UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

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.
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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
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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
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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 
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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 
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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 99.9th 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. 
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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 intermediateterm 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 website1.

 

1

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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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. 

 
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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
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Table 2.2.3. Tolerance Summary for Thiabendazole. § 180.242

Commodity Current/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

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
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Table 2.2.3. Tolerance Summary for Thiabendazole. § 180.242

Commodity Current/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

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.
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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.
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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.

N

H

N

S

N

N

H

N

N

H

N

S

HO N
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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.
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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)
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 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-U14C] 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.

[

14C]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 
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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. 
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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).
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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 
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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 
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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.
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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 NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQ

PA 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 

intermediateterm (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
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for [Chemical] for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQ

PA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal 

Short-Term

(1-30 day s) 

and 

Intermediateterm (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 

Intermediateterm (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)
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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 ShortTerm (1-30 

day s) and 

Intermediateterm (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 

Intermediateterm (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)
Thiabendazole/060101 Human Health Risk Assessment D416471

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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, 20132and 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 

website3.

 

2

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.

3

http://www.epa.gov/endo/
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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. 
Thiabendazole/060101 Human Health Risk Assessment D416471

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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-hydroxythiabendazole (free and 

conjugated), and 

benzimidazole

thiabendazole, 5-hydroxythiabendazole (free and 

conjugated), and 

benzimidazole

Poultry

thiabendazole, 5-hydroxythiabendazole (free and 

conjugated), and 

benzimidazole

thiabendazole, 5-hydroxythiabendazole (free and 

conjugated), and 

benzimidazole

Drinking Water thiabendazole Not Applicable
Thiabendazole/060101 Human Health Risk Assessment D416471

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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 nonquantifiable 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.

LAFT2 HAFT2 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 

Residues3

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 

Residues3

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 

Residues3

10 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A

Alfalfa Hay – 1

st Thiabendazole 0.02-0.05 42-253 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A
Thiabendazole/060101 Human Health Risk Assessment D416471

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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.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Cutting Benzimidazole (22-56) 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Combined 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

19 <0.02 <0.088 <0.02 <0.083 0.020 0.024 0.015
Thiabendazole/060101 Human Health Risk Assessment D416471

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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.

LAFT2 HAFT2 Median Mean Std. 

Dev.

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

6 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A
Thiabendazole/060101 Human Health Risk Assessment D416471

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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.

LAFT2 HAFT2 Median Mean Std. 

Dev.

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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 

Residues3

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; 
Thiabendazole/060101 Human Health Risk Assessment D416471

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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 μg/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 2.4011.551

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/.
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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.
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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 99.9th 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 99.9th 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.
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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 (nonoccupational) 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-
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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 99.9th 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.

7.2 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 
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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 0.11390

General Population 0.000379 0.02 490

Fraction of Thiabendazole Transferred From Sponge to Surface = 5%

Children 1-2 0.001562 0.005531400

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 99.9th 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.
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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 intermediateterm 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).
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Table 9.1.1 Summary of Short-/Intermediate-Term Handler Exposures/Risks for Thiabendazole Seed Treatment

Seed 

Type

Max 

Application 

Rate1

Unit Exposure2

(mg/lb ai)

Amount 

of Seed 

Treated3

Absorbed Dose

(mg/kg/day)4 MOE5

Total

MOE6

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
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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) × application rate (lb ai/lb seed) × amount treated (lb seed/day) × 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)]
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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 

Ratea

Unit Exposureb

(mg/lb ai)

Amount of 

Seed 

Planted 

Per Dayc

Absorbed Dose

(mg/kg/day) d MOEe

Total

MOEf

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) × application rate (lb ai/lb seed) × amount treated (lb seed/day) × 

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)]
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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 reentry 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.
Thiabendazole/060101 Human Health Risk Assessment D416471

Page 43 of 74

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® 340-F (EPA Reg. No. 100-889) as a Seed 

Treatment.
Thiabendazole/060101 Human Health Risk Assessment D416471

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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)
Thiabendazole/060101 Human Health Risk Assessment D416471

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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 Toxicityrabbit46556302 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
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

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.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

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 highdose females, while very slight to slight follicular cell 

hypertrophy was observed in high-dose males and 

females.

870.4100

24-Month 

Chronic/Carcinog

enicity -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 7th week), 

63-121, 184-372 

mg/kg/day for males 

and 

0,,94-131 ( reduce to 

5.7-9.9 on 7th

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.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

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 μg/plate 

to 6000 μg/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 μg/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 

μg/mL). Precipitation of the test material was observed 

at ≥500 μg/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.
Thiabendazole/060101 Human Health Risk Assessment D416471

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

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/nonGuideline

The test is negative up to the highest dose tested (50 

μg/mL) without S9 activation. 

870-5385

in vitro

mammalian cell 

cytogenetic assay

in W1-38 human 

fibroblasts

00125297 (1977)

Acceptable/nonGuideline

The test is negative up to precipitating levels (1000 μg 

/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/Nonguideline

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)
Thiabendazole/060101 Human Health Risk Assessment D416471

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

pharmacokinetics

(Rat)

42114701 (1990)

Acceptable/Guideline

phenyl-U14Cthiabendazole (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.

14C-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)
Thiabendazole/060101 Human Health Risk Assessment D416471

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

Non- guideline

Special study: 

Thyroxine 

clearance (male 

rat)

43593202 (1995)

Acceptable/nonguideline

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 
Thiabendazole/060101 Human Health Risk Assessment D416471

Page 52 of 74

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. 

 

 = ( ) =

50	mg/kg	(NOAEL)

 ()

= 0.05	mg/kg
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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 highdose females. Reduced body weight gains (↓15, ↓28, and ↓19%, p≤0.05) for the mid- and highdose 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 
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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).

 =  =

10	mg/kg/day	(NOAEL)

 ()

= 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 
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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.
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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) 
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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 
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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 
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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.
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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.
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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, treatmentrelated 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 
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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 postcohabitation 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.
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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 highdose animals, absolute thyroid weights were increased by 22% (not significant), while relative 

thyroid weights were increased by 33% (p≤0.05). 
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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 highdose females. Reduced body weight gains (↓15, ↓28, and ↓19%, p≤0.05) for the mid- and highdose 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.
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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.
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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 
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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).
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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-U14C]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.

[

14C]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.
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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 1x108SRBC (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/106spleen 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/106spleen cells), and total spleen activity (AFC/spleen) were noted when compared to the 

vehicle control group, which validated the functionality of the assay.
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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 lowdose 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 middose 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 
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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.
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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) 

N

H

N

S

N

N

H

N

N

H

N

S

HO N
Thiabendazole/060101 Human Health Risk Assessment D416471

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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, 8th edition

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

Dissociation constant, pKa pKa1 = 4.73; pKa2 = 12.00 Thiabendazole RED 10/02

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

UV/visible absorption spectrum Neutral solution

32,170 L/mol*cm3at 205.5 nm

Acidic solution

41,520 L/mol*cm3at 303.5 nm

Neutral solution

40,553 L/mol*cm3at 215.5 nm

MRID 462868011

1 Data were referenced in MRID 47705121. 
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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.