilistic acute dietary assessment (food and drinking water), the dietary exposure at the 99.9[th] percentile of exposure used 26% of the acute population adjusted dose (aPAD) for the general population and 69% of the aPAD for Children 1-2 years, the population subgroup with the highest estimated acute dietary exposure.  Acute dietary (food and drinking water) exposures are below HED's level of concern (<100% aPAD) for all population subgroups.

 For the chronic dietary assessment, the dietary exposure used 1.1 % of the chronic population adjusted dose (cPAD) for the general population and 4.7% of the cPAD for Children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure.  Chronic dietary (food and drinking water) exposures are below HED's level of concern (<100% cPAD) for all population subgroups.

Exposure/Risk Assessment and Risk Characterization

Residential Exposure

The proposed uses do not result in residential exposures, however, existing residential uses as antimicrobial ingredients in household items (e.g., paint and sponges) were evaluated in a previous assessment provided by the Antimicrobial Division (AD memo of 6/23/10, T. Leighton, D379421).  No risk estimates of concern were identified.

Aggregate Exposure

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

Occupational Handler Exposure

Based on the proposed use pattern, short-/intermediate-term durations of exposure are expected for occupational handlers.  The estimates of exposure to pesticide seed treatment handlers (treatment and planting) are based upon ExpoSAC Policies 14, 15, and 15.1 and a memorandum from the Biological and Economic Analysis Division (BEAD), "Acres Planted Per Day and Seeding Rates of Crops Grown in the United States" (J. Becker, March 2011).

Short-/intermediate-term exposure and risk for seed treatment resulted in total (combined dermal and inhalation) MOEs ranging from 650 to 2,200,000 for primary handlers (seed treaters) and 1,600 to 220,000 for secondary handlers (seed planters).  Note that the short- and intermediate-term PODs are the same, and the intermediate-term exposure inputs are less conservative than the short-term exposure inputs for seed treatment; therefore, short-term exposure risk estimates are protective of intermediate-term exposure risk estimates.  These risk estimates are not of concern.

Occupational Post-application Exposure

A quantitative post-application assessment is not required for exposure to treated seeds that have already been planted.

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 data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); ExpoSAC Policy 14, 15, and 15.1 (SOPs for Seed Treatment) are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.
2.0	HED Recommendations

Based on residue chemistry considerations only, HED concludes that tolerances can be supported for residues of thiabendazole and its regulated metabolite benzimidazole in vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3-07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa; spinach (including baby); or small grain (wheat, barley, oats, rye, and triticale) commodities grown from treated seed; in the processed commodities of wheat; and in rotational crops as a result of seed treatment use proposed in this petition.  Additional data are needed as a condition of registration as outlined in section 2.1 below.  The specific tolerance recommendations are discussed in 2.2, and label modifications are discussed in section 2.3.

2.1	Data Deficiencies/Conditions of Registration

Residue Chemistry

The current tolerance expression is not in accord with our current guidance.  See recommendation in 40 CFR §180.242.  Updating the tolerance expression will be accomplished during registration review.

Provided that the use directions are revised as requested and analytical standards are submitted as requested, HED concludes that, based on the available residue data, the requested use of thiabendazole as a seed treatment for vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3-07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa; spinach (including baby); and small grains (wheat, barley, oats, rye, and triticale) may be registered once tolerances are established as recommended in 40 CFR §180.242.

860.1650 Submittal of Analytical Reference Standards

   * For benzimidazole, a new standard must be submitted.  For 5-hydroxy-thiabendazole, the registrant must either recertify the lot in the repository and send in an updated certificate of analysis (COA), or submit new standards (different lot #) if the previous lots will not be recertified.

Toxicology

::  Developmental Thyroid Toxicity Study in Rats (non-guideline). Based on a WOE approach considering all the available hazard and exposure information for thiabendazole, the HED HASPOC concluded that the developmental thyroid toxicity study, a non-guideline study, is required (TXR 0056686). The developmental thyroid toxicity study is required since there is clear evidence of thyroid toxicity in adult animals and thus a concern for potential toxicity during pregnancy, infancy and child hood. The developmental thyroid toxicity study will better address this concern than a developmental neurotoxicity study.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Acceptable enforcement analytical methods are available for thiabendazole and benzimidazole in plant commodities. Four spectrophotofluorometric methods for the determination of thiabendazole are published in the Pesticide Analytical Manual (PAM) Vol. II, and a high performance liquid chromatography (HPLC) method with fluorescence detection (FLD) for the determination of benzimidazole (free and conjugated) is identified in the U.S. EPA Index of Residue Analytical Methods under thiabendazole as Study No. 93020. The validated limits of detection (LODs) for the thiabendazole methods range from 0.05-0.1 ppm, and the validated limit of quantitation (LOQ) for the benzimidazole method is 0.1 ppm.

2.2.2	International Harmonization

There is no issue with International Harmonization. Neither CODEX nor Canada has established any established maximum residue limits (MRLs) for thiabendazole on the requested commodities. We note that the U.S. tolerance expression is not harmonized with Canada or CODEX.

2.2.3	Recommended Tolerances

Under the current action, Syngenta has submitted a petition for tolerances associated with the proposed use, PP# 3F8166. Tolerances at the total limit of quantitation of 0.02 ppm were proposed for residues of thiabendazole and its metabolite benzimidazole on vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3-07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa seed, forage, and hay; and spinach (including baby); and at 0.05 ppm on barley, oats, rye, and triticale grains; 0.15 ppm on barley hay and straw and rye straw; 0.2 ppm on wheat, oats, rye, and triticale forage; and 0.09 ppm on wheat hay and oats and triticale hay and straw. Syngenta submitted residue data to support the proposed uses. Syngenta also has included field trial and processing studies on soybean, and storage stability data, both of which were required under the Reregistration Eligibility Document (RED).  The field trial data submitted for wheat may fulfill the RED data requirement for data for wheat, and constitute a full set of residue data, so these data may be used to reevaluate the existing wheat tolerances.

Table 2.2.3. 	Tolerance Summary for Thiabendazole.  § 180.242
Commodity
Current/Proposed Tolerance (ppm)
Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
alfalfa, forage
                                     0.02
                                     0.02
Alfalfa, forage
alfalfa, hay
                                     0.02
                                     0.02
Alfalfa, hay
alfalfa, seed
                                     0.02
                                       -
Tolerances are not normally set for alfalfa seed
barley, grain
                                     0.05
                                     0.05
Barley, grain
barley, hay
                                     0.15
                                     0.30
Barley, hay
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
barley, straw
                                     0.15
                                     0.30
 Barley, straw
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
Brassica, Head and Stem, subgroup 5-A
                                     0.02
                                     0.02

oats, forage
                                      0.2
                                     0.30
Oats, forage
Revised level based on OECD tolerance calculation procedures, and to be consistent across all cereal grain forages.
oats, grain
                                     0.05
                                     0.05
Oats, grain
oats, hay
                                     0.09
                                     0.30
Oats, hay
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
oats, straw
                                     0.09
                                     0.30
Oats, straw
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
Onion, bulb, Subgroup 3-07A
                                     0.02
                                     0.02

