Document ID: EPA-HQ-OPP-2013-0268-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-25T04:00Z

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 4.5.4.1 and 4.5.4.2.

Table 4.5.4.1  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 4.5.4.2 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
(AD memo of 6/23/10, T. Leighton, D379421)

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. The Antimicrobials Division has previously conducted an assessment of these uses (D379421, T. Leighton, 6/23/10). No risks of concern were identified.
 
There are several thiabendazole uses which may result in residential exposures  -  exposures to adults and/or children in residential settings. Two antimicrobial exposure scenarios have been assessed for residential exposures. The two uses include treated paint and impregnated sponges. Other antimicrobial uses of thiabendazole are not expected to cause exposure in residential settings.  These uses are use on carpet backing, canvas textiles, wallboard and ceiling tiles, polyurethane foam, plastics and rubber, paper, and coatings and filters used in HVAC systems. These additional uses are not expected to result in exposures in residential settings because there is no direct contact to the treated articles, the vapor pressure of thiabendazole is very low, and the unlikelihood that the treated plastics and rubbers would be used in toys.

Residential exposure and risk to residential handlers of thiabendazole-treated paints, using  brush/roller application and airless sprayer application was assessed.  This exposure is expected to be short-term in duration.  The dermal MOEs of 17,000 and 6,800 for brush/roller application and airless sprayer application, respectively, are not of concern.  The inhalation MOEs of 70,000 and 3,200 for brush/roller and for airless sprayer applications, respectively, are also not of concern, since these MOEs are much greater than the target MOE of 300.

Thiabendazole treated sponges are limited to 600 ppm thiabendazole on a sponge.  Various residue amounts may be transferred from the sponge to food contact surfaces, such as countertops and utensils/glassware, and then to food and subsequently ingested.  A screening-level assessment was conducted by assuming exposures would be similar to a hard surface sanitizer.  If we assume that all of the thiabendazole leaches out of the sponge in a single day, and a new sponge is used every day, then there may be risks of concern to children.  

It is very unlikely that a sponge would release all of the thiabendazole used to treat it in a single day, and the user would use a new sponge every day.  Since this is a very unrealistic assumption, a second aggregate assessment was conducted assuming that 100% of the thiabendazole on a treated sponge is transferred to surfaces over 20 days and that each 20 days the user would use a new sponge (5% released per day).  This assumption is still conservative because (1) sponges will generally be used much longer than 20 days; (2) it is unlikely that 100% of the thiabendazole would be released from the sponge in such a short period; and (3) it is very unlikely that 100% of any released thiabendazole would be transferred to countertops because this assumption does not account any thiabendazole that is washed down the sink or that normally degrades. With this assumption, none of the aggregate exposures represent risks of concern, as all MOEs are greater than the target MOE of 300.

6.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1	Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of thiabendazole (food and drinking water). The acute dietary risk estimates are not of concern to HED (<100% aPAD) at the 99.9[th] exposure percentile for the general U.S. population and all other population subgroups.  Therefore, the acute aggregate risk associated with the proposed uses of thiabendazole is not of concern to HED for the general U.S. population or any population subgroups.

82.2 Short- and Intermediate-Term Aggregate Risk

To assess short- and intermediate-term aggregate risk likely to result from the new and existing thiabendazole uses, HED combined average food and water exposure values with estimates of residential exposure for both adult painters and the general population and small children (ages 1-2 years old) exposed to surfaces cleaned with treated sponges. Tables 7.1 and 7.2 show the aggregate risks for the painters and sponge scenarios. For the painters, the aggregate MOEs were 2000, showing no risks of concern.

A potential risk of concern would be the use of thiabendazole treated sponges, if the Agency assumes that 100% of the thiabendazole on a treated sponge is transferred to surfaces each day. Since this is a very unrealistic assumption, a second aggregate assessment was conducted assuming that 5% of the thiabendazole on sponges is transferred to the surface each day. With this assumption, none of the aggregate exposures represent risks of concern, as all MOEs are greater than the target MOE of 300 (Table 7.2).

Table 7.1.  Short- and Intermediate- Term Aggregate Risk Calculations  - Residential Painter LOC =300
                              Population Subgroup
                                    Average
                           Food & Water Exposure
                                   mg/kg/day
                             Residential Exposure1
                                   mg/kg/day
                                 Aggregate MOE
                                   (food and
                                 residential)2
General U.S. Population
                                   0.000379
                                    0.0046
                                     2000
Youth 13-19 yrs
                                   0.000295
                                       
                                     2000
Adults 20-49 yrs
                                   0.000267
                                       
                                     2000
Adults 50+ yrs
                                   0.000276
                                       
                                     2000
Females 13-49 yrs
                                   0.000256
                                       
                                     2000
1 Residential Exposure = [Dermal exposure + Inhalation Exposure].  
2 Aggregate MOE = [NOAEL (10 mg/kg/day (Avg Food & Water Exposure + Residential Exposure)]

Table 7.2.  Short- and Intermediate- Term Aggregate Risk Calculations  - LOC =300
Population Subgroup
Average
Food & Water
Exposure
mg/kg/day
Residential Exposure1
mg/kg/day
Aggregate MOE
(food and
residential)2
Fraction of Thiabendazole Transferred Daily From Sponge to Surface = 100%
Children 1-2
0.001562
0.113
90
General Population
0.000379
0.02
490
Fraction of Thiabendazole Transferred From Sponge to Surface = 5%
Children 1-2
0.001562
0.00553
1400
General Population
0.000379
0.001
7300
1 Residential Exposure = [Incidental Oral Exposure].  
2 Aggregate MOE = [NOAEL (10 mg/kg/day/ (Avg Food & Water Exposure + Residential Exposure)]
3 These exposure values have been adjusted from the original AD memo to reflect the current, more protective, assumptions for child body weight (11 kg, rather than the 15 kg used previously).

7.3	Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account exposure estimates from dietary consumption of thiabendazole (food and drinking water). The chronic dietary risk estimates are not of concern to HED (<100% aPAD) at the 99.9[th] exposure percentile for the general U.S. population and all other population subgroups. Therefore, the chronic aggregate risk associated with the proposed uses of thiabendazole is not of concern to HED for the general U.S. population or any population subgroups.

8.0	Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to thiabendazole and any other substances and thiabendazole does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that thiabendazole has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Characterization

9.1	Short- and Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protective gear or controls used by a handler can cause exposure levels to differ in a manner specific to each application event.  

Based on the proposed seed treatment registrations, occupational handler exposure is expected.  Occupational seed treatment handlers may experience short- and intermediate-term exposure to thiabendazole while performing seed treatment activities in commercial settings (mixing, loading, applying liquid formulations; bagging treated seed; sewing bags; and multiple activities). In addition, occupational handlers may experience short- and intermediate-term exposure while planting thiabendazole-treated seeds (for the purposes of regulatory seed treatment, planting treated seeds are referred to as `secondary handlers').  However, since the same dermal and inhalation endpoints were selected for short- and intermediate-term exposure durations, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure.  While the number of days treating the proposed seed crops could potentially exceed the typical intermediate-term duration used in HED's occupational assessments, HED has no information to indicate that the same chemical is used consecutively for a long-term duration.  Therefore, chronic occupational handler exposure for seed treatment was not assessed.
Dermal and inhalation risk estimates were combined in this assessment because the toxicological effects for these exposure routes were similar.  

The results of the occupational handler exposure and risk assessment indicate that short-/ intermediate-term dermal and inhalation risks are not of concern (i.e., MOEs >= 300).  Total MOEs range from 650 to 2,200,000 for seed treaters and 1,600 to 220,000 for seed planters. (Tables 9.1.1 and 9.1.2).

Table 9.1.1	Summary of Short-/Intermediate-Term Handler Exposures/Risks for Thiabendazole Seed Treatment
                                   Seed Type
                            Max Application Rate[1]
                               Unit Exposure[2]
                                  (mg/lb ai)
                           Amount of Seed Treated[3]
                                 Absorbed Dose
                                (mg/kg/day)[4]
                                    MOE[5]
                                     Total
                                    MOE[6]
                                       
                                 lb ai/lb seed
                                    Dermal
                                    Inhal.
                                  lb seed/day
                                    Dermal
                                    Inhal.
                                    Dermal
                                    Inhal.
                                       
                  LOADER/APPLICATOR (single layer, no gloves)
                                    alfalfa
                                    0.0020
                                     0.079
                                    0.00034
                                    125,000
                                    1.2E-03
                                    1.1E-03
                                     8,100
                                     9,400
                                                                          4,300
                                    barley
                                    0.00093
                                       
                                       
                                    360,000
                                    1.6E-03
                                    1.4E-03
                                     6,100
                                     7,100
                                                                          3,300
                                     oats
                                    0.0012
                                       
                                       
                                    360,000
                                    2.1E-03
                                    1.8E-03
                                     4,700
                                     5,400
                                                                          2,500
                                      rye
                                    0.0012
                                       
                                       
                                    360,000
                                    2.1E-03
                                    1.8E-03
                                     4,700
                                     5,500
                                                                          2,500
                                   triticale
                                    0.0015
                                       
                                       
                                    360,000
                                    2.7E-03
                                    2.3E-03
                                     3,800
                                     4,400
                                                                          2,000
                                     wheat
                                    0.0012
                                       
                                       
                                    360,000
                                    2.1E-03
                                    1.8E-03
                                     4,700
                                     5,500
                                                                          2,500
                                   Brassica
                                    0.00085
                                       
                                       
                                     3,000
                                    1.3E-05
                                    1.1E-05
                                    800,000
                                    930,000
                                                                        430,000
                                   bulb veg
                                    0.00084
                                       
                                       
                                     3,000
                                    1.2E-05
                                    1.1E-05
                                    810,000
                                    940,000
                                                                        430,000
                                   cucurbits
                                    0.0046
                                       
                                       
                                     3,000
                                    6.8E-05
                                    5.8E-05
                                    150,000
                                    170,000
                                                                         79,000
                                    spinach
                                    0.00060
                                       
                                       
                                     3,000
                                    8.9E-06
                                    7.7E-06
                                   1,100,000
                                   1,300,000
                                                                        600,000
                                   root veg
                                    0.0018
                                       
                                       
                                     3,000
                                    2.6E-05
                                    2.2E-05
                                    380,000
                                    440,000
                                                                        210,000
                                    soybean
                                    0.00024
                                       
                                       
                                    281,250
                                    3.3E-04
                                    2.9E-04
                                    30,000
                                    35,000
                                                                         16,000
                        SEWER (single layer, no gloves)
                                    alfalfa
                                    0.0020
                                    0.0062
                                    0.00023
                                    125,000
                                    9.7E-05
                                    7.2E-04
                                    100,000
                                    14,000
                                                                         12,000
                                    barley
                                    0.00093
                                       
                                       
                                    360,000
                                    1.3E-04
                                    9.6E-04
                                    77,000
                                    10,000
                                                                          9,200
                                     oats
                                    0.0012
                                       
                                       
                                    360,000
                                    1.7E-04
                                    1.2E-03
                                    60,000
                                     8,100
                                                                          7,100
                                      rye
                                    0.0012
                                       
                                       
                                    360,000
                                    1.7E-04
                                    1.2E-03
                                    60,000
                                     8,100
                                                                          7,200
                                   triticale
                                    0.0015
                                       
                                       
                                    360,000
                                    2.1E-04
                                    1.6E-03
                                    48,000
                                     6,400
                                                                          5,700
                                     wheat
                                    0.0012
                                       
                                       
                                    360,000
                                    1.7E-04
                                    1.2E-03
                                    60,000
                                     8,100
                                                                          7,200
                                   Brassica
                                    0.00085
                                       
                                       
                                     3,000
                                    9.8E-07
                                    7.3E-06
                                  10,000,000
                                   1,400,000
                                                                      1,200,000
                                   bulb veg
                                    0.00084
                                       