radish, tops
                                     0.02
                                     0.02
Radish, tops
rye, forage
                                      0.2
                                     0.20
Rye, forage
rye, grain
                                     0.05
                                     0.05
Rye, grain
rye, straw
                                     0.15
                                     0.30
Rye, straw
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
spinach
                                     0.02
                                     0.02
Spinach
triticale, forage
                                      0.2
                                     0.23
Triticale, forage
Revised level based on OECD tolerance calculation procedures, and to be consistent across all cereal grain forages.
triticale, grain
                                     0.05
                                     0.05
Triticale, grain
triticale, hay
                                     0.09
                                     0.15
Triticale, hay
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
triticale, straw
                                     0.09
                                     0.15
Triticale, straw
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
Vegetable, Cucurbit group 9
                                     0.02
                                     0.02
Vegetable, Cucurbit, group 9
Vegetable, root (except sugarbeet), subgroup 1B
                                     0.02
                                     0.02
Revised level based on OECD tolerance calculation procedures.
Wheat, grain
                                      1.0
                                     0.05
Current tolerance for wheat grain is 1.0 ppm, tolerance recommended in RED was 0.2 ppm.  Current recommendation is based on full new data set showing all non-quantifiable residues.
wheat, forage
                                      0.2
                                     0.30
Wheat, forage
Revised level based on OECD tolerance calculation procedures, and to be consistent across all cereal grain forages.
wheat, hay
                                     0.09
                                     0.30
Wheat, hay
Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws.
Wheat, straw
                                      1.0
                                     0.30
RED recommended lowering tolerance.  Current recommendation is to be consistent across all hays and straws.

2.2.4	Revisions to Petitioned-For Tolerances

The current tolerance expression for thiabendazole is:

"(1) Tolerances are established for the combined residues of the fungicide thiabendazole (2-(4-thiazolyl)benzimidazole) and its metabolite benzimidazole (free and conjugated) in or on the following food commodities:" for plant commodities.

And

"(2) Tolerances are established for the combined residues of thiabendazole (2-(4-thiazolyl)benzimidazole) and its metabolites 5-hydroxythiabendazole (free and conjugated) and benzimidazole in or on the following food commodities:" for livestock commodities.

The tolerance expressions need to be updated as follows to reflect our current guidance. This will be accomplished during Registration Review.

There are established tolerances for residues of thiabendazole and metabolite on wheat grain and straw.  The currently established tolerance for wheat grain is 1.0 ppm based on the originally submitted data set for foliar uses on wheat, showing interferences in the analytical method.  Although the residues were all non-quantifiable, the tolerance was set at 1.0 ppm because of the interference. In the RED, the tolerance for residues in wheat grain was proposed to be reduced to 0.2 ppm, and in wheat straw to 0.5 ppm; these tolerances were based on foliar applications of thiabendazole to wheat.   However, since that time, the foliar applications for wheat have been canceled, and in connection with the current petition, a full new data set was submitted for all wheat commodities at the currently registered use pattern.  The residues of thiabendazole and benzimidazole on wheat grain were all <LOQ (<0.01 ppm each, or <0.02 ppm total residues).  Thus, we conclude that the current tolerance for residues of thiabendazole and benzimidazole on wheat grain may be reduced to 0.05 ppm.  See Table 2.2.3.

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

860.1200 Directions for Use

   * 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).

2.3.2	Recommendations from Occupational Assessment
THE RISK ASSESSMENT SUPPORTS THE PROPOSED thiabendazole seed treatment labels requiring only baseline level of clothing (i.e., long-sleeve shirt, long pants, shoes/socks) without use of chemical-resistant gloves. However, additional personal protective equipment (PPE) may be needed based on the acute toxicity of the end-use product.  HED recommends that the Registration Division (RD) ensure that the appropriate PPE (e.g., chemical-resistant gloves) be included on the final label if necessary based on WPS requirements.

2.3.3	Recommendations from Residential Assessment

There are no label recommendations based on the residential assessment.

3.0	Introduction

3.1	Chemical Identity

The chemical structure and nomenclature of thiabendazole and its regulated metabolites are presented in Table 3.1.

Table 3.1.	Test Compound Nomenclature.
Compound

Common name
Thiabendazole
Company experimental name
None
IUPAC name
2-(thiazol-4-yl)benzimidazole
CAS name
2-(4-thiazolyl)-1H-benzimidazole
CAS registry number
148-79-8
End-use product (EP)
4.1 lb ai/gal FlC formulation (Mertect 34F; EPA Reg. No 100-889)
Compound

Common name
Benzimidazole
Chemical name
1H-benzimidazole
CAS registry number
51-17-2
Compound

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

3.2	Physical/Chemical Characteristics

Thiabendazole is a benzimidazole fungicide used as seed treatments and seed piece treatments on mushrooms and post-harvest on fruits.  Technical thiabendazole is a colorless crystalline solid with a melting point of 304-305 C, bulk density of 25-30 cc (tapped), octanol/water partition coefficient (Kow) of 240-285 at pH7, and has a low vapor pressure of 4 X 10[-9] mm Hg at 25°C. Thiabendazole is sparingly soluble in water at 0.028-0.030 mg/mL at 25°C, and is soluble in several organic solvents.

The physicochemical properties of the technical grade of thiabendazole are presented in Appendix C.
3.3	Pesticide Use Pattern

Syngenta has submitted a draft label (dated 10/23/2013) and a description of the proposed use for the 4.1 lb ai/gal FlC formulation (Mertect 34F Fungicide; EPA Reg No. 100-889).

The proposed use directions are summarized in Table 3.3. See Section 2.3 for recommended modifications to the proposed label.

Table 3.3	Summary of Directions for Use of Thiabendazole.
Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate
                          Max. No. Applic. per Season
                                      PHI
                                    (days)
                        Use Directions and Limitations
                                    Alfalfa
Seed treatment,
Seed treatment application equipment
                                4.1 lb ai/gal F
                                   [100-889]
                   0.004 mg ai/seed or 5.8 fl oz/100 lb seed
                                       1
                                      N/A
Assumes an average seed size of
210,000 seeds/lb
             Cereal Grains  -  Barley, Oats, Rye, Triticale, Wheat
Seed treatment,
Seed treatment application equipment
                                4.1 lb ai/gal F
                                   [100-889]
                               0.03 mg ai/seed
                         Barley 2.6 fl oz/100 lb seed
                          Oats 3.4 fl oz/100 lb seed
                           Rye 3.2 fl oz/100 lb seed
                        Triticale 2.6 fl oz/100 lb seed
                          Wheat 3.1 fl oz/100 lb seed

                                       1
                                      N/A

Barley- assumes an average seed size of 12,500 seeds/lb
Oats- assumes an average seed size of 12,500 seeds/lb
Rye - assumes an average seed size of 15,600 seeds/lb
Triticale - assumes an average seed size of 12,750 seeds/lb
Wheat - assumes an average seed size of 15,000 seeds/lb
Brassica Head & Stem subgroup; Bulb Vegetables; Vegetables, Root subgroup (except sugar beets)
Seed treatment,
Seed treatment application equipment
                                4.1 lb ai/gal F
                                   [100-889]
                               0.002 mg ai/seed
                                       1
                                      N/A

                              Cucurbit Vegetables
Seed treatment,
Seed treatment application equipment
                                4.1 lb ai/gal F
                                   [100-889]
                                0.1 mg ai/seed
                                       1
                                      N/A

                                    Spinach
Seed treatment,
Seed treatment application equipment
                                4.1 lb ai/gal F
                                   [100-889]
                               0.006 mg ai/seed
                                       1
                                      N/A

                                   Soybeans
Seed treatment,
Seed treatment application equipment
                                4.1 lb ai/gal F
                                   [100-889]
                                0.03 mg ai/seed
                                       1
                                      N/A

3.4	Anticipated Exposure Pathways
THE REGISTRATION DIVISION HAS REQUESTED AN ASSESSMENT OF HUMAN HEALTH RISK TO SUPPORT THE PROPOSED NEW SEED TREATMENT USES OF THIABENDAZOLE ON VARIOUS COMMODITIES.  HUMANS MAY BE EXPOSED TO THIABENDAZOLE IN FOOD AND DRINKING WATER. The proposed seed treatment uses of thiabendazole are not expected to result in residential (non-occupational) exposures. However, residential exposure is possible via antimicrobial uses in products such as paints and sponges. Occupational exposure is expected for primary handlers (seed treaters) and secondary handlers (seed planters). Post application exposure is not expected for workers.

Risk assessments have been previously prepared for the existing uses of thiabendazole.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of thiabendazole, but also considers the existing uses as well, particularly for the dietary exposure assessment.

3.5	Consideration of 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," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

4.1	Toxicology Studies Available for Analysis

The toxicology database for thiabendazole is complete with the exception of a developmental thyroid study. HASPOC waived the requirement for the 21/28 day inhalation toxicity study, but required a developmental thyroid study  (TXR # 0056686). The developmental thyroid toxicity study is required since there is clear evidence of thyroid toxicity in adult animals and thus a concern for potential toxicity during pregnancy, infancy and child hood. The available studies listed below, however, are adequate for evaluating and characterizing its toxicity and selecting endpoints for purposes of this risk assessment.

   * Acute: Oral, dermal, inhalation, eye irritation, dermal irritation, and skin sensitization
   * Subchronic: 90-day oral toxicity (rat, dog, mouse), 21-day dermal toxicity (rabbit)
   * Developmental toxicity: developmental toxicity (rat , rabbit and mouse)
   * Reproduction: 2-generation reproduction (rat)
   * Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogenicity (mouse), chronic oral toxicity (dog)
   * Neurotoxicity: Acute and Subchronic neurotoxicity (rat),
   * Other: mutagenicity battery, metabolism, in vivo and in vitro dermal penetration studies.

4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)

The absorption, distribution, metabolism, and excretion of thiabendazole were studied in rats.  In a rat metabolism study (MRID 42114701), [phenyl-U-[14]C] thiabendazole (99.1% a.i.) was administered to five Crl:CD BR strain rats/sex/dose by gavage as a single dose at 25 or 400 mg/kg or as a single dose at 25 mg/kg following a 14-day pretreatment with unlabeled thiabendazole at 25 mg/kg/day.

[[14]C]Thiabendazole was readily absorbed by male and female rats following oral dosing.  The rate of urinary excretion for both sexes in the high dose groups was lower during the initial 24 hours compared to the low dose groups.  For all test groups, ∼51-73% of the dose was excreted in the urine during the first 48 hours.  Dose rate and pretreatment with thiabendazole had no apparent effect on absorption.  Within 168 hours of dosing at 25 mg/kg (with or without pretreatment) or 400 mg/kg, 94.3-98.9% of the administered dose was recovered from both sexes, of which 67.3-74.6% was in the urine, 21.3-26.7% was in the feces, and 0.3-2.5% was in the cage washes.  Based upon data from a preliminary study, significant levels of radioactivity were not expected in organic volatiles.  For all dose groups, concentrations of radioactivity were highest in the cellular fraction of the blood.  Residue levels in tissues/organs were generally highest in heart, lungs, spleen, kidneys, and liver, and lowest in fat.

The metabolic profile in urine was similar between the test groups; no unchanged thiabendazole was detected in urine.  The majority of the administered dose was recovered in the urine identified as the glucuronide conjugate of 5-hydroxythiabendazole (7.3-21.3% of dose) and the sulfate conjugate of 5-hydroxy thiabendazole (23.7-44.9% of dose).  Males produced lower amounts of the glucuronide conjugate and higher amounts of the sulfate conjugate than females.  Minor amounts (<1% of dose) of free 5-hydroxythiabendazole (HTBZ) were present in urine from rats from all dose groups.  HPLC analyses of fecal extracts isolated minor amounts of thiabendazole from males in the preconditioned low dose group and from both sexes treated in the high dose groups, and minor amounts of free HTBZ in all dose groups.

The data indicate that renal excretion is the primary pathway for the elimination of thiabendazole from rats. At the low dose level, it was shown that thiabendazole oxidizes to form 5-hydroxythiabendazole, followed by conjugation to form glucuronide and sulfate conjugates of 5-hydroxythiabendazole.

4.2.1	Dermal Absorption

Earlier risk assessments used a dermal absorption factor (DAF) of 60% based on a ratio of LOAELs in short-term toxicity studies. The registrant (Syngenta) submitted a Triple Pack of in vivo dermal absorption study in rats (MRID 47705131), in vitro rat skin (MRID 47705102), and  in vitro human skin (MRID 47705101) with thiabendazole formulated as TECTO 500 SC. The triple pack approach was reviewed by the Agency and concluded that a DAF of 0.5% should be used for thiabendazole (TXR 0055373). The Triple Pack approach presumes that if in vitro techniques performed using animal skin is shown to be a good predictor of animal in vivo dermal absorption for a chemical, that is, if the ratio of animal in vitro/animal in vivo ≈ 1, then the identical technique performed in vitro with human skin may be useful in extrapolating human dermal absorption. Consequently, when identical protocols are used in both the in vivo and in vitro studies, these data can then be used in the Triple Pack approach to derive a refined dermal absorption factor for human health risk assessments. OPP evaluated the Triple Pack of dermal absorption studies with TECTO 500 SC and agrees that these studies are suitable for deriving a refined DAF. Critical parameters that were the same in the in vivo rat study and the in vitro rat skin and in vitro human skin studies were the use of the same test material, the same doses, the same times, and the same treatment of the skin (e.g. when it was washed).  Also critical was that the concentrations of the test material and durations of exposure were relevant to occupational exposures.