                                       
                                     3,000
                                    9.7E-07
                                    7.2E-06
                                  10,000,000
                                   1,400,000
                                                                      1,200,000
                                   cucurbits
                                    0.0046
                                       
                                       
                                     3,000
                                    5.3E-06
                                    4.0E-05
                                   1,900,000
                                    250,000
                                                                        220,000
                                    spinach
                                    0.00060
                                       
                                       
                                     3,000
                                    7.0E-07
                                    5.2E-06
                                  14,000,000
                                   1,900,000
                                                                      1,700,000
                                   root veg
                                    0.0018
                                       
                                       
                                     3,000
                                    2.1E-06
                                    1.5E-05
                                   4,900,000
                                    660,000
                                                                        580,000
                                    soybean
                                    0.00024
                                       
                                       
                                    281,250
                                    2.6E-05
                                    1.9E-04
                                    380,000
                                    52,000
                                                                         45,000
                       BAGGER (single layer, no gloves)
                                    alfalfa
                                    0.0020
                                    0.0091
                                    0.00016
                                    125,000
                                    1.4E-04
                                    5.0E-04
                                    70,000
                                    20,000
                                                                         16,000
                                    barley
                                    0.00093
                                       
                                       
                                    360,000
                                    1.9E-04
                                    6.7E-04
                                    53,000
                                    15,000
                                                                         12,000
                                     oats
                                    0.0012
                                       
                                       
                                    360,000
                                    2.5E-04
                                    8.6E-04
                                    41,000
                                    12,000
                                                                          9,000
                                      rye
                                    0.0012
                                       
                                       
                                    360,000
                                    2.4E-04
                                    8.6E-04
                                    41,000
                                    12,000
                                                                          9,100
                                   triticale
                                    0.0015
                                       
                                       
                                    360,000
                                    3.1E-04
                                    1.1E-03
                                    33,000
                                     9,300
                                                                          7,200
                                     wheat
                                    0.0012
                                       
                                       
                                    360,000
                                    2.4E-04
                                    8.6E-04
                                    41,000
                                    12,000
                                                                          9,100
                                   Brassica
                                    0.00085
                                       
                                       
                                     3,000
                                    1.4E-06
                                    5.1E-06
                                   6,900,000
                                   2,000,000
                                                                      1,500,000
                                   bulb veg
                                    0.00084
                                       
                                       
                                     3,000
                                    1.4E-06
                                    5.0E-06
                                   7,000,000
                                   2,000,000
                                                                      1,500,000
                                   cucurbits
                                    0.0046
                                       
                                       
                                     3,000
                                    7.8E-06
                                    2.8E-05
                                   1,300,000
                                    360,000
                                                                        280,000
                                    spinach
                                    0.00060
                                       
                                       
                                     3,000
                                    1.0E-06
                                    3.6E-06
                                   9,800,000
                                   2,800,000
                                                                      2,200,000
                                   root veg
                                    0.0018
                                       
                                       
                                     3,000
                                    3.0E-06
                                    1.1E-05
                                   3,300,000
                                    940,000
                                                                        740,000
                                    soybean
                                    0.00024
                                       
                                       
                                    281,250
                                    3.8E-05
                                    1.3E-04
                                    260,000
                                    74,000
                                                                         58,000

                              MULTIPLE ACTIVITIES
(combination of loader/applicator without gloves + no coveralls, sewer without gloves, stacker without gloves)
                                    alfalfa
                                    0.0020
                                     0.134
                                    0.0016
                                    125,000
                                    2.1E-03
                                    5.0E-03
                                     4,800
                                     2,000
                                                                          1,400
                                    barley
                                    0.00093
                                       
                                       
                                    360,000
                                    2.8E-03
                                    6.7E-03
                                     3,600
                                     1,500
                                                                          1,100
                                     oats
                                    0.0012
                                       
                                       
                                    360,000
                                    3.6E-03
                                    8.6E-03
                                     2,800
                                     1,200
                                                                            820
                                      rye
                                    0.0012
                                       
                                       
                                    360,000
                                    3.6E-03
                                    8.6E-03
                                     2,800
                                     1,200
                                                                            820
                                   triticale
                                    0.0015
                                       
                                       
                                    360,000
                                    4.5E-03
                                    1.1E-02
                                     2,200
                                      930
                                                                            650
                                     wheat
                                    0.0012
                                       
                                       
                                    360,000
                                    3.6E-03
                                    8.6E-03
                                     2,800
                                     1,200
                                                                            820
                                   Brassica
                                    0.00085
                                       
                                       
                                     3,000
                                    2.1E-05
                                    5.1E-05
                                    470,000
                                    200,000
                                                                        140,000
                                   bulb veg
                                    0.00084
                                       
                                       
                                     3,000
                                    2.1E-05
                                    5.0E-05
                                    480,000
                                    200,000
                                                                        140,000
                                   cucurbits
                                    0.0046
                                       
                                       
                                     3,000
                                    1.2E-04
                                    2.8E-04
                                    87,000
                                    36,000
                                                                         26,000
                                    spinach
                                    0.00060
                                       
                                       
                                     3,000
                                    1.5E-05
                                    3.6E-05
                                    660,000
                                    280,000
                                                                        200,000
                                   root veg
                                    0.0018
                                       
                                       
                                     3,000
                                    4.4E-05
                                    1.1E-04
                                    230,000
                                    94,000
                                                                         67,000
                                    soybean
                                    0.00024
                                       
                                       
                                    281,250
                                    5.6E-04
                                    1.3E-03
                                    18,000
                                     7,400
                                                                          5,200
1	Application Rates based on proposed label uses for thiabendazole (see Table 4.1).
2	Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment.  In cases where available data represents workers wearing chemical-resistant gloves.  Unit exposures representing workers without chemical-resistant gloves were calculated by increasing exposure to the hands-only portion of the total dermal exposure measurement assuming chemical-resistant gloves provide 90% protection (i.e., dividing non-gloved hand exposures by 0.1), the standard protection factor assumption for chemical-resistant gloves.
3	HED default for lb seed treated per day from HED Exposure Science Advisory Council Interim Policy 15.1 and the BEAD memo "Acres Planted Per Day and Seeding Rates of Crops Grown in the United States" (J. Becker, March 2011).	
4	Daily Absorbed Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x Absorption (0.5 % for dermal) / body weight (80 kg.
5	MOE = NOAEL (dermal = 10 mg/kg/day for short-/intermediate-term exposure; inhalation = 10 mg/kg/day for short-/intermediate-term) / Absorbed Dose (mg/kg/day).  LOC = 300.
6	Total MOE = 1 /[(1 / Dermal MOE) + (1 / Inhalation MOE)]

Table 9.1.2.	Summary of Secondary Handler (Planter) Exposures and Risks for Thiabendazole 
(Single Layer, No Gloves during Loading Only).
                                   Seed Type
                            Max Application Rate[a]
                               Unit Exposure[b]
                                  (mg/lb ai)
                       Amount of Seed Planted Per Day[c]
                                 Absorbed Dose
                                 (mg/kg/day) d
                                    MOE[e]
                                     Total
                                    MOE[f]
                                       
                                 lb ai/lb seed
                                    Dermal
                                    Inhal.
                                  lb seed/day
                                    Dermal
                                    Inhal.
                                    Dermal
                                    Inhal.
                                       
                                    alfalfa
                                    0.0020
                                     1.51
                                    0.0034
                                                                          3,000
                                    5.7E-04
                                    2.6E-04
                                    18,000
                                    39,000
                                                                         12,000
                                    barley
                                    0.00093
                                       
                                       
                                                                         27,600
                                    2.4E-03
                                    1.1E-03
                                     4,100
                                     9,200
                                                                          2,900
                                     oats
                                    0.0012
                                       
                                       
                                                                         18,000
                                    2.0E-03
                                    9.2E-04
                                     4,900
                                    11,000
                                                                          3,400
                                      rye
                                    0.0012
                                       
                                       
                                                                         21,800
                                    2.4E-03
                                    1.1E-03
                                     4,100
                                     9,100
                                                                          2,800
                                   triticale
                                    0.0015
                                       
                                       
                                                                         21,800
                                    3.1E-03
                                    1.4E-03
                                     3,200
                                     7,200
                                                                          2,200
                                     wheat
                                    0.0012
                                       
                                       
                                                                         37,600
                                    4.2E-03
                                    1.9E-03
                                     2,400
                                     5,300
                                                                          1,600
                                   Brassica
                                    0.00085
                                       
                                       
                                                                            400
                                    3.2E-05
                                    1.4E-05
                                    310,000
                                    690,000
                                                                        220,000
                                   bulb veg
                                    0.00084
                                       
                                       
                                                                          2,480
                                    2.0E-04
                                    8.8E-05
                                    51,000
                                    110,000
                                                                         35,000
                                   cucurbits
                                    0.0046
                                       
                                       
                                                                          6,970
                                    3.0E-03
                                    1.4E-03
                                     3,300
                                     7,400
                                                                          2,300
                                    spinach
                                    0.00060
                                       
                                       
                                                                          2,000
                                    1.1E-04
                                    5.1E-05
                                    88,000
                                    200,000
                                                                         61,000
                                   root veg
                                    0.0018
                                       
                                       
                                                                          5,230
                                    8.7E-04
                                    3.9E-04
                                    11,000
                                    26,000
                                                                          7,900
                                    soybean
                                    0.00024
                                       
                                       
                                                                         33,300
                                    7.5E-04
                                    3.4E-04
                                    13,000
                                    29,000
                                                                          9,100
a	Application Rates based on proposed label uses for thiabendazole (see Table 4.1).
b	Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment.  Available data represents workers wearing chemical-resistant gloves.  Unit exposures representing workers without chemical-resistant gloves were calculated by increasing exposure to the hands-only portion of the total dermal exposure measurement assuming chemical-resistant gloves provide 90% protection (i.e., dividing non-gloved hand exposures by 0.1), the standard protection factor assumption for chemical-resistant gloves.
c	HED default for lb seed planted per day from HED Exposure Science Advisory Council Interim Policy 15 and the BEAD memo "Acres Planted Per Day and Seeding Rates of Crops Grown in the United States" (J. Becker, March 2011).
d	Daily Absorbed Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x Absorption (0.5% for dermal) / body weight (80 kg).
e	MOE = NOAEL (dermal = 10 mg/kg/day for short-/intermediate-term exposure; inhalation = 10 mg/kg/day for short-/intermediate-term) / Absorbed Dose (mg/kg/day).  LOC = 300.
f	Total MOE = 1 / [(1 / Dermal MOE) + (1 / Inhalation MOE)]

9.2	Short-/Intermediate Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. The potential for dermal and inhalation post-application exposures following the planting of thiabendazole-treated seeds is unlikely because sustained levels of contact with treated seed after it has been placed in the soil or other planting media would not be expected because no routine cultural practice required for the production of agricultural commodities involves such an activity as defined in the no/low contact criteria in the WPS. Therefore, while the requirement of a 12 hour restricted entry interval (REI) for potential contact with treated seed following planting applies based on the acute toxicity of technical thiabendazole, so does the potential exception to this requirement per WPS guidance for situations where contact with residue is not expected. 

Similarly, a post-application inhalation exposure assessment is not required, as exposure is expected to be negligible. However, the seed treatment handler assessments provide quantitative inhalation exposure assessments for seed treaters and planters, both of which would be protective of most post-application inhalation exposure scenarios. 

10.0	References

Cropp-Kohlligian, B. 3/10/14. D416470. Thiabendazole: Acute Probabilistic and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Registration for New Seed Treatment Uses on Assorted Vegetables/Small Grains and Increased Seed Treatment Use Rate on Soybean.