4.3	Toxicological Effects

In subchronic and chronic oral studies, the thyroid and liver (centrilobular hypertrophy) are the primary target organs of thiabendazole toxicity. Thiabendazole produced a treatment-related increase in absolute and relative liver weights in both sexes in a chronic dog study. Other treatment related effects reported were histopathological changes in kidneys (hyperplasia of transitional epithelium, tubular degeneration) and spleen (congested and pigmented) in rats. Additional toxic effects observed in these studies included decreases in body weight and/or food consumption. The available database indicates that thiabendazole is not neurotoxic. In an acute neurotoxicity rat study (ACN), decreases in the Functional Observation Battery (FOB) (reduced body temperature in males, reduced rearing in females (↓54%,), and reduced locomotor activity in males and females(↓37-46%,) at time of peak effect (approximately 3 hours post-dose) were seen without morphological or histopathological effects on the brain. Thiabendazole was not neurotoxic in rats in a subchronic neurotoxicity study.  In a 21-day dermal toxicity study in rats, no systemic or dermal effects were seen at the limit dose (1000 mg/kg/day).  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.

In the adult animal, effects on the thyroid following thiabendazole exposure were observed at a dose lower than the neurotoxicity dose observed in the ACN. There are no thiabendazole data with which to determine whether this is also the case in the fetus/postnatal animal. Based on a WOE approach considering all the available hazard and exposure information for thiabendazole, the HED HASPOC concluded that the developmental thyroid toxicity study is required (TXR 0056686). The developmental thyroid toxicity study is required since there is clear evidence of thyroid toxicity in adult animals and thus a concern for potential toxicity during pregnancy, infancy and child hood. The developmental thyroid toxicity study will better address this concern than a developmental neurotoxicity study.

In an immunotoxicity study, thiabendazole produced significant decreased spleen activity at the highest dose tested (5000 ppm equivalent to1027 mg/kg/day) which also produced significant increased liver weight.

The acceptable genetic toxicology studies on thiabendazole indicate that it is not genotoxic 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. Thiabendazole did not induce tumors in mice. Thiabendazole has been classified by the HED Cancer Assessment Review Committee (CARC) "Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower than those which could cause a disturbance of this hormonal balance (TXR 0050554). A quantification of cancer risk is not required since the NOAEL (10 mg/kg/day) for non-cancer risk assessment is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation.

Thiabendazole showed no significant toxicity in a battery of acute toxicity tests (Toxicity Category IV for acute oral and dermal toxicity and dermal irritation, and Toxicity Category III for acute inhalation and eye irritation) and is not a sensitizer.

The complete toxicity profile for thiabendazole is provided in Appendix A.

4.4	Safety factor for Infants and Children (FQPA Safety Factor)

No evidence of increased quantitative or qualitative susceptibility was seen following in utero exposure to thiabendazole with rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study. There is no evidence for neurotoxicity following oral exposures to thiabendazole. Thyroid toxicity was seen following subchronic and chronic exposures to adult rats in multiple studies. There is, however, no data regarding the potential effects of thiabendazole on thyroid homeostasis in the young animals. This lack of characterization creates uncertainty with regards to potential life stage sensitivities due to exposure to thiabendazole and raises the Agency's level of concern. Therefore, the Agency is requiring a developmental thyroid assay in rats with thiabendazole. This study will better address the concern for potential thyroid toxicity in the young. There are no residual uncertainties in the thiabendazole residue database with regards to dietary or occupational exposure. Therefore, the FQPA Safety Factor is retained at 10X in the form of a database uncertainty factor (UFDB). For the acute dietary endpoint the total UF is 1000 (An interspecies scaling factor of 10X, an intraspecies variability factor of 10X, a FQPA database uncertainty factor of 10X for lack of a developmental thyroid study). For the remaining endpoints, the combined total UF is 300 (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, an FQPA database uncertainty factor of 10X for lack of a developmental thyroid study was applied).

4.4.1	Completeness of the Toxicology Database

The toxicology database for thiabendazole is complete with the exception of a developmental thyroid toxicity study. Based on a WOE approach considering all the available hazard and exposure information for thiabendazole, the HED HASPOC concluded that a developmental thyroid toxicity study is required (TXR 0056686). The developmental thyroid toxicity study is required since there is clear evidence of thyroid toxicity in adult animals and thus a concern for potential toxicity during pregnancy, infancy and child hood. The developmental thyroid toxicity study will better address this concern than a developmental neurotoxicity study.   Acceptable studies are available for developmental, reproduction, chronic, subchronic, subchronic neurotoxicity and immunotoxicity.

4.4.2	Evidence of Neurotoxicity

The available database indicates that thiabendazole is not neurotoxic. In an acute neurotoxicity rat study (ACN), decreases in the Functional Observation Battery (FOB) (reduced body temperature in males, reduced rearing in females (↓54%), and reduced locomotor activity in males and females(↓37-46%,) at time of peak effect (approximately 3 hours post-dose) were seen without morphological or histopathological effects on the brain. Thiabendazole was not neurotoxic in rats in a subchronic neurotoxicity study at the highest dose tested (1500 ppm equivalent to 95 mg/kg/day).

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

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 was deemed not required by HED HIARC (TXR 0013601).

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.  Thus, the absence of the developmental thyroid study raises concern whether infants and children are sufficiently protected from developmental effects.

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary and/or non-dietary occupational exposure to thiabendazole. The acute and chronic dietary assessments conducted with DEEM-FCID were refined analyses. The assessments utilized anticipated residues, default processing factors, and available percent crop treated data.  The DEEM analysis also used Tier 1 drinking water estimates.  For these reasons it can be concluded that the DEEM-FCID analysis does not underestimate risk from acute or chronic exposure to thiabendazole. Similarly, HED does not believe that the non-dietary occupational exposures are underestimated because they are also based on conservative assumptions, including maximum application rates, and standard values for unit exposures and acreage treated/amount handled.
4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, and residential exposure scenarios are summarized below.  A detailed description of the studies used as a basis for the selected endpoints are presented in Appendix A.

An acute POD of 50 mg/kg (NOAEL) was selected for all populations including infants and children from an acute neurotoxicity study in rats based on decreases in the Functional Observation Battery (FOB) (reduced body temperature in males, reduced rearing in females (↓54%,), and reduced locomotor activity in males and females (↓37-46%,) at time of peak effect (approximately 3 hours post-dose) at the LOAEL of 200 mg/kg. The total UF is 1000 (an interspecies scaling factor of 10X, an intraspecies variability factor of 10X, a database uncertainty factor of 10X for lack of a developmental thyroid study, an FQPA SF of 1X).

[Note: In earlier risk assessment (D275829, 6/21/01), an acute endpoint of toxicity was derived from a developmental study in rats based on decreases in maternal and pup body weight gains. Re-evaluation of the suitability of this study for an acute endpoint by senior HED leadership considered this study to be inappropriate, in that reduced fetal weights/decreased maternal body weights were not effects that were likely to occur after a single dose of exposure (TXR 0054506). However, the HED leadership confirmed the earlier HIARC decision (TXR 0013601) regarding the suitability of this study for short-term risk assessments. The acute neurotoxicity used for this current risk assessment was submitted recently. The RA team, in consultation with HED Senior Toxicologist, Elizabeth Mendez, selected this study for the acute dietary endpoint.]

A chronic POD of 10 mg/kg/day (NOAEL) was selected for the general population from a 2-year chronic/carcinogenicity study in rats based on decreased body weight and liver hypertrophy at the LOAEL of 30 mg/kg/day. This chronic endpoint is supported by the endpoint from a subchronic rat oral toxicity study of 10 mg/kg/day based on reduced body weight and histopathological changes in the bone marrow, liver and thyroid at the LOAEL of 40 mg/kg/day. For the chronic dietary endpoint, 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, an FQPA database uncertainty factor of 10X for lack of a developmental thyroid study was applied, are all combined for a total uncertainty factor of 300X.

Incidental oral, short-/intermediate-term dermal and short-/intermediate-term inhalation PODs of 10 mg/kg/day were selected from a subchronic rat oral toxicity study based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid at the LOAEL of 40 mg/kg/day. An acceptable 21-day dermal toxicity study in rabbits showed no effects at the limit dose of 1000 mg/kg/day.  However since reduced fetal body weights seen in the developmental study were not measured in the dermal study and a concern for the thyroid effects, the findings from dermal toxicity study may not be protective of these effects. The selected subchronic oral toxicity study for assessing all of these exposure scenarios is supported by other studies in the thiabendazole toxicity data base with a NOAEL of 10 mg/kg/day based on similar effects including body weight gain reductions, liver and thyroid effects at 30-40 mg/kg/day doses. A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from oral toxicity studies. The dermal factor converts the oral dose to an equivalent dermal dose for the risk assessment. A dermal absorption factor based on in vivo, and in vitro studies of 0.5% was used for the dermal exposure assessment (TXR 0055373)  This is a deviation from earlier risk assessments the used a dermal absorption factor of 60%  prior to the submission of the dermal absorption studies.

[Note: In earlier risk assessments (D269360, 9/28/2000; D275829, 6/21/01; D326592, 11/20/2006; D401756, 9/19/2012), short -term dermal/inhalation endpoint of toxicity was derived from a developmental study in rats based on decreases in maternal and pup body weight. In this current risk assessment, this endpoint of toxicity was re-evaluated by the RA Team and the subchronic oral toxicity study was selected as the basis for the toxicity end point for assessing the risk from these exposures since it is more comprehensive of the various toxicity effects seen in the thiabendazole toxicity data base as well as being protective of any developmental effects.]

An uncertainty factor of 300X was applied to endpoints selected for incidental oral, short-/intermediate-term dermal and short-/intermediate-term inhalation exposures (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).

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational exposures, dermal, and inhalation exposures should be aggregated for thiabendazole, because the same oral toxicity endpoint was selected for both exposure routes.    When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures.
There is potential residential handler exposure to adults via the dermal and inhalation routes and indirect dietary exposure from sponges on countertops.  Dietary, dermal and inhalation endpoints for thiabendazole are based on common toxicological effects.  Therefore, exposures from food, dermal and inhalation routes can be aggregated for this assessment.

4.5.3	Cancer Classification and Risk Assessment Recommendation

Thiabendazole has been classified by the HED Cancer Assessment Review Committee (CARC) "Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower that those which could cause a disturbance of this hormonal balance (TXR 0050554). A quantification of cancer risk is not required since the NOAEL (10 mg/kg/day) for non-cancer risk assessment is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation.
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Toxicological doses/endpoints selected for the thiabendazole risk assessment are provided in Tables <IP_ADDRESS> and <IP_ADDRESS>.

Table <IP_ADDRESS>  Summary of Toxicological Doses and Endpoints for [Chemical] for Use in Dietary and Non-Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary
(general population including females 13  -  49 years and children)
NOAEL =
50 mg/kg
UFA = 10X
UFH = 10X
FQPA UFDB = 10X

aRfD =
0.05mg/kg/day
aPAD =
0.05 mg/kg
Acute neurotoxicity Study (MRID 48996310)
LOAEL = 200 mg/kg based decreases in the FOB (reduced body temperature in males p<0.05, and reduced rearing in females ↓54%, p<0.01), reduced locomotor activity in males and females (↓37-46%, p<0.01), at time of peak effect (approximately 3 hours post-dose). Reduced body weight gain (p<0.01) and food consumption (↓44%, p<0.01) occurred on day 1.
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 chronic carcinogenicity in the Rat (MRID 43593201)
Chronic LOAEL = 30 mg/kg/day based on decreased body weight gains and liver hypertrophy.  Thiabendazole induced thyroid adenomas in male rats at dosages of >=30 mg/kg/day.

Supported by subchronic toxicity rat  study (MRID 42942802)

Subchronic LOAEL = 40 mg/kg/ based on reduced body weight and body weight gains ((↓11%) and histopathological changes in the bone marrow (erythroid hyperplasia), liver (centrilobular hypertrophy), thyroid (follicular cell hypertrophy) and spleen (pigmented).
Incidental Oral (Short  - term (1-30 days) and intermediate- term (1-6 months)
NOAEL= 10mg/kg/day
UFA= 3x
UFH=10x
FQPA UFDB = 10x
Residential LOC for MOE = 300
Subchronic oral toxicity study  -  rat
 MRID 42942802
LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid
Dermal Short-Term (1-30 day s) and Intermediate-term (1-6 months)
DAF = 0.5%
NOAEL= 10mg/kg/day

DAF = 0.5%
UFA= 3x
UFH=10
FQPA UFDB = 10x
Residential LOC for MOE = 300

Subchronic oral toxicity study  -  rat
 MRID 42942802
LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid
Inhalation Short-Term (1-30 days) and Intermediate-term (1-6 months)
NOAEL= 10mg/kg/day
UFA= 3x
UFH=10x
FQPA UFDB = 10x

Residential  LOC for MOE = 300
Subchronic oral toxicity study  -  rat
 MRID 42942802
LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid
Cancer (oral, dermal, inhalation)
Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower that those which could cause a disturbance of this hormonal balance (TXR 0050554). Quantification of cancer risk is not required.
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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable. DAF = dermal absorption factor (TXR 0055373)

Table <IP_ADDRESS> Summary of Toxicological Doses and Endpoints for [Chemical] for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                              Uncertainty Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal Short-Term (1-30 day s) and Intermediate-term (1-6 months)
DAF = 0.5%
NOAEL= 10mg/kg/day

DAF = 0.5%
UFA= 3x
UFH=10
UFDB = 10x
Occupational l LOC for MOE = 300

Subchronic oral toxicity study  -  rat
 MRID 42942802
LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid
Inhalation Short-Term (1-30 days) and Intermediate-term (1-6 months)
NOAEL= 10mg/kg/day
UFA= 3x
UFH=10x
UFDB = 10x

Occupational LOC for MOE = 300
Subchronic oral toxicity study  -  rat
 MRID 42942802
LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid
Cancer (oral, dermal, inhalation)
Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower that those which could cause a disturbance of this hormonal balance (TXR 0050554). Quantification of cancer risk is not required.
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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable. DAF = dermal absorption factor (TXR 0055373)

4.6	Endocrine Disruption

 As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals.  Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring.  For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision for thiabendazole, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.  However, as required by FFDCA section 408(p), thiabendazole is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

 EPA has developed the 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.

 Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.  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.  A second list of chemicals identified for EDSP screening was published on June 14, 2013 and includes some pesticides scheduled for registration review and chemicals found in water. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

 For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website.

5.0	Dietary Exposure and Risk Assessment

5.1	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is understood based on acceptable plant metabolism studies conducted in wheat, soybean, and sugar beet. In the three plant metabolism studies submitted, the parent compound and benzimidazole (free and conjugated) were the major residues. In the confined rotational crop study, thiabendazole, benzimidazole, and 5-hydroxy thiabendazole were identified. The residues of concern in primary and rotational crops for purposes of tolerance enforcement and risk assessment are thiabendazole and its metabolite benzimidazole (free and conjugated). The nature of the residue in livestock is understood based on acceptable hen and goat metabolism studies. The major metabolite in goat milk and tissues is the 5-OH-TBZ compound (and its conjugates); BNZ and TBZ are also present. TBZ degrades predominantly to 5-OH-TBZ and its conjugates in hens. Varying amounts of BNZ and unchanged TBZ are also present in eggs and hen tissues. The residues of concern in livestock commodities are thiabendazole, 5-hydroxy-thiabendazole (free and conjugated), and benzimidazole.

5.1.2	Summary of Environmental Degradation

Environmental fate studies show that thiabendazole is persistent and immobile. Thiabendazole is stable to hydrolysis and soil photolysis and degrades slowly in aerobic (half-life ~ 700 days) and anaerobic soil environments (>200 days). Aquatic photolysis, with a half-life of 1.2 days in clear water, appears to be the only significant degradation pathway. Under anaerobic aquatic conditions thiabendazole showed no evidence of abiotic or biotic degradation but moved rapidly from water phase to the sediment phase. Thiabendazole binds tightly to soil due to its high soil/water partitioning coefficients (Kocs > 1,000 mL/goc), thus limiting the amount available for leaching into ground water and for solution phase runoff into surface water. With the high sorption capacity, thiabendazole would be transported on eroded sediment. Sorption was weakly correlated to organic carbon. Terrestrial field dissipation studies showed thiabendazole to be extremely persistent with no observable leaching. Vapor pressure and Henry's Constant indicate that thiabendazole has a low potential to volatilize from soil and water.

5.1.3	Comparison of Metabolic Pathways

In the plant metabolism studies submitted, the parent compound and benzimidazole (free and conjugated) were the major residues when foliar application was used. Although 5-hydroxy thiabendazole is a major metabolite in rats and livestock, it is minor in plants. In the confined rotational crop study, thiabendazole, benzimidazole, and 5-hydroxy thiabendazole were identified. The major metabolite in livestock is the 5-OH-TBZ compound (and its conjugates); BNZ and TBZ are also present.

5.1.4	Residues of Concern Summary and Rationale

Residues of Concern:  The qualitative nature of the residue in plants is adequately understood based on soybean, sugar beet and wheat metabolism studies reflecting foliar treatments.  The HED Metabolism Assessment Review Committee (MARC) determined that residues of concern in plants for regulation and dietary risk assessment include thiabendazole and its metabolite benzimidazole (free and conjugated).  No residues of 5-hydroxythiabendazole were identified in these plant metabolism studies.  [Note:  The 5-hydroxythiabendazole metabolite was identified as a minor residue in rotational crops.]  Post harvest treatments are expected to result in the highest potential residues of thiabendazole per se in/on plant commodities and potential residues of benzimidazole (free and conjugated) are unlikely to contribute significantly to the total thiabendazole residues of concern for these uses.  Based on re-evaluation of the available foliar metabolism data, the reviewer has determined that maximum total thiabendazole residues of concern in soybean (foliage, immature plant, straw and seed), sugar beet roots, sugar beet tops and wheat (foliage, forage, straw and grain) may be estimated by multiplying the thiabendazole residue level by 1.5x, 1.4x, 1.8x and 1.8x, respectively.

The qualitative nature of the residue in animals is adequately understood based on acceptable ruminant and poultry metabolism studies. The HED Metabolism Committee determined that residues of concern in livestock for regulation and dietary risk assessment include thiabendazole, 5-hydroxythiabendazole (free and conjugated), and benzimidazole.

Table 5.1.4  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
thiabendazole and benzimidazole (free and conjugated)
thiabendazole and benzimidazole (free and conjugated)

Rotational Crop
thiabendazole and benzimidazole (free and conjugated)
thiabendazole and benzimidazole (free and conjugated)
Livestock
Ruminant
thiabendazole, 5-hydroxy-thiabendazole (free and conjugated), and benzimidazole
thiabendazole, 5-hydroxy-thiabendazole (free and conjugated), and benzimidazole

Poultry
thiabendazole, 5-hydroxy-thiabendazole (free and conjugated), and benzimidazole
thiabendazole, 5-hydroxy-thiabendazole (free and conjugated), and benzimidazole
Drinking Water
thiabendazole
Not Applicable

5.2	Food Residue Profile

Adequate crop field trial data have been submitted to support the proposed seed treatment uses on vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3-07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa; spinach (including baby); and small grains (wheat, barley, oats, rye, and triticale). Residues of thiabendazole and benzimidazole were each below the method LOQ of 0.01 ppm (total LOQ of 0.02 ppm) in all samples of vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3-07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa; and spinach. Finite residues were reported in some samples of barley and wheat grain, forage, hay and straw. Additionally, field trial data were submitted for soybeans, in response to a RED data requirement. The wheat and soybean field trial data submitted with this petition satisfy the RED data requirement for additional field trial data for wheat and soybeans.

Adequate wheat and soybean processing studies were submitted, both reflecting a 5x application rate. The soybean processing study was submitted in response to a RED data requirement. The wheat samples treated at a 5x application rate were processed into bran, flour, middlings, shorts and germ using simulated commercial procedures. Residues of thiabendazole were non-quantifiable in wheat grain and all wheat processed commodities.  The soybean samples treated at a 5x application rate were processed into meal, hulls, refined oil, flour, milk, tofu, soy sauce, miso, pollard and crude oil using simulated commercial procedures. Residues of thiabendazole were non-quantifiable in soybeans and all soybean processed commodities. Therefore, HED concludes that residues of thiabendazole or its regulated metabolite, benzimidazole, are not likely to concentrate in the processed commodities of wheat and soybeans.

A limited field rotational crop study was required in the RED and was included in the current submission.  In 13 rotational crop trials, after application to the soil at a rate typical of seed treatment application rates, residues of thiabendazole and benzimidazole were non-quantifiable (<0.02 ppm total) in samples of lettuce, radish, and wheat commodities planted 30, 60, and 270 days after treatment.  This study satisfies the RED data requirement for rotational crop studies.