Dunbar, A. 7/11/13. TXR No. 0056686. Thiabendazole:  Summary of Hazard and Science Policy Council (HASPOC) Meeting on June 6, 2013:  Recommendations on Data Requirement for a Subchronic Inhalation Toxicity Study and Thyroid Assays in Pregnant Animals, Fetuses, Postnatal Animals, and Adult Animals.

Hummel, S. 12/13/13. D410807, D410833, D313507. Thiabendazole.  PP# 3F8166.  New Seed Treatment 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).  Summary of Analytical Chemistry and Residue Data.  Multiresidue Method Data.

Hummel, S. 8/12/10. D381074. Thiabendazole Human Health Risk Assessment for Seed Treatment use on Corn.

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

O'Rourke, K. 2/19/14. D416472. Thiabendazole:  Occupational/Residential Exposure Assessment for Proposed Seed Treatment Uses on Alfalfa, Brassica, Bulb Vegetables, Cucurbits, Root Vegetables, Small Grain Cereals, Spinach and Soybeans.

Wolf, J., Hetrick, J., et al. 2/24/14. D410805. Thiabendazole: Drinking Water Assessment for Proposed New Uses of the Fungicide Mertect(R) 340-F (EPA Reg. No. 100-889) as a Seed Treatment.

Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

Thiabendazole Guideline Toxicology Data Requirements: The toxicology data requirements (40 CFR 158.340) for food use are presented in Table A.1.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

            Table A.1.1. Guideline Data Requirements: Thiabendazole
                                     Test
                                       
                                   Technical
                                       
                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Primary Eye Irritation	
870.2500    Primary Dermal Irritation	
870.2600    Dermal Sensitization	
                                      yes
                                      yes
                                     yes*
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)	
870.3150    Oral Subchronic (nonrodent)	
870.3200    21-Day Dermal	
870.3250    90-Day Dermal	
870.3465    28/90-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      no
                                     no**
                                      yes
                                      yes
                                      yes
                                       -
                                       -
870.3700a  Developmental Toxicity (rodent)	
870.3700b  Developmental Toxicity (nonrodent)	
870.3800    Reproduction	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Oncogenicity (rat)	
870.4200b  Oncogenicity (mouse)	
870.4300    Chronic/Oncogenicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5375    Mutagenicity -- Structural Chromosomal Aberrations	
870.5500    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotox. (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotox. Screening Battery (rat)	
870.6200b  90-Day Neuro. Screening Battery (rat)	
870.6300    Develop. Neuro	
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                       -
                                       -
                                      yes
                                      yes
                                       -
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
xxxxxxx    Developmental thyroid study	
                                      yes
                                      yes
                                      yes
                                    yes***
                                      yes
                                      yes
                                      yes
                                       -
                                       
* waived for Thiabendazole hypophosphite (HED Doc No. 010140)
** waived (HASPOC TXR: 0056686)
*** required (HASPOC TXR: 0056686)
A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Thiabendazole 
                                 Guideline No.
                                  Study Type
                                    MRID #
                                    Results
                               Toxicity Category
870.1100
Acute Oral Toxicity -  rat
46556301
LD50 >5000 mg/kg
                                      IV
870.1200
Acute Dermal Toxicity-rabbit
46556302
LD50  >5000 mg/kg
                                      IV
870.1300
Acute Inhalation Toxicity -  rat

47321101
LC50 >0.53 mg/L(both sexes)
                                      III
870.2400
Acute Eye Irritation
46556303
Reversible within 48 hours
                                      III
870.2500
Acute Dermal Irritation
46556304
Non-irritating
                                      IV
870.2600
Skin Sensitization
46556305
Non sensitizer
                                       -

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile 
                           Guideline No./ Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100
3- month oral toxicity study - rats (gavage)
 42942801 (1990)
Acceptable/Guideline
0, 25, 100, 400 mg/kg/day
TXR 0013986
LOAEL = 100 mg/kg/day based on histopathological changes in the liver (centrilobular hypertrophy), thyroid (follicular cell hyperplasia), kidneys (hyperplasia of transitional epithelium, tubular degeneration) and spleen (congested and pigmented).
NOAEL = 25 mg/kg/day
870.3100
3- month oral toxicity study - rats (gavage)
42942802 (1990)
Acceptable/Guideline
0, 10, 40, 160, 320 mg/kg/day
TXR 0013986
LOAEL = 40 mg/kg/day 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). 
NOAEL = 10 mg/kg/day
870.3150
3-month dog (capsule)
42993601 (1993)
Acceptable/Guideline
0, 35, 75, 150 mg/kg/day
TXR 0013986
Increased emesis and gall bladder epithelial cytoplasmic vacuolation at the mid and high dose.  LOAEL is equivocal because the toxicological significance of emesis and gall bladder epithelial cytoplasmic vacuolation could not be determined. 
NOAEL is 150 mg/kg/day
870.3200
21 - Day dermal toxicity - rabbits
41259501  (1989)
Acceptable/Guideline
0, 50, 200, 1000 mg/kg/day 
LOAEL for systemic toxicity = >1000 mg/kg/day
NOAEL for systemic toxicity = 1000 mg/kg/day
LOAEL for dermal toxicity = >1000 mg/kg/day
LOAEL for systemic toxicity = 1000 mg/kg/day
870.3700a
Developmental Toxicity- Rat
gavage

42942803 (1990)
Acceptable/Guideline
0, 10, 40, 80 mg/kg/day GD 6-17
TXR 0013986
Maternal LOAEL =  40 mg/kg/day, based on reduced maternal body weight gains (↓12 %) and reduced feed consumption (↓11-15 %) throughout the treatment period.. 
Maternal NOAEL = 10 mg/kg/day.
Developmental LOAEL = 40 mg/kg/day, based on decreased fetal body weights. At dose levels of 40 and 80 mg/kg/day, fetal body weights were slightly but significantly (p<=0.05) reduced (5-6%) in females and were slightly but significantly (p<=0.05) reduced in males (5%) at 80 tug/kg/day but not at 40 mg/kg/day (3%). There were no treatment-related malformations or variations noted in the fetuses at any dose level. 
Developmental NOAEL = 10 mg/kg/day.
870.3700b
Developmental Toxicity- Rabbit
42942804 (1991) 42993602 (1993)
42942807 (1989) - range finding study
Acceptable/Guideline
0, 50, 150, 600 mg/kg/day
GD 6-18
TXR 0013986

Maternal LOAEL = 600 mg/kg/day, based on reduced maternal body weight gain (↓69%, p<= 0.05, days 6-19) and reduced feed consumption (↓6-30%, days 7 and 13-19; ↓1%, day 10; p<=0.05) with a recovery during the post-treatment period.. 
Maternal NOAEL = 150 mg/kg/day.
Developmental LOAEL = 600 mg/kg/day, based on increases in the total number of resorptions (12 vs. 6 for controls), increased litter (37.5% vs. 8.3% for controls) and fetal (10.4% vs 1.7% for controls) incidences of variation of lung lobation and incompletely ossified metacarpals in the fetal (28.1% vs. 8.5% for controls) and litter incidence (56.2% vs. 16.7% for controls) as well as decreased fetal body weights (↓13% males, ↓11% females; p<=0.05). . 
Developmental NOAEL = 150 mg/kg/day.
870.3700c
Developmental Toxicity- Mice
Gavage

 43753702 (1995)
Acceptable/Guideline
0, 25, 100, 200 mg/kg/day
GD 6-15
TXR 0013986
Maternal LOAEL = 100 mg/kg/day, based on reduced maternal body weight gains (↓15 %) throughout the treatment period and reduced feed consumption (↓13 %) during GD day 12-14. 
Maternal NOAEL = 25 mg/kg/day.
Developmental LOAEL = 100 mg/kg/day, based on decreased fetal body weights (↓3-5%). No malformations or variations were observed at doses of thiabendazole up to 200 mg/kg/day.
Developmental NOAEL = 25 mg/kg/day.
870.3800
2-Generation reproduction- Rat
Dietary
43190301 (1994)
Acceptable/Guideline
0, 10, 30, 90 mg/kg/day
Systemic toxicity LOAEL = 30 mg/kg/day based on reduced body weight gain (10-16%, p<=0.05, F0 males; 7-18%, p<=0.05, F1 males) and food consumption (3-4%, p<=0.05, F0 males; 4-5%, p<=0.05, F1 males ) vs. controls. Females were not affected at this dose.  At 90 mg/kg/day, these effects were pronounced in males and females.
 Systemic toxicity NOAEL = 10 mg/kg/day.

Reproductive toxicity LOAEL = >= 90 mg/kg/day. 
Reproductive toxicity NOAEL = 90 mg/kg/day.

Developmental toxicity LOAEL = 90 mg/kg/day based on reduced body weights in the offspring during lactation in both sexes of the F1 (↓5-8%, days 4-21, p<=0.05) and F2 (↓7-10%, days 14-21, p<=0.05) generations.
Developmental toxicity NOAEL = 30 mg/kg/day.
870.4100
12-Month Chronic Oral Toxicity (capsule) - Dogs

42809701 (1993)
Acceptable/Guideline
0, 10, 40, 160 mg/kg/day
LOAEL = 40 mg/kg/day based on increased liver weight, splenic erythropoiesis and hemosiderosis in both sexes.
NOAEL = 10 mg/kg/day
Thyroids had very slight follicular enlargement in high-dose females, while very slight to slight follicular cell hypertrophy was observed in high-dose males and females.
870.4100
24-Month Chronic/Carcinogenicity -Rats
Dietary
43593201 ((1993)
Acceptable/Guideline
0, 10.1, 30.2, 91.8 mg/kg/day
LOAEL = 30 mg/kg/day based on reduced body weight and body weight gains and liver hypertrophy (males).
NOAEL = 10 mg/kg/day
Thiabendazole induced thyroid adenomas in male rats at dosages of >=30 mg/kg/day.
870.4200
24-Month Carcinogenicity in Mice, Dietary
00031447 (1980)
Acceptable/Guideline
 0,  31-42 (reduced to 5.6-8.3 on 7[th] week), 63-121, 184-372 mg/kg/day for males and 
0,,94-131 ( reduce to 5.7-9.9 on 7[th] week),209-368, and 534-1005 mg/kg/day for females 
LOAEL = 209-368 mg/kg/day for ♀, 63-21 mg/kg/day for ♂ based on decreased body weight gains and increased liver weights.
NOAEL =  5.7-9.9 mg/kg/day for ♀, 5.6-8.3 mg/kg/day for ♂

There were no treatment-related neoplastic lesions detected in the animals when compared to controls.
870.6200 
Acute neurotoxicity in rats
48996310 (2012)
Acceptable/Guideline
0, 50, 200, 2000 mg/kg
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.
NOAEL = 50 mg/kg
870.6200 
Subchronic neurotoxicity in rats
48996309 (2012)
Acceptable/Guideline
0 , 200, 750, and 1500 ppm
M: 0, 13, 47, 95 mg/kg/day
F: 0, 15, 54, 108 mg/kg/day

Systemic toxicity LOAEL = 1500 ppm (95 mg/kg/day) based on decreased mean body weight gains, mean absolute body weights, and mean food consumption.
Systemic toxicity NOAEL = 750 ppm (47 mg/kg/day)
Neurotoxicity LOAEL > 1500 ppm (>95 mg/kg/day). 
Neurotoxicity NOAEL = 1500 ppm (95 mg/kg/day).
870-5100
Bacterial reverse mutation
Salmonella typhimurium strains and Escherichia coli strains 
42361801 (1992)
Acceptable/Guideline

Five doses of thiabendazole ranging from 100 ug/plate to 6000 ug/plate +/- S9, did not induce mutations. Compound precipitation and cytotoxicity for the majority of strains was observed at levels >=1000 ug/plate +/- S9.  Based on these findings, it was concluded that thiabendazole was tested over an appropriate range of concentrations and was not genotoxic.
870.5300
In Vitro Gene Mutation assay in mouse lymphoma cells (mammalian cell gene mutation assay)
46561901 (2005)
Acceptable/Guideline
Excessive cytotoxicity was observed at 250 ug/mL and above (+/-S9).  There was no evidence of induced mutant colonies by thiabendazole over background in the presence or absence of S9 activation.
870.5375
In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay in Human Peripheral Blood Lymphocytes)
46561902 (2005)
Acceptable/Guideline
Thiabendazole was tested up to the limit dose (2013 ug/mL).  Precipitation of the test material was observed at >=500 ug/mL.  The positive controls induced the appropriate response in the presence and absence of S9 in both trials.  There was no evidence of chromosome aberrations in cultured human lymphocytes induced by thiabendazole over background in the presence or absence of S9-activation.
870-5385
(in vivo bone marrow chromosome aberration assay, male CRL:CO-I mice) - Mouse

43328304 (1994)
Acceptable/Guideline
Single oral dose of Thiabendazole (99.8% purity) in methylcellulose at levels of 200, 667, and 2,000 mg/kg bodyweight. Bone marrow was sampled 6, 24, and 48 hours after treatment.
All mice survived to their scheduled termination and clinical signs of toxicity were noted at 667 and 2,000 mg/kg. There were no significant increases in the incidence of chromosome aberrations at any sampling time. The positive control induced significant increases in cells with chromosome aberrations.
870-5385
In vitro mammalian cell cytogenetic assay in human embryo fibroblasts
00098002 (1977)
Acceptable/non-Guideline

The test is negative up to the highest dose tested (50 ug/mL) without S9 activation. 
870-5385
in vitro mammalian cell cytogenetic assay in W1-38 human fibroblasts
00125297 (1977)
Acceptable/non-Guideline

The test is negative up to precipitating levels (1000 ug /mL) without S9 activation. 
870-5385
In vivo cytogenetic assay
00098002 (1977)
Acceptable/Guideline

The test was negative in Wistar rats administered single doses of
10-1000 mg/kg by oral gavage or 30-300 mg/kg once daily for 5 consecutive days. Lethality was seen in the high-dose group but there was no evidence of bone marrow cytotoxicity. The study is classified as Acceptable and satisfies the 
870-5550
In vitro Alkaline/Elution in rat hepatocytes
41170103 (1989)
Acceptable/Non-guideline
Thiabendazole did not induce DNA strand breakage in primary rat hepatocytes exposed to concentrations up to the level of its insolubility (1.3 mM) in culture medium.
870.5450
Dominant lethal assay in mice

42085301 (1991)
Unacceptable, doubtful if an adequate high dose was used.
Reportedly negative for the induction of dominant lethal in mice treated for 5 days up to 500 mg/kg/day.  However, no clinical or reproductive effects at HDT (TXR 0010290)
870.7485
Metabolism and pharmacokinetics
(Rat)
42114701 (1990)
Acceptable/Guideline
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.

[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.
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.
870.7600
Dermal penetration
(Rat)
 47705131 (2004), 47705102 (2004), 47705101(2004), 47705106 (2009)
Acceptable/Guideline 

TXR 0055373.
Triple Pack of dermal absorption studies with thiabendazole formulated as TECTO 500 SC.  OPP has reviewed the data and calculated a DAF of 0.5%.  This DAF of 0.5% for TECTO 500 SC is also appropriate for thiabendazole formulated as Maxim Quattro.
870-7800
Immunotoxicity
48996311 (2012)
Acceptable/Guideline

Systemic toxicity LOAEL = 5000 ppm (1027 mg/kg/day) based on significant increase in liver weight (> 25%)
Systemic toxicity NOAEL = 1000 ppm (205.6 mg/kg bw/day)
Immunotoxicity LOAEL = 5000 ppm (1027 mg/kg/day) based on significant decrease in total spleen activity
Immunotoxicity NOAEL = 1000 ppm (205.6 mg/kg bw/day)
Non- guideline Special study: Thyroxine clearance (male rat) 
43593202 (1995)
Acceptable/non-guideline
0, 10, 90, 270 mg/kg/day for 13 weeks followed by 14 week recovery
LOAEL = 90 mg/kg/day based on centrilobular hepatocellular
hypertrophy and thyroid follicular cell hyperplasia
NOAEL = 10 mg/kg/day

The data support the hypothesis that thiabendazole alters thyroid hormone homeostasis in male rats resulting in hypothyroidism. The study authors contend that the primary effect of thiabendazole is on the liver, resulting in hepatocellular hypertrophy [microsomal enzyme induction presumed, but not measured in the study]. Enhanced hepatic metabolism of the thyroid hormones leads to decreased serum levels. The decreased serum levels of the hormones cause an increased release of TSH. The higher serum TSH levels, in turn, causes thyroid hypertrophy and hyperplasia.

A.3	Hazard Identification and Endpoint Selection

A.3.1	Acute Reference Dose (aRfD) - General Population
      
Study Selected:  Acute neurotoxicity study-rat 	

MRID No: 48996310

Executive Summary: In an acute neurotoxicity study (MRID 48996310), groups of 10 nonfasted, 6-week-old Crl:CD(SD) rats/sex/dose) were given a single oral dose of thiabendazole (99.3% a.i., batch/lot # HK 1998/011) in 0.5% carboxymethylcellulose at doses of 0, 50, 200, or 2000 mg/kg bw and observed for 14 days.  Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was performed in 10 animals/sex/group prior to the initiation of dosing (day -6), at the time of peak effect (~ 3 hours post dosing) on study day 0, and on study days 7 and 14.  Cholinesterase activity was not determined.  At study termination, 5 randomly selected rats/sex/group were euthanized and perfused in situ for neuropathological examination.  Of the perfused animals, rats from the control and 2000 mg/kg bw groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues. 

Treatment with 200 and 2000 mg/kg bw of thiabendazole produced multiple signs of transient neurotoxicity in males and females at the peak time of dosing on day 0.  Effects at 200 mg/kg bw included reduced body temperature in males (p<0.05), reduced rearing counts in females (↓54%), and statistically significant (<0.01) reductions in both cumulative total activity counts (↓37-39%) and cumulative ambulatory counts (46%) in both males and females.  Neurotoxic effects at 2000 mg/kg bw were more pronounced, and included reduced rearing and reduced body temperature in both males and females; lacrimation, slightly drooping eyelids, increased time to first step, and a "slightly impaired but definite" gait score (in one animal) in females; and statistically significant reductions in cumulative total activity counts and cumulative ambulatory counts in both males and females.  All signs of neurotoxicity were transient, as no effects were observed on Day 7 or 14.  No adverse, treatment-related neurotoxic effects were observed in males or females at 50 mg/kg bw.

In addition to neurotoxicity, treatment with 200 and 2000 mg/kg bw of thiabendazole also produced statistically significant reductions in body weight, body weight gain, and food consumption.  Mean absolute body weights were reduced throughout the study in males at 2000 mg/kg bw with final body weight reduced by 10%, while reductions in absolute body weights in females at 2000 mg/kg bw were transient, returning to values comparable to controls by study day 9.  Overall body weight gain (Days 0-15) was significantly reduced in males (↓33%), but not females, at 2000 mg/kg bw.  Daily body weight gains over days 0-1 were significantly reduced in males and females at 200 mg/kg bw and females at 50 mg/kg bw, but no differences were observed in mean absolute body weight or overall body weight gain.  Reductions in food consumption were transient, with daily consumption values in males and females at 2000 mg/kg bw returning to those of controls by study day 6.  However, overall food consumption in males was significantly reduced compared to controls (↓16%).  Food consumption was also reduced over days 0-1 in males and females at 200 mg/kg bw.  The transient decrease in food consumption and body weight gain that occurred over days 0-1 in males and females at 200 mg/kg bw are considered an adverse effect of treatment when considered in conjunction with the adverse neurotoxicity signs.   

Treatment with thiabendazole did not affect clinical signs, neuropathology, brain weight, or brain dimensions.     

Based on the effects seen in this study, the LOAEL for Sprague-Dawley rats was 200 mg/kg bw based on transient changes 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), and reduced body weight gain (p<0.01) and food consumption (↓44%, p<0.01) on day 1 with a NOAEL of 50 mg/kg bw.

Dose and Endpoint for Establishing an aRfD:  50 mg/kg based on transient changes 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), and reduced body weight gain (p<0.01) and food consumption (↓44%, p<0.01) on day 1 at the LOAEL of 200 mg/kg
      
Uncertainty Factor (UF): 1000 (10x for interspecies extrapolation , 10x for intraspecies variation and 10x data base uncertainty factor for lack of a developmental thyroid study).
      
Comments about Study/Endpoint:  The observed effects occurred after a single oral exposure. This endpoint is appropriate for the acute dietary exposure risk assessment. 
      
        
      aRfD=aPAD(General Population)=50 mg/kg (NOAEL)1000 UF=0.05 mg/kg
A.3.2 	Chronic Reference Dose (RfD)  -  General Population

Study Selected: Chronic/Carcinogenicity in rats

MRID No.:  43593201.

Executive Summary: In a combined chronic/oncogenicity study (MRID 43593201), thiabendazole (>98.9% a.i.) was administered to 50 Sprague-Dawley Crl:CD BR rats/sex/dose in the diet at dose levels of 0, 10, 30, or 90 mg/kg/day (achieved average doses of 0, 10.1, 30.2, or 91.8 mg/kg/day) for 104 weeks.

There were no treatment-related effects on survival, clinical signs, food consumption, ophthalmoscopic findings, urinalysis, or gross pathology.  Body weights and body weight gains were generally lower (↓7-30%) throughout the study for the mid- and high-dose males and high-dose females.  Reduced body weight gains (↓15, ↓28, and ↓19%, p<=0.05) for the mid- and high-dose males and high-dose females, respectively, compared to the controls were observed at week 103.  A reduced body weight gain (↓10%, not statistically significant) was also noted at this time for the mid-dose females.

Significant increases (↑36-79%, p<=0.05) in total serum cholesterol observed in the high-dose group were judged to be treatment-related.  In the high-dose males, increased (↑29%, p<=0.05) relative (to body) liver weights and an increased incidence of centrilobular hepatocellular hypertrophy (28/50 treated vs 0/50 controls) were also detected.  Centrilobular hepatocellular hypertrophy was also observed in 7/50 mid-dose males.  In the high-dose females, an increased (↑45%, p<=0.05) relative thyroid weights and increased incidences of thyroid focal cystic follicular cell hyperplasia (6/50 treated/2/50 controls) and diffuse follicular cell hypertrophy (2/50 treated vs 0/50 controls) were observed.  Thyroid diffuse follicular cell hypertrophy was also observed (4/50 treated vs 0/50 controls) in the high-dose males.  The systemic LOAEL is 30 mg/kg/day based on reduced body weights and body weight gains and liver hypertrophy (males).  The systemic NOAEL is 10 mg/kg/day.

Dose and Endpoint for establishing cRfD: 10 mg/kg/day based on decreased body weight gains and liver hypertrophy at 30 mg/kg/day.
      
Uncertainty Factor (UF): 300 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a thyroid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thyroid study).

Comments about Study/Endpoint/Uncertainty Factor(s): The chronic toxicity/carcinogenicity study in rats provides the appropriate route and duration of exposure. The results of the 14-week feeding study in rats (MRID No. 42942802) with a NOAEL of 10 mg/kg/day 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) provide support for the critical study.  Also the chronic dog gavage study (MRID 42809701) provides a NOAEL of 10 mg/kg/day based on increased liver weight, splenic erythropoiesis and hemosiderosis in both sexes at 40 mg/kg/day. Thyroids had very slight follicular enlargement in high-dose females, while very slight to slight follicular cell hypertrophy was observed in high-dose males and females (dogs).
 
      cRfD=cPAD=10 mg/kg/day (NOAEL)300 UF=0.033 mg/kg/day

A.3.3   	Incidental Oral Exposure (Short- and Intermediate-Term)
      
Study Selected: Subchronic Oral Toxicity Study in Rats (MRID 42942802).  