TABLE 5.2.	Summary of Residue Data with Thiabendazole.
Commodity
                                    Analyte
                                  Total Rate
                                    lb ai/A
                                  (g ai/ha)
                                      DAP
                                    (days)
                            Residue Levels (ppm)[1]

                                       n
                                  Sample Min.
                                  Sample Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
Alfalfa Forage -1[st] Cutting
                                 Thiabendazole
                                   0.02-0.05
                                    (22-56)
                                    45-253
                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Alfalfa Forage  -  2[nd] Cutting
                                 Thiabendazole
                                   0.02-0.05
                                    (22-56)
                                    70-292
                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Alfalfa Forage  -  3[rd] Cutting
                                 Thiabendazole
                                   0.02-0.05
                                    (22-56)
                                    110-323
                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      10
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Alfalfa Hay  -  1[st] Cutting
                                 Thiabendazole
                                   0.02-0.05
                                    (22-56)
                                    42-253
                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Alfalfa Hay  -  2[nd] Cutting
                                 Thiabendazole
                                   0.02-0.05
                                    (22-56)
                                    70-292
                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Alfalfa Hay  -  3[rd] Cutting
                                 Thiabendazole
                                   0.02-0.05
                                    (22-56)
                                    110-323
                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      10
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Alfalfa Seed
                                 Thiabendazole
                                  0.003-0.04
                                   (3.4-45)
                                    185-374
                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       2
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Barley Hay
                                 Thiabendazole
                                   0.03-0.20
                                    52-242
                                      12
                                   <0.01
                                     0.12
                                   <0.01
                                     0.12
                                     0.010
                                     0.023
                                     0.032

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.13
                                   <0.02
                                   <0.13
                                     0.020
                                     0.033
                                     0.032
Barley Grain
                                 Thiabendazole
                                   0.03-0.20
                                    83-256
                                      12
                                   <0.01
                                     0.031
                                   <0.01
                                     0.029
                                     0.010
                                     0.012
                                     0.005

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.041
                                   <0.02
                                   <0.039
                                     0.020
                                     0.022
                                     0.005
Barley Straw
                                 Thiabendazole
                                   0.03-0.20
                                    83-256
                                      12
                                   <0.01
                                     0.085
                                   <0.01
                                     0.082
                                     0.010
                                     0.024
                                     0.024

                                 Benzimidazole

                                      12
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      12
                                   <0.02
                                   <0.095
                                   <0.02
                                   <0.092
                                     0.020
                                     0.034
                                     0.024
Wheat Forage
                                 Thiabendazole
                                   0.08-0.14
                                   (90-157)
                                    39-236
                                      19
                                   <0.01
                                     0.21
                                   <0.01
                                     0.20
                                     0.010
                                     0.025
                                     0.044

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.22
                                   <0.02
                                   <0.21
                                     0.020
                                     0.035
                                     0.044
Wheat Hay
                                 Thiabendazole
                                   0.08-0.14
                                   (90-157)
                                    51-265
                                      19
                                   <0.01
                                     0.066
                                   <0.01
                                     0.062
                                     0.010
                                     0.015
                                     0.015

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.076
                                   <0.02
                                   <0.072
                                     0.020
                                     0.025
                                     0.015
Wheat Grain
                                 Thiabendazole
                                   0.08-0.14
                                   (90-157)
                                    84-304
                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Wheat Straw
                                 Thiabendazole
                                   0.08-0.14
                                   (90-157)
                                    84-304
                                      19
                                   <0.01
                                     0.078
                                   <0.01
                                     0.073
                                     0.010
                                     0.014
                                     0.015

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.088
                                   <0.02
                                   <0.083
                                     0.020
                                     0.024
                                     0.015
Carrot roots
                                 Thiabendazole
                                 0.0003-0.007
                                  (0.34-7.8)
                                    79-134
                                       8
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       8
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       8
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Radish roots
                                 Thiabendazole
                                  0.002-0.004
                                   (2.2-4.5)
                                     26-60
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       5
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Radish tops
                                 Thiabendazole
                                  0.002-0.004
                                   (2.2-4.5)
                                     26-60
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       5
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Cantaloupe
                                 Thiabendazole
                                  0.002-0.008
                                   (2.2-9.0)
                                    62-119
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       6
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Cucumber
                                 Thiabendazole
                                  0.005-0.012
                                  (5.6-13.4)
                                     49-81
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       6
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Summer
Squash
                                 Thiabendazole
                                  0.001-0.007
                                   (1.1-7.8)
                                     33-62
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       5
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Cabbage heads w/wrapper leaves
                                 Thiabendazole
                                0.00025-0.00077
                                (0.28-0.86)[4]
                                    84-190
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       6
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Broccoli head and stem
                                 Thiabendazole
                                0.00019-0.0008
                                  (0.21-0.90)
                                    73-137
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       6
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Spinach Leaves
                                 Thiabendazole
                                  0.001-0.014
                                  (0.8-15.7)
                                     47-89
                                       8
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       8
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       8
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Immature (Baby) Spinach Leaves
                                 Thiabendazole
                                  0.001-0.014
                                  (0.8-15.7)
                                     43-54
                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       2
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Soybean Forage
                                 Thiabendazole
                                  0.012-0.024
                                  (13.5-26.9)
                                     46-94
                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Soybean Hay
                                 Thiabendazole
                                  0.012-0.024
                                  (13.5-26.9)
                                     46-94
                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Soybean Seed
                                 Thiabendazole
                                  0.012-0.024
                                  (13.5-26.9)
                                    109-153
                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                      19
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                      19
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
Dry Bulb Onion
                                 Thiabendazole
                                  0.001-0.003
                                   (1.1-3.4)
                                    113-252
                                       8
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                                 Benzimidazole

                                       8
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      N/A

                             Combined Residues[3]

                                       8
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A
[1]  Except for sample min/max, values reflect per trial averages; n = no. of field trials.  N/A = Not Applicable
[2]  LAFT = lowest average field trial; HAFT = highest average field trial.
3  Combined residues of thiabendazole and benzimidazole.  Residues of benzimidazole were not converted to parent equivalents; no conversion was necessary for this study because residues of benzimidazole were below the LOQ (<0.01 ppm) in/on all matrices.

5.3	Water Residue Profile
EFED Memo:	D410805, 2/24/14, J. Wolf. (Drinking Water Assessment (DWA))

The drinking water estimates used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED; D410805).  EFED conducted a Tier I drinking water assessment for thiabendazole in surface water using the FQPA Index Reservoir Screening Tool (FIRST) model and in ground water using the Pesticide Root Zone Model for GroundWater (PRZM-GW).  The highest Estimated Drinking Water Concentrations (EDWCs) resulted from the currently registered use of thiabendazole on wheat as a seed treatment and not from the proposed new uses or requested soybean use rate increase.  Surface water estimates were higher than ground water estimates.  The highest EDWCs for peak and annual mean were 3.80 and 0.47 μg/L (ppb), respectively.  The peak concentration of 0.0038 ppm and annual mean of 0.00047 ppm were used in the acute and chronic dietary exposure analyses, respectively.  See Table 5.3 below for details.

Table 5.3.  Summary of Tier 1 Estimated Drinking Water Concentrations in Surface and Ground Water for the New Uses and Previously Assessed Wheat Use.