Executive Summary:  In a subchronic toxicity study (MRID 42942802), thiabendazole (99.4% a.i.) was administered to Crl:CD(SD) albino rats (10/sex/dose) in the diet at nominal dose levels of 10, 40, 160, or 320 mg/kg/day (achieved doses:  0, 9.4, 37, 149, and 302 mg/kg/day for males; 0, 9.4, 38, 152, and 302 mg/kg/day for females) for 13 weeks.  

Clinical signs observed during the study included alopecia in animals dosed at 160 and 320 mg/kg/day and appeared to be treatment-related.  In each of these groups 2/10 males and 2/10 females had alopecia and thin fur; 1/10 males and 1/10 females from the control, 10 mg/kg/day and 40 mg/kg/day groups were also affected.  Histological examination of the skin did not reveal any abnormalities in these animals.  No rats died as a result of treatment.

Body weights and body weight gains were adversely affected by treatment throughout the study.  Mean body weights at week 13, statistically, and biologically (> 10%), significantly decreased in 40 mg/kg/day males (11%) and 160 and 320 mg/kg/day males (25 and 39%, respectively) and females (17 and 27%, respectively).  Total mean body weight gains were also decreased in 40 mg/kg/day males (17%) and 160 and 320 mg/kg/day males (41 and 69%, respectively) and females (38 and 57%, respectively). 

Clinical pathology revealed treatment-related changes in hematology and clinical chemistry, but not in the urinalyses.  Male and female rats were slightly anemic (decreased RBC count, hemoglobin and hematocrit) at 160 and 320 mg/kg/day.  Increased cholesterol levels and blood urea nitrogen values and decreased glucose levels were noted in 160 and 320 mg/kg/day males and females, compared to the controls.  

There were statistically significant increases in liver and thyroid weights with increasing dose.  Statistically significant increases in absolute liver weights were observed at 160 mg/kg/day and higher in females and relative liver weights at 40 mg/kg/day in females and 160 mg/kg/day and higher in males and females.  Statistically significant increases in absolute thyroid weights were observed in females dosed at 160 mg/kg/day and higher and relative thyroid weights in males and female rats dosed at 160 mg/kg/day and higher.

Histopathological examination revealed treatment-related changes in the liver, thyroid, bone marrow, spleen, and kidney.  At 40, 160, and 320 mg/kg/day, centrilobular hypertrophy was observed in the livers of males (7/10, 9/10, and 9/10, respectively) and females (1/10, 9/10, and 9/10, respectively).  At these same doses, follicular cell hypertrophy was observed in the thyroids of males (1/10, 2/10, and 6/10, respectively) and females (3/10, 10/10, and 10/10, respectively).  Very slight erythroid hyperplasia was observed in the bone marrow of 5/10 females dosed at 40 mg/kg/day 8/10 females each from the 160 and 320 mg/kg/day dose groups; affected males included 4/10 at 160 mg/kg/day and 8/10 at 320 mg/kg/day.  The spleens of 9/10 rats per sex were very slightly to slightly pigmented with hemoglobin at 320 mg/kg/day and 1/10 males and 3/10 females, at 160 mg/kg/day; 1/10 females dosed at 10 mg/kg/day were also affected.

Rats in the 10 mg/kg/day treatment groups exhibited no treatment-related responses.

No neoplastic changes were observed in rats in the treatment and control groups.

The LOAEL for this study is 40 mg/kg/day, based on reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid.  The NOAEL is 10 mg/kg/day.

Dose and Endpoint for risk Assessment: 10 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid at 37 or/40 mg/kg/day. 
      
Uncertainty Factor (UF): 300 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a thyroid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thyroid study).

Comments about Study/Endpoint/Uncertainty Factor(s):   The reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid at 37 or/40 mg/kg/day were also seen in the other studies in the thiabendazole toxicity data base at similar doses.  This endpoint is appropriate for the exposure durations.

A.3.4	Dermal Absorption

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.

A.3.5	Dermal Exposure (Short  -  and Intermediate-Term)

Study Selected: Subchronic Oral Toxicity Study in Rats (MRID 42942802).  

Executive Summary:  See A.3.3. above.

Dose and Endpoint for risk Assessment: 10 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid at 37 or 40 mg/kg/day. 
      
Uncertainty Factor (UF): 300 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a thyroid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thyroid study).

Comments about Study/Endpoint/Uncertainty Factor(s):  A 21-day dermal toxicity study in rabbits is available.  However, no effects were seen at the highest dose (1000 mg/kg/day).  An oral study was selected for the dermal endpoint because: 1) of the consistent pattern in the effect observed (i.e., decrease in body weight gain) in the chronic study at the same LOAEL (40 mg/kg/day); and, 2) the duration of this study is appropriate for this exposure period of concern (1-6 months).  Since an oral NOAEL was selected, a dermal absorption factor of 0.5% should be used for this risk assessment. The reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid at 37 or 40 mg/kg/day were also seen in the other studies in the thiabendazole toxicity database at similar doses.  This endpoint is appropriate for the exposure durations.

Margin of Exposure (MOE): 300 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a thyroid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thyroid study).

A.3.6. Inhalation Exposure (Short  -  and Intermediate-Term)

Study Selected: Subchronic Oral Toxicity Study in Rats (MRID 42942802).  

Executive Summary:  See A.3.3. above.

Dose and Endpoint for risk Assessment: 10 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid at 37 or 40 mg/kg/day. 

Uncertainty Factor (UF): 300 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a thyroid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thyroid study).

Comments about Study/Endpoint/Uncertainty Factor(s):   There is no inhalation toxicity study for thiabendazole, and the study was waived. An oral study was selected for the inhalation endpoint because: 1) of the consistent pattern in the effect observed (i.e., decrease in body weight gain) in the chronic study at the same LOAEL (40 mg/kg/day); and, 2) the duration of this study is appropriate for this exposure period of concern (1-6 months).  The reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid at 37 or 40 mg/kg/day were also seen in the other studies in the thiabendazole toxicity database at similar doses.  This endpoint is appropriate for the exposure durations.

Margin of Exposure (MOE): 300 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicodynamic reasons (rats eliminate thyroxine (a thyroid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thyroid study).

A.4	Executive Summaries

A.4.1	Subchronic Toxicity

	870.3100	  90-Day Oral Toxicity - Rat
   (a) In a subchronic toxicity study (MRID# 42942801), thiabendazole (purity not specified, but purity (98.9%) is specified for Lot#L-585, 216-000S159 in MRID# 43592301, chronic/oncogenicity study) was administered to Crl:CD(SD) albino rats (20/sex/dose) by gavage at dose levels of 0, 25, 100, or 400 mg/kg/day for 14 weeks.  In rats in the 400 mg/kg/day treatment group, the most significant response to treatment was a 31-46% depression in total mean body weight gains compared to the controls.  Relative food efficiency was also decreased in males (34%) and females (32%) at 400 mg/kg/day.   Very slight to slight centrilobular hypertrophy was observed in the livers of 13/20 males and 11/20 females, and absolute and relative liver weights were increased 42-77%.  Calculus and very slight to slight hyperplasia of transitional epithelium were observed in the kidneys of 5-8/20 females, and very slight tubular degeneration was observed in the kidneys of 15/20 rats per sex.  Relative kidney weights were increased 32-40%.  Slight to moderate follicular cell hyperplasia was observed in the thyroids of 18-19/20 rats per sex; absolute and relative thyroid weights were increased 56-64% and 104-136%, respectively.  The spleens of 11-15/20 rats per sex were very slightly to slightly congested and pigmented; relative spleen weights were increased 38-50%.  Abnormalities of the stomach included very slight acanthosis or degeneration of the nonglandular mucosa (3/20 males, 7/20 females), very slight focal cytoplasmic rarefaction (10/20 males, 15/20 females), and very slight to slight focal necrosis of glandular mucosa (0/20 males, 4/20 females).  Rats were slightly anemic, with depressed erythrocyte counts (19-23%) and hemoglobin and hematocrit values (12-13%).  At 13 weeks, both sexes had cholesterol levels 68-92% higher and serum aspartate aminotransferase activities 25-40% lower than the controls, and females had total bilirubin values 78% higher than the controls.  Rats had a slightly lower mean urine pH and increased urine bilirubin, urobilinogen, and nitrite levels compared to the control groups; amorphous urate crystals were detected at 6 and 13 weeks.  In addition, rats (5/20 males, 10/20 females) had increased incidence in alopecia/thin fur of the hindlimbs, inguinal area, scrotum, cervical, abdominal, sacral, thoracic, and/or lumbar region.  In the 100 mg/kg/day treatment groups, mean total body weight gains were 12-14% lower than the controls; food consumption was slightly reduced.  Centrilobular hypertrophy was observed in the livers of 2/20 males and 5/20 females; follicular cell hyperplasia was observed in the thyroids of 8/20 males and 8/20 females; and calculus (1/20 males, 5/20 females) and hyperplasia of transitional epithelium (1/20 males, 2/20 females) were observed in the kidneys.  The spleens of 7/20 males and 2/20 females were congested, and of 2/20 females were pigmented.  Absolute liver weights (females only) and relative liver, kidney, and thyroid weights were increased 10-29%.  At 13 weeks, cholesterol levels of males and females were 19 and 69% higher, respectively, than the controls.  In addition, rats (2/20 males, 4/20 females) had increased incidence in alopecia/thin fur of the hindquarters.  In the 25 mg/kg/day treatment groups, 10% of the rats exhibited alopecia/thin fur of the hindquarters.  No rats died as a result of treatment.  No behavioral or ophthalmoscopic abnormalities were noted during the study.  No neoplastic tissue was observed in rats in the treatment and control groups.  The LOAEL for this study is 100 mg/kg/day, based on histopathological changes of the liver thyroid, kidneys, and spleen.  The NOAEL is 25 mg/kg/day.

(b) In a subchronic toxicity study (MRID 42942802), thiabendazole (99.4% a.i.) was administered to Crl:CD(SD) albino rats (10/sex/dose) in the diet at nominal dose levels of 10, 40, 160, or 320 mg/kg/day (achieved doses:  0, 9.4, 37, 149, and 302 mg/kg/day for males; 0, 9.4, 38, 152, and 302 mg/kg/day for females) for 13 weeks.  

Clinical signs observed during the study included alopecia in animals dosed at 160 and 320 mg/kg/day and appeared to be treatment-related.  In each of these groups 2/10 males and 2/10 females had alopecia and thin fur; 1/10 males and 1/10 females from the control, 10 mg/kg/day and 40 mg/kg/day groups were also affected.  Histological examination of the skin did not reveal any abnormalities in these animals.  No rats died as a result of treatment.

Body weights and body weight gains were adversely affected by treatment throughout the study.  Mean body weights at week 13, statistically, and biologically (> 10%), significantly decreased in 40 mg/kg/day males (11%) and 160 and 320 mg/kg/day males (25 and 39%, respectively) and females (17 and 27%, respectively).  Total mean body weight gains were also decreased in 40 mg/kg/day males (17%) and 160 and 320 mg/kg/day males (41 and 69%, respectively) and females (38 and 57%, respectively). 

Clinical pathology revealed treatment-related changes in hematology and clinical chemistry, but not in the urinalyses.  Male and female rats were slightly anemic (decreased RBC count, hemoglobin and hematocrit) at 160 and 320 mg/kg/day.  Increased cholesterol levels and blood urea nitrogen values and decreased glucose levels were noted in 160 and 320 mg/kg/day males and females, compared to the controls.  

There were statistically significant increases in liver and thyroid weights with increasing dose.  Statistically significant increases in absolute liver weights were observed at 160 mg/kg/day and higher in females and relative liver weights at 40 mg/kg/day in females and 160 mg/kg/day and higher in males and females.  Statistically significant increases in absolute thyroid weights were observed in females dosed at 160 mg/kg/day and higher and relative thyroid weights in males and female rats dosed at 160 mg/kg/day and higher.

Histopathological examination revealed treatment-related changes in the liver, thyroid, bone marrow, spleen, and kidney.  At 40, 160, and 320 mg/kg/day, centrilobular hypertrophy was observed in the livers of males (7/10, 9/10, and 9/10, respectively) and females (1/10, 9/10, and 9/10, respectively).  At these same doses, follicular cell hypertrophy was observed in the thyroids of males (1/10, 2/10, and 6/10, respectively) and females (3/10, 10/10, and 10/10, respectively).  Very slight erythroid hyperplasia was observed in the bone marrow of 5/10 females dosed at 40 mg/kg/day 8/10 females each from the 160 and 320 mg/kg/day dose groups; affected males included 4/10 at 160 mg/kg/day and 8/10 at 320 mg/kg/day.  The spleens of 9/10 rats per sex were very slightly to slightly pigmented with hemoglobin at 320 mg/kg/day and 1/10 males and 3/10 females, at 160 mg/kg/day; 1/10 females dosed at 10 mg/kg/day were also affected.

Rats in the 10 mg/kg/day treatment groups exhibited no treatment-related responses.
No neoplastic changes were observed in rats in the treatment and control groups.

The LOAEL for this study is 40 mg/kg/day, based on reduced body weight gains and histopathological changes in the bone marrow, liver, and thyroid.  The NOAEL is 10 mg/kg/day.
	
	870.3100	90-Day Oral Toxicity - Mouse

None.
	
	870.3150	90-Day Oral Toxicity - Dog

In a subchronic toxicity study (MRID 42993601), thiabendazole (99.4% a.i.) was administered orally in capsules to four beagle dogs/sex/dose at dose levels of 0, 35, 75 or 150 mg/kg/day for 14 weeks.

No treatment-related differences in body weight gains, ophthalmoscopic, clinical chemistry, urinalysis or electrocardiographic parameters; all animals survived to terminal sacrifice.   Thiabendazole produced concentration-dependent increases in the incidence of emesis in the 75 and 150 mg/kg/day treatment groups.  Hematological evaluation revealed the development of possible borderline anemia, as characterized by slight, non-significant, decreases in RBC count, hemoglobin concentration and hematocrit at the high-dose level.  Other differences, including decreased body weights and food consumption, did not appear to be treatment-related. 

Post-mortem evaluations did not reveal any treatment-related changes organ weights or gross pathological findings; however, microscopic lesions were observed in the gallbladders.  An increase of gallbladder epithelial cytoplasmic vacuolation in the mid- and high-dose groups over the background incidence may have been treatment-related.  Although there was no increase in the severity of these findings, they were more severe in the 52-week chronic dog study.  The gallbladders of 2/4 males and 4/4 females treated at 150 mg/kg/day exhibited very slight or slight epithelial cytoplasmic vacuolation.  The gallbladders of 2/4 males and 3/4 females treated at 75 mg/kg/day exhibited very slight epithelial cytoplasmic vacuolation.  The toxicological significance of this finding could not be determined.  

No neoplastic lesions were observed.						

The LOAEL for this study is equivocal because the toxicological significance of emesis and gall bladder epithelial cytoplasmic vacuolation could not be determined.    Therefore, the NOAEL is 150 mg/kg/day.

This 14-week subchronic toxicity study is classified Acceptable (guideline) and satisfies the Subdivision F guideline requirement for a subchronic toxicity study (82-1b) in non-rodents.

	870.3200	21/28-Day Dermal Toxicity  -  Rat

In this dermal toxicity study (MRID 41259501), forty rabbits were assigned to four groups.   Thiabendazole 98.9% was administered topically to 5 Nra:(NZW)SPF rabbits/sex/dose daily, at dose levels of 0, 50, 200, 1000 mg/kg/day.  The test material was applied to a shaved area 6 hours per day, 7 days/week for either 21 or 22 days.  No treatment related mortality was observed.   No systemic or dermal toxicities were noted at doses up to 1000 mg/kg/day (Limit dose). Therefore, the LOAEL for systemic toxicity is > 1000 mg/kg/day.  The systemic NOAEL is 1000 mg/kg/day.  The dermal toxicity LOAEL >= 1000 mg/kg/day.  The dermal NOAEL is 1000 mg/kg/day.

	870.3465	90-Day Inhalation  -  Rat

Waived by HASPOC (TXR No. 0056686)

A.4.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID 42842803), thiabendazole (technical, >98.9% a.i.) was administered by gavage to 25 female Sprague-Dawley rats [Crl:CD (SD) BR] in 0.5% methylcellulose at dose levels of 0, 10, 40, or 80 mg/kg/day from days 6 through 17 of gestation.
			
Maternal toxicity was noted at 40 and 80 mg/kg/day consisted of statistically significant (p<=0.05) decreases in mean body weight gain of 12 and 26%, respectively, throughout the treatment period.  Statistically significant (p<=0.05) reduction in feed consumption was noted in mid- (11-15%) and high- (22-28%) dose animals during treatment.  No treatment-related changes in body weight gain or feed consumption were noted at 10 mg/kg/day compared to controls.  No deaths occurred, there were no treatment-related gross pathologic findings, and no abortions were observed at any treatment level.  Clinical signs of toxicity observed during the study consisted of ptosis in 4 dams in the 80 mg/kg/day treatment group on gestational day 6.  The maternal LOAEL is 40 mg/kg/day, based on reduced maternal body weight gains and reduced feed consumption.  The maternal NOAEL is 10 mg/kg/day.

At dose levels of 40 and 80 mg/kg/day, fetal body weights were slightly but significantly (p<=0.05) reduced (5-6%) in females and were slightly but significantly (p<=0.05) reduced in males (5%) at 80 mg/kg/day but not at 40 mg/kg/day (3%).  No developmental effects were observed at treatment levels of 10 mg/kg/day.  There were no treatment-related malformations or variations noted in the fetuses at any dose level. The developmental LOAEL is 40 mg/kg/day, based on decreased fetal body weights.  The developmental NOAEL is 10 mg/kg/day.

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID 42942804), thiabendazole (technical, >98.9% a.i.) was administered by gavage to 18 female New Zealand White rabbits in 0.5% methylcellulose at dose levels of 0, 50, 150, or 600 mg/kg/day from days 6 through 18 of gestation.
Maternal toxicity was noted at 600 mg/kg/day as a treatment-related reduction in body weight gain during treatment (↓69%, p<=0.05, days 6-19) with a statistically significant rebound in the post-treatment interval (↑47%, p<=0.05, days 19-28).  In addition at 600 mg/kg/day, treatment-related decreases in feed consumption were observed during treatment (↓6-30%, days 7 and 13-19; ↓1%, day 10; p<=0.05) with a recovery during the post-treatment period.  No differences in body weight gain or feed consumption were observed at 50 or 150 mg/kg/day as compared to controls.  No deaths occurred and there were no treatment-related gross pathologic findings at any treatment level.  Two abortions occurred in control females and one in a 50 mg/kg/day female.  Sporadic, non-treatment-related clinical signs of toxicity observed were alopecia, blood in pan, diarrhea, and soft or mucoid feces.

The maternal LOAEL is 600 mg/kg/day, based on reduced maternal body weight gain and reduced feed consumption.  The maternal NOAEL is 150 mg/kg/day.

At 600 mg/kg/day of thiabendazole, fetal body weights were significantly (p<=0.05) reduced in both sexes (↓13% males, ↓11% females).  At this dose, there was also increase in the total number of resorptions (12 vs. 6 for controls).  In addition at the high-dose, a treatment-related increase in the litter (37.5% vs. 8.3% for controls) and fetal (10.4% vs 1.7% for controls) incidence of variation of lung lobation was observed.  There was also an increase at 600 mg/kg/day in the fetal (28.1% vs. 8.5% for controls) and litter incidence (56.2% vs. 16.7% for controls) of incompletely ossified metacarpals which was considered treatment-related.  Although the differences from controls in these variations were not statistically significant, the fetal incidences of these findings were outside of the reported historical controls (9 and 19%, respectively).  No developmental effects were observed at treatment levels of 50 and 150 mg/kg/day.

The developmental LOAEL is 600 mg/kg/day, based on increases in the total number of resorptions, the fetal and litter incidences of variation of lung lobation and incompletely ossified metacarpals as well as decreased fetal body weights.  The developmental NOAEL is 150 mg/kg/day.

	870.3700b Prenatal Developmental Toxicity Study  - Mouse

In a developmental toxicity study (MRID 43753702), thiabendazole (technical, 99.8% a.i.) in olive oil was administered by gavage to 25 female Jcl:ICR mice/dose at dose levels of 0, 25, 100, or 200 mg/kg/day from days 6 through 15 of gestation.  Doses were selected based on maternal toxicity at 200-800 mg/kg/day in a range-finding study (MRID 43753701).

All animals survived to terminal sacrifice without the appearance of any treatment-related clinical signs.  No treatment-related gross pathological findings were observed.

Maternal toxicity was noted at 100 and 200 mg/kg/day by significant (p<=0.05) reductions in mean body weight gain of 15 and 24%, respectively, throughout the treatment period.  The weight reductions were accompanied by significant (p<=0.05) reductions in feed consumption by 9-13% at 200 mg/kg/day during gestational days 6-8, 12-14, 14-16, and 16-18, and at 100 mg/kg/day, by 13% during gestational days 12-14.  No treatment-related changes in body weight gain or feed consumption were noted at 25 mg/kg/day compared to controls.

The maternal LOAEL is 100 mg/kg/day, based on reduced maternal body weight gains and reduced feed consumption.  The maternal NOAEL is 25 mg/kg/day.

Developmental toxicity, characterized as slight but significant (p<=0.05) decrease in fetal body weights (3-5%) for both sexes, was observed at 100 and 200 mg/kg/day.  No developmental effects were observed at treatment levels of 25 mg/kg/day.  No malformations or variations were observed at doses of thiabendazole up to 200 mg/kg/day.

The developmental LOAEL is 100 mg/kg/day, based on decreased fetal body weights.  The developmental NOAEL is 25 mg/kg/day.

A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study (MRID 43190301) thiabendazole (>99% a.i.) was administered in the diet to 33 Sprague-Dawley rats/sex/dose at dose levels of 0, 10, 30, or 90 mg/kg/day (achieved doses of 9.4-9.8, 28.1-29.3, or 84.1-85.9 mg/kg/day).  Exposure to F0 generation animals began at 8 weeks of age and lasted for 9 weeks prior to mating to produce F1 pups.  At weaning, F1 pups (25 males and 27 females/dose level) were selected to become the parents of the F2 generation and were given the same concentration test diets as their dam. F1 animals were given test diets for 13 weeks prior to mating.  The animals were exposed to the test material continuously in the diet throughout the study. 

Parental toxicity was demonstrated at 30 mg/kg/day during the pre-mating and post-cohabitation intervals in F0 generation males as treatment-related decreases in body weight gains (10-16%, p<=0.05) and food consumption (3-4%, p<=0.05), and in F1 generation males as treatment-related decreases in body weight gains (7-18%, p<=0.05) and food consumption (4-5%, p<=0.05) vs. controls.