New Uses and Reassessment
Thiabendazole

Peak Concentration
Annual Average
Surface Water
Crop (app rate lb a.i./A)
Model
ug/L

New Uses (0.15)
FIRST
2.85
0.35

Wheat (0.20)
FIRST
3.80
0.47

From RED
Peak Concentration
56-day Average

Wheat  (0.20)
GENEEC
2.40[1]
1.55[1]
Groundwater

Highest Daily Concentration
Average Concentration after Breakthrough

New Uses (0.15)
PRZM-GW
0.46
-

Wheat (0.20)
PRZM-GW
0.62
-
[1]  The highest EDWCs in surface water for thiabendazole were previously prepared for the 2002 Reregistration Eligibility Decision (RED), using the Tier 1 GENEEC model (which has since been replaced by the FIRST model) for surface water and the SCI-GROW model (which has since been replaced with PRZM-GW) for groundwater.  The peak concentrations are higher than previously determined for the RED primarily due to changes in the conceptual model (GENEEC vs. FIRST) (e.g., differences of field size and shape and the implementation of the Index Reservoir) and difference in fate input values for modeling. The chronic EDWCs are lower than before due the inclusion of the Index Reservoir (e.g., size and flow through the reservoir).

The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

With regards to food, refined acute probabilistic and chronic dietary exposure assessments were conducted for thiabendazole using anticipated residue estimates for all existing uses except, cereal grains, citrus oil/peel, dried beans/peas and soybeans.  Established/recommended tolerances were used for cereal grains (corn tolerance at the method limit of quantitation; estimated at (1/2) LOQ), citrus oil/peel, dried beans, soybeans and the proposed new seed treatment uses.  Maximum residues based on field trial data were used for dried peas.  Anticipated residue estimates for carrot, potato, sweet potato, cantaloupe, orange, apple, pear baby food, strawberry, mushrooms, avocado, banana, mango, and papaya were based on USDA PDP monitoring data for thiabendazole and translated, as appropriate to yams, other citrus fruits, other pome fruits and plantains.  Because USDA PDP monitoring data did not include benzimidazole (free and conjugated), an additional factor based on available metabolism data reflecting foliar use was applied to sweet potato/yam, avocado, cantaloupe, strawberry and mushrooms to account for this residue.

There is no reasonable expectation of finite residues of thiabendazole in poultry and eggs.  Anticipated residue estimates in meat and milk considered exposure from thiabendazole-treated feedstuffs as well as from the use of thiabendazole as an animal drug, regulated by FDA.  Anticipated residue estimates in tissues with the exceptions of beef meat and beef fat were based on feeding study data.  Anticipated residue estimates in the meat and fat of beef were based on tolerances established under 21 CFR §556.730 for residues of thiabendazole at 0.1 ppm for negligible residues of thiabendazole in tissues.  The anticipated residue estimate in milk was based on USDA PDP data for parent and available feeding study data for its metabolite, 5-hydroxythiabendazole (free and conjugated).  All estimates were supported by available ruminant metabolism data.

 DEEM default processing factors were used for all commodities except potato chips/granules/flakes and wheat processed commodities which relied on empirical data demonstrating that residues do not concentration in these processed commodities.  Also, the maximum theoretical concentration factor for citrus peel (3.3x) was applied to orange and lemon peel, since the use on citrus is post harvest and most of the residues should be found in/on the peel.

The available percent crop treated (%CT or PCT) data for the currently registered seed treatment uses of thiabendazole on soybeans and wheat (SLUA report 2/22/13) were used in the acute (maximum %CT for both <2.5) and chronic (average %CT for both <1) dietary assessments. The available %CT data for the currently registered seed treatment use of thiabendazole on potatoes was not use since there is also a post harvest use on potatoes.  No other %CT data are available according to BEAD (Email dated 12/12/13 from S. Haddad (BEAD) to T. Morton (HED)) and, therefore, 100% crop treated was assumed for all other existing/proposed uses.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The available percent crop treated (%CT or PCT) data for the currently registered seed treatment uses of thiabendazole on soybeans and wheat (SLUA report 2/22/13) were used in the acute and chronic dietary assessments. The following maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered for thiabendazole: soybeans 2.5% and wheat 2.5%. The following average percent crop treated estimates were used in the chronic dietary risk assessment for the following crops that are currently registered for thiabendazole: soybeans 1% and wheat 1%. The available %CT data for the currently registered seed treatment use of thiabendazole on potatoes was not use since there is also a post harvest use on potatoes. No other %CT data are available according to BEAD (Email dated 12/12/13 from S. Haddad (BEAD) to T. Morton (HED)) and, therefore, 100% crop treated was assumed for all other existing/proposed uses.

5.4.3	Acute Dietary Risk Assessment

Estimated acute and chronic dietary exposures to thiabendazole from food and drinking water are below HED's level of concern for all population subgroups. The combined acute dietary exposure from food and drinking water at the 99.9[th] percentile of exposure is estimated at 0.012953 mg/kg/day for the general population, equivalent to 26% of the aPAD. The population subgroup with the highest estimated acute dietary exposure is children 1-2 years, with an estimated exposure at the 99.9[th] percentile of 0.034322 mg/kg/day, equivalent to 69% of the aPAD.

5.4.4	Chronic Dietary Risk Assessment

Chronic dietary exposure estimates for food and drinking water are well below HED's level of concern (<100% CPAD) for all population subgroups.  The dietary exposure is estimated at 0.000379 mg/kg/day for the general population (1.1% of the cPAD) and 0.001562 mg/kg/day (4.7% of the cPAD) for Children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure.  The results for all populations are summarized in Table 5 below.

5.4.5	Cancer Dietary Risk Assessment

Since thiabendazole is classified as "Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower that those which could cause a disturbance of this hormonal balance," a cancer dietary exposure assessment is not required. 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.

5.4.6	Summary Table

 Table 5.4 6 Summary of Dietary (Food and Drinking Water) Exposure and Risk for Thiabendazole.
                              Population Subgroup
                                 Acute Dietary
                               (99.9 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
 0.012953
                                       26
 0.000379
                                      1.1

 All Infants (<1 year old)
 0.021098
                                       42
 0.000612
                                      1.9
                                      N/A
                                      N/A
 Children 1-2 years old*
 0.034322
                                       69
 0.001562
                                      4.7

 Children 3-5 years old
 0.028211
                                       56
 0.001081
                                      3.3

 Children 6-12 years old
 0.017865
                                       36
 0.000597
                                      1.8

 Youth 13-19 years old
 0.009042
                                       18
 0.000295
                                      0.9

 Adults 20-49 years old
 0.007528
                                       15
 0.000267
                                      0.8

 Adults 50-99 years old
 0.007786
                                       16
 0.000276
                                      0.8

 Females 13-49 years old
 0.007789
                                       16
 0.000256
                                      0.8

*The population subgroup(s) with the highest risk estimates.

6.0 	Residential (Non-Occupational) Exposure/Risk Characterization