At 90 mg/kg/day, parental toxicity was demonstrated during the pre-mating and post-cohabitation intervals in F0 generation males as treatment-related decreases in body weight gains (29-46%, p<=0.05) and food consumption (11-13%, p<=0.05), and in F1 generation males as treatment-related decreases in body weight gains (↓13-41%, p<=0.05) and food consumption (11%, p<=0.05) vs. controls.  Body weight gains for females during the pre-mating interval were decreased (29%, p<=0.05) in the F0 generation and (14%, p<=0.05) in the F1 generation vs. controls.  Food consumption for females during the pre-mating interval was decreased (12%, p<=0.05) in the F0 generation.  In addition, a decrease was noted in body weight gains (8%, p<=0.05) vs. controls in the F0 generation during gestation with a subsequent 3.5 fold increase during the lactation period.  No change in body weight gains occurred in the F1 generation during gestation; however, an increase (18 g) at 90 mg/kg/day vs. a decrease (5 g) for controls was noted during the lactation period.  Although not statistically significant, food consumption was decreased vs. controls during gestation in the F0 (4-16%) and F1 (4-10%) generation females.

No systemic toxicity was observed at 10 mg/kg/day.

The systemic toxicity LOAEL is 30 mg/kg/day based on reduced body weight gain and food consumption.  The systemic toxicity NOAEL is 10 mg/kg/day.

Developmental toxicity was characterized at 90 mg/kg/day as treatment-related decreases in mean pup weights in both sexes of the F1 (5-8%, days 4-21, p<=0.05) and F2 (7-10%, days 14-21, p<=0.05) generations.

No reproductive toxicity was observed at doses up to 90 mg/kg/day. 

The developmental toxicity LOAEL is 90 mg/kg/day based on reduced body weights in the offspring during lactation.  The developmental toxicity NOAEL is 30 mg/kg/day.
  
The LOAEL for reproductive toxicity is >= 90 mg/kg/day.
The NOAEL for reproductive toxicity is 90 mg/kg/day.

A.4.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity  -  Rat

See Section 870.4200a Carcinogenicity Study - rat

	870.4100b Chronic Toxicity - Dog

In a chronic toxicity study (MRID 42809701), thiabendazole (99% a.i.) was administered orally in capsules to four beagle dogs/sex/dose at dose levels of 0, 10, 40 or 160 mg/kg/day for 52 weeks.

Dogs lost weight during the first half of the study primarily due to emesis.  One mid-dose male dog died of acute hepatitis after two weeks of treatment 

Clinical pathology revealed treatment-related changes in some of the hematology parameters; clinical chemistry and urinalysis parameters were unaffected by treatment.  Both sexes were mildly anemic, with decreased red blood cell counts, hematocrits, and hemoglobin values, and had increased activated partial thromboplastin time (10-14%) and platelet counts (51-65%).  However, none of the values were outside of the historical control range.  There was also a higher incidence of polychromasia and hypochromia compared to the controls during weeks 4, 12, and 26.  

At terminal sacrifice, treatment-related changes in organ weights and incidence of histopathological findings were observed.  The absolute and relative (% of body weight) liver weights were statistically significantly (p<=0.05) higher in mid- (14 and 20%, respectively, combined sexes) and high- (37 and 41%, respectively, combined sexes) dose animals.  In high-dose animals, absolute thyroid weights were increased by 22% (not significant), while relative thyroid weights were increased by 33% (p<=0.05). 

Histopathological evaluations identified lesions in the liver, thyroid, gallbladder, kidney, urinary bladder and spleen.  Livers exhibited slight to moderate bile duct vacuolation in mid- (4/4 males; 2/4 females) and high- (3/4 males; 3/4 females) dose animals.  Thyroids had very slight follicular enlargement high-dose females (1/4), while very slight to slight follicular cell hypertrophy was observed in high-dose males (1/4) and females (2/4).  Dogs in the 10, 40 and 160 mg/kg/day treatment groups had gallbladders which exhibited cytoplasmic lipid vacuolation and discolored foci of the mucosa; dose-related increases in severity (very slight to marked) were observed.  The kidneys of mid- (3/4) and high- (4/4) dose females showed very slight to slight distal tubule vacuolation, compared to 1/4 females each in the control and low-dose groups.  Urinary bladders of all high-dose dogs had very slight to slight epithelial cytoplasmic inclusions; this finding was also observed in 3/4 males and 2/4 females in the mid-dose group.  The toxicological significance of the above findings could not be determined.  Spleens exhibited very slight to slight increases in erythropoiesis in mid- (1/4 males; 1/4 females) and high- (2/4 males; 3/4 females) dose animals; hemosiderin deposits were observed in mid- (2/4 males; 2/4 females) and high- (1/4 males; 4/4 females) dose animals. No neoplastic changes were observed at any dose level.  The LOAEL for this study is 40 mg/kg/day, based on increased liver weight, splenic erythropoiesis and hemosiderosis in both sexes.  The NOAEL is 10 mg/kg/day.

A.4.5	Carcinogenicity

	870.4200a Carcinogenicity Study - rat

 In a combined chronic/oncogenicity study (MRID 43593201), thiabendazole (>98.9% a.i.) was administered to 50 Sprague-Dawley Crl:CD BR rats/sex/dose in the diet at dose levels of 0, 10, 30, or 90 mg/kg/day (achieved average doses of 0, 10.1, 30.2, or 91.8 mg/kg/day) for 104 weeks.

There were no treatment-related effects on survival, clinical signs, food consumption, ophthalmoscopic findings, urinalysis, or gross pathology.  Body weights and body weight gains were generally lower (↓7-30%) throughout the study for the mid- and high-dose males and high-dose females.  Reduced body weight gains (↓15, ↓28, and ↓19%, p<=0.05) for the mid- and high-dose males and high-dose females, respectively, compared to the controls were observed at week 103.  A reduced body weight gain (↓10%, not statistically significant) was also noted at this time for the mid-dose females.

Significant increases (↑36-79%, p<=0.05) in total serum cholesterol observed in the high-dose group were judged to be treatment-related.  In the high-dose males, increased (↑29%, p<=0.05) relative (to body) liver weights and an increased incidence of centrilobular hepatocellular hypertrophy (28/50 treated vs 0/50 controls) were also detected.  Centrilobular hepatocellular hypertrophy was also observed in 7/50 mid-dose males.  In the high-dose females, an increased (↑45%, p<=0.05) relative thyroid weights and increased incidences of thyroid focal cystic follicular cell hyperplasia (6/50 treated/2/50 controls) and diffuse follicular cell hypertrophy (2/50 treated vs 0/50 controls) were observed.  Thyroid diffuse follicular cell hypertrophy was also observed (4/50 treated vs 0/50 controls) in the high-dose males.  The systemic LOAEL is 30 mg/kg/day based on reduced body weights and body weight gains and liver hypertrophy (males).  The systemic NOAEL is 10 mg/kg/day.
	870.4200b Carcinogenicity (feeding) - Mouse

In a 105-week carcinogenicity toxicity study (Accession No. 242116), Thiabendazole, 98.5% a.i. was administered to 50 mice (Charles River CD-1)/sex /dose in diet at dose levels of 0, 5.6-8.3, 31-42, 63-121, 184-372 mg/kg/day for males and 0, 5.7-9.9, 94-131, 209-368, and 534-1005 mg/kg/day for females.

There was an increase in mortality in all dose groups. Body weight gains were significantly lower in high dose females (28%) and males (18%).  There was an increase in the absolute liver weight of high-dose females, and an increase in the relative liver weight in mid-dose females and high-dose males and females.  There was an increase in the relative liver: brain weight ratio in high-dose males and females.

The LOAEL for systemic toxicity is 209-368 mg/kg/day for females and 63-121 mg/kg/day for males, based on decreased body weight gains and increased liver weights.  The NOAEL is 5.7-9.9 mg/kg/day for females and 5.6-8.3 mg/kg/day for males.

It was noted that there were sufficient number of animals alive at 15 and 18 month intervals to assess the carcinogenic response.  However, no treatment-related increase in tumor incidence above background level was observed.  Although the dosing was variable, and assuming that the animals received the lowest dose of the range for each dose group, a compound-related effect (i.e. increased mortality) was noted in both sexes at the mid- and high dose at 18 month and at the high dose at 15 month.  Therefore, the dosing was considered to be adequate and the study was acceptable and satisfies the guideline requirement for a carcinogenicity study (83-5) in mice. 
 
At the doses tested, there was no treatment related increase in tumor incidence when compared to controls in this strain of mice. 

A.4.6	Mutagenicity

Mutagenicity. 870.5100, 870-5300, 870.5375, 870.5385, 870.5550    

Eight acceptable mutagenicity studies on thiabendazole are available:

   * Reverse gene mutation, S. typhimurium,  E. Coli (MRID 42361801)
   * In vitro gene mutation assay - mouse lymphoma cells (MRID 46561901)
   * Chromosome aberration, human peripheral blood lymphocytes (MRID 46561902)
   * Two in vitro mammalian cytogenic assay - human embryo fibroblasts  (MRID 00098002, MRID 00125297)
   * in vivo cytogenetics, bone marrow chromosome aberration assay in male mice (MRID43328304)
   * in vivo cytogenic assay in male rats (MRID 00098002)
   * in vitro alkaline/elution in rat hepatocytes (MRID 41170103)
 	
Results in all eight studies were negative for genotoxicity.

A.4.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study - Hen

Not Required.

	870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 48996310), groups of 10 nonfasted, 6-week-old Crl:CD(SD) rats/sex/dose) were given a single oral dose of thiabendazole (99.3% a.i., batch/lot # HK 1998/011) in 0.5% carboxymethylcellulose at doses of 0, 50, 200, or 2000 mg/kg bw and observed for 14 days.  Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was performed in 10 animals/sex/group prior to the initiation of dosing (day -6), at the time of peak effect (~ 3 hours post dosing) on study day 0, and on study days 7 and 14.  Cholinesterase activity was not determined.  At study termination, 5 randomly selected rats/sex/group were euthanized and perfused in situ for neuropathological examination.  Of the perfused animals, rats from the control and 2000 mg/kg bw groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues. 

Treatment with 200 and 2000 mg/kg bw of thiabendazole produced multiple signs of transient neurotoxicity in males and females at the peak time of dosing on day 0.  Effects at 200 mg/kg bw included reduced body temperature in males (p<0.05), reduced rearing counts in females (↓54%), and statistically significant (<0.01) reductions in both cumulative total activity counts (↓37-39%) and cumulative ambulatory counts (46%) in both males and females.  Neurotoxic effects at 2000 mg/kg bw were more pronounced, and included reduced rearing and reduced body temperature in both males and females; lacrimation, slightly drooping eyelids, increased time to first step, and a "slightly impaired but definite" gait score (in one animal) in females; and statistically significant reductions in cumulative total activity counts and cumulative ambulatory counts in both males and females.  All signs of neurotoxicity were transient, as no effects were observed on Day 7 or 14.  No adverse, treatment-related neurotoxic effects were observed in males or females at 50 mg/kg bw.

In addition to neurotoxicity, treatment with 200 and 2000 mg/kg bw of thiabendazole also produced statistically significant reductions in body weight, body weight gain, and food consumption.  Mean absolute body weights were reduced throughout the study in males at 2000 mg/kg bw with final body weight reduced by 10%, while reductions in absolute body weights in females at 2000 mg/kg bw were transient, returning to values comparable to controls by study day 9.  Overall body weight gain (Days 0-15) was significantly reduced in males (↓33%), but not females, at 2000 mg/kg bw.  Daily body weight gains over days 0-1 were significantly reduced in males and females at 200 mg/kg bw and females at 50 mg/kg bw, but no differences were observed in mean absolute body weight or overall body weight gain.  Reductions in food consumption were transient, with daily consumption values in males and females at 2000 mg/kg bw returning to those of controls by study day 6.  However, overall food consumption in males was significantly reduced compared to controls (↓16%).  Food consumption was also reduced over days 0-1 in males and females at 200 mg/kg bw.  The transient decrease in food consumption and body weight gain that occurred over days 0-1 in males and females at 200 mg/kg bw are considered an adverse effect of treatment when considered in conjunction with the adverse neurotoxicity signs.   

Treatment with thiabendazole did not affect clinical signs, neuropathology, brain weight, or brain dimensions.     

Based on the effects seen in this study, the LOAEL for Sprague-Dawley rats was 200 mg/kg bw based on transient changes 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), and reduced body weight gain (p<0.01) and food consumption (↓44%, p<0.01) on day 1 with a NOAEL of 50 mg/kg bw.

	870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID 48996309) thiabendazole (99.3% a.i., batch/lot # HK 1998/011) was administered continuously in the diet to 12 Crl:CD(SD) rats/sex/group at dose levels of 0, 200, 750, or 1500 ppm (equivalent to 0, 13, 47, and 95 mg/kg bw/day in males and 0, 15, 54, and 108 mg/kg bw/day in females) for 13 weeks.  Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 12 animals/sex/group prior to the initiation of dose administration (study week -1) and during study weeks 1, 3, 7 and 12.  Cholinesterase activity was not determined.  At study termination, 12 animals/sex/group were euthanized and 5 animals/sex/group were perfused in situ for neuropathological examination.  Of the perfused animals, 5 animals/sex from the control and high dose groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues.  Treatment with 1500 ppm adversely affected body weight, body weight gain, and food consumption in both males and females. Mean absolute body weight was statistically significantly (p<0.05) decreased compared to controls in males on days 84 and 92 (↓11% for both days) and in females starting on day 14 and continuing to study termination on day 91 (ranged from ↓11-19%; final body weight ↓17%).  Overall body weight gain (Days 0-91) was statistically significantly reduced by 18% and 36% in males and females, respectively. Reductions in body weights and body weight gains were accompanied by reduced food consumption.  Food consumption was statistically significantly reduced in males over several weeks (↓11-17%) and in females at all weekly intervals (↓13-22%), with overall food consumption reduced by 8% and 17%, respectively.  No treatment related effects on body weight, body weight gain, or food consumption were observed in males or females treated with 200 or 750 ppm. Dietary treatment with up to 1500 ppm thiabendazole did not result in any signs of neurotoxicity as indicated by clinical observations, FOB observations, motor activity counts, or neurohistopathological evaluation, and no treatment-related effects were noted during ophthalmoscopic examination, gross pathology or in brain weight and brain dimension measurements.  Based on the effects seen in this study, the LOAEL for Sprague-Dawley rats was 1500 ppm (equivalent to 95 mg/kg bw/day in males and 108 mg/kg bw/day in females) based on significant reductions in mean absolute body weights (↓11for males, 19% for females) and body weight gains ((↓18% for males, ↓36% for females) and food consumption (↓8% for males and ↓17% for females), with a NOAEL of 750 ppm (equivalent to 47 mg/kg bw/day in males and 54 mg/kg bw/day in females).
	870.6300 Developmental Neurotoxicity Study

Not required (TXR No. 0013601). 

A.4.8	Metabolism

	870.7485	Metabolism - Rat

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.

[[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 (soluble and insoluble).  

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 and was isolated by HPLC and identified by enzymatic reactions 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 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.

This metabolism study in the rat is classified acceptable (§85-1) and satisfies the guideline requirement for a metabolism study.

	870.7600	Dermal Absorption - Rat

Individual executive summaries of these studies are not available; only a review of these studies is available in TXR 0055373.

A.4.9	Immunotoxicity

	870.7800	Immunotoxicity

In an immunotoxicity study (MRID # 48996311), Thiabendazole (99.3% a.i., lot # HK1998/011, WIL ID no. 110085) was administered to 10 female Crl:CD1(ICR) mice/dose in the diet at dose levels of 0, 100, 1000, or 5000 ppm (0, 20.9, 205.6, or 1027.0 mg/kg bw/day, respectively) for at least 28 days. A concurrent positive control group received 50 mg/kg/day cyclophosphamide monohydrate [CPS] once daily during study days 24-27 via IP injection. All animals were immunized via an intravenous injection with 0.2 mL of 1x10[8] SRBC (Sheep Red Blood Cell) in the tail vein on study day 24. All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily, and detailed physical examinations were performed weekly.  Individual body weights were recorded twice weekly, and food consumption was recorded approximately weekly. On study day 28, blood samples for serum IgM antibody analysis were collected from all animals from the caudal vena cava. The mesenteric lymph node, Peyer's patch, spleen, and thymus were collected.  In addition, organ weights for the spleen and thymus were recorded at the scheduled necropsy, and the spleens for the AFC (antibody forming cell) assay.

Over the entire 4-week study period, there were no test substance-related effects on survival, body weight, food consumption, or parameters evaluated during gross pathological examinations. Thiabendazole-related higher mean liver weights were noted in the 1000 and 5000 ppm groups, when compared to the vehicle control group. The higher mean liver weight noted at 5000 ppm was greater than 25% of the vehicle control group and was considered an adverse effect.

The systemic toxicity LOAEL is 5000 ppm (1027.0 mg/kg bw/day), based on significant increase in liver weight (> 25%).  The NOAEL for systemic toxicity is 1000 ppm (205.6 mg/kg bw/day).

Lower (53%) total spleen activity (measured as AFC/spleen) was noted in the 5000 ppm group when compared to the vehicle group; however, there were no effects of thiabendazole on mean total spleen cell numbers or specific activity (measured as AFC/10[6] spleen cells) at any dietary concentration evaluated. This finding was noted only at the highest dose level administered in the diet, a dose that also produced statistically significantly higher mean absolute liver weight and mean adjusted liver weights of 37.5% and 41.2%, respectively, as compared to the vehicle control group. In the positive control group (CPS), lower spleen cell numbers, specific activity (AFC/10[6] spleen cells), and total spleen activity (AFC/spleen) were noted when compared to the vehicle control group, which validated the functionality of the assay.

A review of previous thiabendazole regulatory toxicity studies in rats, mice, and dogs failed to show any treatment-related changes in a variety of indicators of potential Immunotoxicity (including leukocyte counts, lymphocyte counts, globulin concentration, macroscopic findings [lymph nodes, thymus, and spleen], organ weights [spleen and thymus], and microscopic findings [bone marrow, lymph nodes, spleen, and thymus]).

Under conditions of this study, the immunotoxicity LOAEL is 5000 ppm (1027.0 mg/kg bw/day), based on significant decrease in total spleen activity. The immunotoxicity NOAEL is 1000 ppm (205.6 mg/kg bw/day).
   
This immunotoxicity study is classified acceptable/guideline, and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in mice.

A.4.9	Special/Other Studies

In a special study (MRID 43593202), thiabendazole (99.8% a.i.) was administered to 35 Crl:CD(SD)BR male rats/dose in the diet at nominal dose levels of 0, 10, 90, or 270 mg/kg/day (actual 0, 10.15, 91.14, and 235.23 mg/kg/day).  After 13 weeks of treatment, 15 rats/dose were sacrificed for pathological evaluation (liver and thyroid only).  During week 14 of the study, blood samples from 5 rats/dose were used for evaluation homeostasis of thyroid hormones and thyroid stimulating hormone; animals were discarded after the final blood sampling.  All remaining rats (14 to 15/dose) were sacrificed after 13 weeks of the treatment-free recovery phase and evaluated pathologically (liver and thyroid only).

Mortality and clinical signs of treated animals were unaffected by treatment.

After 13 weeks of dosing, mean body weights of the mid- and high- dose animals were 12% and 32% lower than controls, respectively.  At the end of the recovery phase, their mean body weights for each of these dose groups were 13% lower than the controls. 

Pathological evaluations of the thyroid and liver showed increased absolute and relative organ weights and increased incidence of microscopic lesions.  In the mid- and high-dose animals, absolute thyroid weights were increased by 20 and 40%, respectively, and relative (to body) thyroid weights, by 26% and 103%, respectively.  Relative liver weights were also increased by 7% and 25%, in mid- and high-dose animals, respectively.  Histopathological examination revealed dark foci in the thyroids of the 6/15 high-dose animals and very slight to slight diffuse follicular cell hyperplasia in the thyroid of 10/15 mid- and 12/16 high-dose animals.  Very slight to slight hepatocellular centrilobular hypertrophy was detected in all (15/15) mid-dose animals and 15/16 high-dose animals.  The thyroid and liver lesions were not observed in any of the low-dose and control main study animals or in any of the recovery phase animals.

Thyroid homeostasis (serum T3, T4 and TSH) was evaluated during treatment weeks 2, 4, 8, and 13 and weeks 6 and 13 of the recovery phase.  T3 levels decreased by 5-10% in mid-dose and 11-19% in high-dose animals compared to controls; TSH levels were increased by 66-160% in mid-dose and 65-189% in high-dose animals.  Evaluations carried out during week 14 of the study, showed effects in mid- and high-dose animals.  For high-dose animals, statistically significant increases in thyroxine clearance (44%, p=0.001), volume of distribution (Vd, 64%,p<0.001), rate of elimination ( kel, 13%, p<0.001), and half-life (T1/2, 16%, p<0.001).  At the mid-dose significant increases in kel (18%, p<0.001), T1/2 (23%, p<0.001) and in Vd (22%, p=0.004) were observed, while no differences in thyroxine clearance was observed.  At the end of the recovery period, TSH levels in the mid- and high-dose animals were comparable to control values while T3 serum levels were higher (9%-19%).  T4 were comparable to controls throughout both the treatment and recovery periods. 

These data support the hypothesis that thiabendazole alters thyroid hormone homeostasis in male rats resulting in hypothyroidism.  The study authors contend that the primary effect of thiabendazole is on the liver, resulting in hepatocellular hypertrophy [microsomal enzyme induction presumed, but not measured in the study].  Enhanced hepatic metabolism of the thyroid hormones leads to decreased serum levels.  The decreased serum levels of the hormones causes an increased release of TSH.  The higher serum TSH levels, in turn, cause thyroid hypertrophy and hyperplasia.

The submitted special study is classified as acceptable/non-guideline.
Appendix B. Chemical Names and Structures

Chemical Names and Structures
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/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) 

Appendix C.  Physical/Chemical Properties

Table C1.	Physicochemical Properties of the Technical Grade Test Compound: Thiabendazole. 
Parameter
Value
Reference
Melting point/range
304-305 °C
Thiabendazole RED 10/02
pH
5.16-5.97
Thiabendazole RED 10/02
Density
25-30 cc (tapped)
Thiabendazole RED 10/02
Water solubility
0.028-0.030 mg/mL at 25 °C
Thiabendazole RED 10/02
Solvent solubility

acetone
benzene
chloroform
dimethylformamide
dimethyl sulfoxide
ethanol 
ethyl acetate
methanol	
25 ºC
4.2 g/L
230 mg/L
80 mg/L
39 g/L
80 g/L
7.9 g/L
2.1 g/L (R.T.)
9.3 g/L
The Pesticide Manual, 8[th] edition
Vapor pressure
4 x 10 [-9] mm Hg at 25 °C
Thiabendazole RED 10/02
Dissociation constant, pKa
pKa1 = 4.73; pKa2 = 12.00
Thiabendazole RED 10/02
Octanol/water partition coefficient
Log(KOW) = 240-285 at pH 7
Thiabendazole RED 10/02
UV/visible absorption spectrum
Neutral solution
32,170 L/mol*cm[3] at 205.5 nm
Acidic solution
41,520 L/mol*cm[3] at 303.5 nm
Neutral solution
40,553 L/mol*cm[3] at 215.5 nm
MRID 46286801[1]
[1] Data were referenced in MRID 47705121. 

Appendix D.  Studies Reviewed for Ethical Conduct

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies were determined to require a review of their ethical conduct, have received that review and have been determined to be ethical.

HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment.