UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** Augu s t 2 6 , 2014 **SUBJECT:** Thiabendazole: Human Health Risk Assessment for the Requested Increase in the C urrently Registered S eed Treatment U se R ate on S oy beans and the N ew Section 3 U ses of Thiabendazole for S eed Treatment on A ssorted V egetables and S mall Grains Including: V egetable, Root ( E xcept Sugar B eet), S ubgroup1B; Radish T ops; O nion, B ulb, S ubgroup 3 - 07A; Brassica , H ead and S tem, S ubgroup 5A; V egetable, C ucurbit Group 9; A lfalfa; S pinach; and a Number of S mall Grains ( B arley , O ats, 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 A**  **ss essment Typ**  **e :**  Single Chemical Aggregate **Case No.:** 2 6 70 **T XR 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 Soy beans. 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.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 2 of 74 **1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 8 **2.1 Da**  **ta 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 Toxico**  **logy 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**  ................................ ............. 34Thiabendazole/060101 Human Health Risk Assessment D416471

Page 3 of 74 **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**  ................................ ................................ .............................. 5 7 **Appendix B. Chemical Names and Structures** ................................ ................................ ......... 72 **Appendix C. Physical/Chemical Properties** ................................ ................................ ............. 73 **Appendix D. Studies Reviewed for Ethical Conduct** ................................ .............................. 74Thiabendazole/060101 Human Health Risk Assessment D416471

Page 4 of 74 **1.0 Ex**  **ecutive Summary** Thiabendazole [2 - (4 - thiazolyl)benzimidazole] is a benzimidazole fungicide currentl y registered for use as a seed or seed piece treatment to dry pea, potato, sweet potato, soy bean, and wheat. It is also registered for use on mushrooms and is mostly used po st - 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 soy bean 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 - hydroxy thiabendazole (free and conjugated), and benzimidazo le. Sy ngenta Crop Protection is requesting registration of new seed treatments uses on assorted v egetables and s mall grain s (vegetable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3 - 07A; Bras sica, head and stem, subgroup 5 A; vegetable, cucurbit group 9; alfalfa; spinach (including bab y); and small grain s (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) flowa ble 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 . Sy ngenta 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 so yb ean 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 e xposure to thiabendazole. Based on the proposed use pattern, short - /intermediate - term durations of exposure are expec ted 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, soy

bean, 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 - hydrox y - thiabendazole (free and conjugated), and benzimidazole. Based on theThiabendazole/060101 Human Health Risk Assessment D416471

Page 5 of 74 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 thy roid study . The FQPA factor is 10 X 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 submitte d to satisfy the new data requirements. In 2013, HED Hazard and Science Policy Council (HASPOC) concluded that a developmental thy roid toxicity study is required, but w aived the requirement for a 28 - day inhalation toxicity

study (TXR No. 0056686). In subchronic and chronic oral studies, the thy roid and liver (centrilobular hy pertrophy) 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 (hy perplasia of transitional epithelium, tubular degeneration) and spleen (congested and pigmented) in rats. Additional toxic effects observed in these stu dies included decreases in body weight, and/or food consumption. The available database indicates that thiabendazole is not neurotoxic. N o systemic or dermal effects were seen at the limit dose (1000 mg/kg/day) i n a 21 - day dermal toxicity

study in rats . Th ere 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 t ested (1027 mg/kg/day) which also produced s ys temic toxicity of significant increased liver weight. Thiabendazole has been classified b y 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 thy roid 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 I II 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 50Thiabendazole/060101 Human Health Risk Assessment D416471

Page 6 of 74 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 t otal UF is 1000 ( an interspecies extrapolation factor of 10 X , an intraspecies variability factor of 10X, an FQPA database uncertainty factor of 10X for lack o f a developmental thy roid 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 thy

roid 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 thy roid 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 pharmacodyn amicall y to thyroid toxicants than humans, the overall composite uncertainty factor for the chronic dietary risk assessment is 300 X ( 10 X for intraspecies variability among humans, 3 X for interspecies ph armacokinetic differences between humans and rats and the 10 X FQPA database uncertainty

factor for the missing developmental thy roid study) . T oxicological endpoint s for incidental oral exposure, short - /intermediate - term dermal and short - /intermediate - ter

m inhalation exposures w ere 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 LOAELof 40 mg/kg/day . A der mal absorption factor of 0.5% was selected from a combination of in vivo and in vitro dermal absorption studies . An uncertainty factor of 3 00X was applied to these endpoints ( an interspecies scaling factor of 3 X , lowered from 10 X for toxicody namic reasons (rats eliminate thy roxine (a thy

roid hormone) at a higher rate than humans), an intraspecies variability factor of 10X, and an FQPA database uncertainty factor of 10 X for lack of a developmental thy roid study was applied). Di etary Exposure Assessment For the probabilistic acute dietary assessment (food and drinking water) , the dietary exposure at the 99.9 th percentile of exposure used 26% of the acute population adjusted dose (aPAD) for the general population and 69% of the aPAD for Children 1 - 2 years, the population subgroup with the highest estimated acute dietary exposure . Acute dietary (food and drinking water) exposures are below HED’s level of concern (<100% aPAD) for all population subgroups. For the chronic dietary assessment, the dietary exposure used 1.1 % of the chronic population adjusted dose (cPAD) for th e general population and 4.7% of the cPAD for Children 1 - 2 years old, the population subgroup with the highest estimated chronic dietary expos ure. C hronic dietary (food and drinking water) exposures are below HED’s level of concern (<100% cPAD) for all population subgroups.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 7 of 74 **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 o f 6/23/10, T. L eighton, D379421 ). No risk estimate s 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 Pol ic ies 14 , 15, and 15.1 and a memorandum from the Biological and Economic Anal ys is Division (BEAD), “Acres Planted Per Day and Seeding Rates of Crops Grown in the United S tates” (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 2,2 00,000 for primary handlers ( seed treaters ) and 1,600 to 220,000 for secondary handlers (seed planters). Note that the short - and intermediate term PODs are the same, and the intermediate - term exposure inputs are less conservative than the short - term exposure inputs for seed treatment; therefore, short - term exposure risk estimates are protective of intermediate - term exposure risk estimates. These risk estimates are not of concern. Occupational Post- application Exposure A quantitative post - application assessment is not required for exposure to treated seeds that have already been planted . Use of Human Studies This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); ExpoSAC Policy 14 , 15, and 15.1 (SOPs for Seed Treatment) are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may

have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1

. 1 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.htmlThiabendazole/060101 Human Health Risk Assessment D416471

Page 8 of 74 **2.0 HED**  **Recommendations** Based on residue chemistry considerations onl y, 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; Bras sic a, head and stem, subgroup 5 A; vegetable, cucurbit group 9; alfalfa; spinach (includi ng bab y); 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 sec tion 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 analy tical standards are submitted as requested, HED concludes that, based on the available residue data, the requested use of thiabendazole as a seed treatment for veg etable, root (except sugar beet); subgroup1B, onion, bulb, subgroup 3 - 07A; Brassica, head and stem, subgroup 5A; vegetable, cucurbit group 9; alfalfa; spinach (including bab y); and small grains (wheat, barley , oats, rye, and triticale) may be registered on ce tolerances are established as recommended in 40 CFR §180.242 **.** 860.1650 Submittal of Analy tical Reference Standards

 For benzimidazole, a new standard must be submitted. For 5 - hydrox y- thiabendazole, the registrant must either recertify the lot in the repository

and send in an updated certificate of anal ys is (COA), or submit new standards (different lot #) if the previous lots will not be recertified. Toxicology • Developmental Thyroid Toxicity Stu dy in Rats (non -guideline). Based on a WOE approach considering all the available hazard and exposure information for thiabendazole , the HED HASPOC conclude d that the developmental thyro id toxicity study , a non - guideline study , is required ( TXR 0056686 ) . The developmental thyr oid 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 .Thiabendazole/060101 Human Health Risk Assessment D416471

Page 9 of 74 **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Acceptable enforcement anal ytical methods are available for thiabendazole and benzimidazole in plant commodities. Four spectrophotofluorometric methods for the determination of thiabendazole are published in the Pesticide Anal ytical Manual (PAM) Vol. II, and a high performance liquid chromatography (HP LC) method with fluorescence detection (FLD) for the determination of benzimidazole (free and conjugated) is identified in the U.S. EPA Index of Residue Anal ytical Methods under thiabendazole as Study No. 9302 0. 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 Internati onal Harmonization. Neither CODEX nor Canada has established any established maximum residue limits (MRL s) for thiabendazole on the requested commodities . We note that the U.S. tolerance expression is not harmonized with Canada or CODEX. **2.2.3 Recommend**  **ed Tolerances** Under the current action, Sy ngenta 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; Bras sica, head and stem, subgroup 5 A; 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. Sy

ngenta submitted residue data to support the proposed uses. Sy n genta also has included field trial and processing studies on so yb ean, 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 requireme nt 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, grainThiabendazole/060101 Human Health Risk Assessment D416471

Page 10 of 74 **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 0.3 0 Barley, hay Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws. barley, straw 0.15 0.3 0 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 0.3 0 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 0.3 0 Oats, hay Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws. oats, straw 0.09 0.3 0 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 0.2 0 Rye, forage rye, grain 0.05 0.05 Rye, grain rye, straw 0.15 0.3 0 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, grainThiabendazole/060101 Human Health Risk Assessment D416471

Page 11 of 74 **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 0.3 0 Wheat, forage Revised level based on OECD tolerance calculation procedures, and to be consistent across all cereal grain forages. wheat, hay 0.09 0.3 0 Wheat, hay Revised level based on OECD tolerance calculation procedures, and to be consistent across all hays and straws. Wheat, straw 1.0 0.3 0 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 c ommodities: ” for plant commodities. And

“ (2) Tolerances are established for the combined residues of thiabendazole (2 - (4 - thiazolyl)benzimidazole) and its metabolites 5 - hydrox ythiabendazole (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.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 12 of 74 There are established t olerance s for residues of thiabendazole an d metabolite on wheat grain and straw. The currentl y established tolerance for wheat grain is 1.0 ppm based on the originall y submitted data set for foliar uses on wheat , showing interferences in the analy tical 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 th iabendazole 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 r esidues 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 inclu ded on the final label if necessary based on WPS requirements. **2.3.3 Recommendations f**  **rom Residential**  **Assessment** There are no label recommendations based on the residential assessment. **3.0 In**  **troduction 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.** Thiabendazole/060101 Human Health Risk Assessment D416471

Page 13 of 74 **Table 3.**  **1. Test Compound Nomenclature.**  Com pound

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

Common name Benzimidazole Chemical name 1 H -benz i midazole CAS registry number 51 - 17 - 2 Com pound

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 c oefficient (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 phy sicoche mical properties of the technical grade of thiabendazole are presented in Appendix C. **3.3 Pesticide Use Pattern**  Sy ngenta 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

N O HThiabendazole/060101 Human Health Risk Assessment D416471

Page 14 of 74 **Table 3.3**  **Summary of Directions for Use of Thiabendazole**  **.** Applic. Timing, Type, and Equip. Form ulation [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 A ssume s 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 - a ssume s an averag e seed size of 12,500 seeds/lb Oats - a ssume s an average seed size of 12,500 seeds/lb Rye - a ssume s an average seed size of 15,600 seeds/lb Triticale - a ssume s an average seed size of 12,750 seeds/lb Wheat - a ssume s 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 Soy beans 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 treatm ent 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 handler s ( seed treaters ) and secondary handlers (seed planters). Post application exposure is not expected for workers.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 15 of 74 Risk assessments have been previousl y prepared for the existing uses of thiabendazole . This risk assessment considers all of the aforemention ed exposure pathway s 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 L ow - 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 anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OP P 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 currentl y in development as OPP has committed resources and expertise to the development of special ized software and models that consider exposure to by standers 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 A**  **nalysis** The toxicology

database for thiabendazole is complete with the exception of a developmental thy roid study . HASPOC waived the requirement for the 21/28 day inhalation toxicity

study , but required a develop m ental thy roid study (TXR # 0056686). The developmental thy roid toxicity study is required since there is clear evidence of thy roid 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, do g, mouse), 21 - day dermal toxicity

(rabbit)  Developmental toxicity : developmental toxicity (rat , rabbit and mouse)  Reproduction: 2 - generation reproduction (rat)Thiabendazole/060101 Human Health Risk Assessment D416471

Page 16 of 74  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 met abolism study

(MRID 42114701), [phenyl - U 14 C] thiabendazole (99.1% a.i.) was administered to five Crl:CD BR strain rats/sex/dose by gavage as a single dose at 25 or 400 mg/kg or as a single dose at 25 mg/kg following a 14 - day pretreatment with unlabeled thiabendazole at 25 mg/kg/day . [ 14 C]Thiabendazole was readil y absorbed b y 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, kidney s, 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 ma jority of the administered dose was recovered in the urine identified as the glucuronide conjugate of 5 - hydroxy thiabendazole (7.3 - 21.3% of dose) and the sulfate conjugate of 5 - hydrox y 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 - hydrox ythiabendazole (HTBZ) were present in urine from rats from all dose groups. HPL C analy ses of fecal extracts isolated minor amount s 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 - hydrox ythiabendazole, followed by conjugation to form glucuronide and sulfate conjugates of 5 - hydrox ythiabendazole. **4.2.1 Dermal Absorption**  Earlier risk a ssessments used a dermal absorption factor (DA F ) of 60% based on a ratio of LOAELs in short - term toxicity studies . The registrant (Sy ngenta) submitted a Triple Pack of in vivo dermal absorption study in rats (MRID 47705131), in vitro rat skin (MRID 4770510 2), and in vitro human skin (MRID 47705101) with thiabendazole formulated as TECTO 500 SC . TheThiabendazole/060101 Human Health Risk Assessment D416471

Page 17 of 74 triple pack approach was reviewed b y the Agency and concluded that a DAF of 0.5% should be used for thiabendazole (TXR 0055373). The Triple Pack approach presum es 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 a nd 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 . Thiabendazo le 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 (hy perplasia 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 neurotoxi city

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 sy stemic or dermal effects were seen at the l imit 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 thy roid 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/p ostnatal animal. Based on a WOE approach considering all the available hazard and exposure information for thiabendazole, the HED HASPOC concluded that the developmental thy roid toxicity

study is required (TXR 0056686). The developmental thy roid toxicity

s tudy is required since there is clear evidence of thy roid toxicity

in adult animals and thus a concern for potential toxicity during pregnancy , infancy and child hood. The developmental thyro id toxicity study will better address this concern than a develop mental neurotoxicity study .Thiabendazole/060101 Human Health Risk Assessment D416471

Page 18 of 74 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 acceptab le genetic toxicology studies on thiabendazole indicate that it is not genotoxic in in vivo and in vitro assay s. Review of literature studies indicated that thiabendazole has weak aneugenic activity

in both somatic and germinal cells. In a chronic rat study, thiabendazole induced thy

roid tumors in males only . Thiabendazole did not induce tumors in mice . Thiabendazole has been classified b y the HED Cancer Assessment Review Committee (CARC) “ **Likely** to be carcinogenic at doses high enough to cause a disturbanc e of the thy roid 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 thy roid hormone homeostasis nor result in thy roid tumor formation. Thiabendazole showed no significant toxicity in a battery

of acute toxicity

tests (Toxicity Category IV for acute oral and dermal toxici ty and dermal irritation , and Toxicity Category I II 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 Fac**  **tor)** 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 . Thy roid 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 thy roid 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 dev e lopmental thy roid assay

in rats with thiabendazole . This study will better address the concern for potential thy roid 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 (UF DB ). For the acute dietary

endpoint the total UF is 1000 (An interspecies scaling factor of 10X, an intraspecies variability

factor of 10X, a FQP A 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 toxicody namic reasons (rats eliminate thy roxine (a thy

roi d 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 thy roid study

was applied) .Thiabendazole/060101 Human Health Risk Assessment D416471

Page 19 of 74 **4.4 .1**  **Completeness o**  **f the**  **Toxicology Database** The toxicology

databa se for thiabendazole is complete with the exception of a developmental thy roid toxicity

study . Based on a WOE approach considering all the available hazard and exposure information for thiabendazole, the HED HASPOC concluded that a developmental thy roid to xicity

study is required (TXR 0056686). The developmental thy roid 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 N**  **eurotoxicity** 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**  **o f Sensitivity/Su**  **sceptibility in the Developing o r 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 earl y 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 b y HED HIARC (TXR 0013601) . There is evidence of thy

roid toxicity

following subchronic and chronic exposures to rats characteriz ed as histopathological changes in the thy roid in multiple studies in rats. Disruption of thy roid homeostasis is the initial, critical effect that may lead to adverse effects on the developing nervous s ys tem. Thus, the absence of the developmental thy roi d study

raises concern whether infants and children are sufficiently protected from developmental effects. **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residual uncertainties in the exposure database. The dietary risk assessment is co nservative 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 anal ys es . The assessments utilized anticipated residues , default proces sing factors, and available percent crop treated data. The DEEM analy sis also used Tier 1 drinking water estimates . For these reasons it can be concluded that the DEEM - FCID analy sis does notThiabendazole/060101 Human Health Risk Assessment D416471

Page 20 of 74 underestimate risk from acute or chronic exposure to thiabendaz ole . 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/amo unt handled. **4.5 Toxicity Endpoint and Point of**  **D eparture 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 t otal UF is 1000 ( an interspecies scaling factor of 10 X , an intraspecies variability factor of 10X, a database uncertainty factor of 10X for lack o f a developmental thy roid study , an FQPA SF of 1X). [Note: In earlier risk assessm ent (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 con sidered this study

to be inappropriate, in that reduced fetal weights/decreased maternal body weights were not effects that were likel y 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 recentl y . The RA team , in consultation with HED Senior Toxicologist, Elizabeth Mendez , selec ted 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 - ye ar chronic/carcinogenicity study in rats based on decreased body weight and liver hy pertrophy at the L OAEL 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 LOAELof 40 mg/kg/day . For the chronic dietary

endpoint, an interspecies scaling factor of 3X, lowered from 10 X for toxicody namic reasons (rats eliminate thy roxine (a thy

roid 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 thy roid 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 w ere selected from a subchronic rat oral toxicity study based on reduced body weight gains and histopathological changes in the bone marrow, liver and thy roid 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 s ince reduced fetal body weights seen in theThiabendazole/060101 Human Health Risk Assessment D416471

Page 21 of 74 developmental study

were not measured in the dermal study and a concern for the thy roid 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, liv er and thy roid 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 o f the dermal absorption studies. [Note: In earlier risk assessment s (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 o n 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 fro m 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 i n cidental oral , short - /intermediate - term dermal and short - /intermediate - term inhalation exposures (an interspecies scaling factor of 3x, lowered from 10x for toxicody namic reasons (rats eliminate thy roxine (a thy roid 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 thy roid 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 route s and indirect dietary

exposure fro m sponges on countertops . Dietary , dermal and inhalation endpoints for thiabendazole are based on common toxicological effects. Therefore, exposure s from food , d ermal 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 thy roid 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 thy roid hormone homeostasis nor result in thy roid tumor formation.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 22 of 74 **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 [Chem** **ical] for Use in Dietary and Non**   ** Occupational Hum** **an 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**

Ac ute Dietary (general population including females 13

– 49 years and children) NOAEL =

50 mg/kg UF A = 10X

UF H = 10X FQPA UF DB = 10X aRfD =

0.05mg/kg/day aPAD = 0.05 mg/kg Ac ute 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 pe ak 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 UF A = 3X

UF H = 10X FQPA UF DB = 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 to xicity rat study (MRID 42942802) Subchronic LOAEL = 40 mg/kg/ based on reduced body weight and body weight gains (( ↓11%) and histopathological changes in the bone marrow (erythroid hyperplasia), liver (centrilobular hypertrophy), thyroid (follicular cell hypertrophy) and spleen (pigmented). Incidental Oral (Short

– term (1 - 30 days) and intermediate term (1 - 6 mo nths) NOAEL=

10mg/kg/day UF A= 3x

UF H=10x FQPA UF DB = 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 thyroidThiabendazole/060101 Human Health Risk Assessment D416471

Page 23 of 74 **Table 4 .5.**  **4 .**  **1 Summary of Toxicological Doses and Endpoints for [Chem** **ical] for Use in Dietary and Non**   ** Occupational Hum** **an 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 Intermediate term (1 - 6 mo nths) DAF = 0.5% NOAEL=

10mg/kg/day DAF = 0.5% UF A= 3x

UF H=10 FQPA UF DB = 10x Residential

LOC for MOE = 300 Subchronic oral toxicity study

– rat

MRID 42942802 LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow , liver and thyroid Inhalation Short - Term (1 - 30 days) and Intermediate term (1 - 6 mo nths) NOAEL=

10mg/kg/day UF A= 3x

UF H=10x FQPA UF DB = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key dat a (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)**Thiabendazole/060101 Human Health Risk Assessment D416471

Page 24 of 74 **Table 4.5. 4**  **.2 Summary of Toxicological Doses and Endpoints for [ Chemical**  **] for Use in Occupational Hum**  **an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 day s) and Intermediate term (1 - 6 mo nths) DAF = 0.5% NOAEL=

10mg/kg/day DAF = 0.5% UF A= 3x

UF H=10 UF DB = 10x Occupational l

LOC for MOE = 300 Subchronic oral toxicity study

– rat

MRID 42942802 LOAEL = 40 mg/kg/day based on reduced body weight gains and histopathological changes in the bone marrow , liver and thyroid Inhalation Short - Term

(1 - 30 days) and Intermediate term (1 - 6 mo nths) NOAEL=

10mg/kg/day UF A= 3x

UF H=10x UF DB = 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 d oses 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to acc ount for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not ap plicable. **DAF = dermal absorption factor (TXR 0055373)** Thiabendazole/060101 Human Health Risk Assessment D416471

Page 25 of 74 **4.6 Endocrine Disruption**  As required b y FIFRA and FFDCA, EPA reviews num erous studies to assess potential adverse outco m es f

r om exposure to che micals. Collecti v ely , these studies inclu d e acute, subchronic and chronic toxicity, including ass e ss m ents of carcinogenicity , n eurotoxicity , develop m ental, reproductive, and general or sy ste mic toxicity . These studies include endpoints which m ay be susceptible to endocrine influ ence, including effects on endocrine target organ histopathology , organ weights, estrus cyclicity , sexual m aturati on, fertility , pregnancy rates, reproductive loss, and sex rati o s in offspring. For ecol o gical h azard assess m ents, EPA evaluates acute tests and chronic s tu dies th at a s s ess growth, develop m ental and repro d uctive effects in different taxono mic groups. As part of its most recent registration decision for thiabendazole, EPA reviewed these data and selected the m o st sen s iti v e endpoints for relevant risk assess m ent scenarios f

rom the existing hazard database. However, as required by FFDCA section 408(p), thiabendazole is subject to the endocrine screening part of the Endocrine D i sruptor Screening Program (EDSP). EPA has developed the EDSP to deter mine whether certain substances (including pesticide active and other ingredients) m ay have an effect in hum ans or wildli f e si milar to an eff

ect produced b y a “naturally occurring estrogen, or o ther such en docrine effec t s as the Admi nistrator m ay

designate.” The EDSP e m ploy s a two - tiered approach to m aking th e statutorily

required determinations. Tier 1 consists of a battery of 11 screening assay s to i d enti f y the potenti al of a chemical substance to i nteract with the estro g en, androgen, or thyr oid (E, A, or T) hormonal s yste m s . Che micals that go through Tier 1 screening and are found to have the potential to int eract with E, A, or T hor m onal sy ste m s will proceed to the next stag e of the EDSP where EPA will deter mine which, if any, of th e Tier 2 tests are neces s ary bas e d on the available data. Tier 2 testing is de signed to id e nti f y any adverse endocrine - related ef f ects caused b y the su

b stance, and establish a dose - response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency m u st screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 che micals, which contains 58 pes ticide active ingredient s and 9 inert ingredients. A second list of ch e micals identi fied for EDSP screening was published on June 14, 2013 2 and includes so m e pesticides scheduled for registration review and chemicals found in water. Neither of these lists should be construed as a list of kno wn or likely endocrine disruptors. For further info rm ation on the status of the EDSP, the policies and procedures, the li s ts of c h e micals, f

uture lists, the test guideli n es and the Tier 1 screening battery , please visit our website 3

.

2 See http://www.regulations.gov/#!doc umentDetail;D=EPA - HQ - OPPT - 2009 - 0477 - 0074 for the final second list of chemicals. 3 http://www.epa.gov/endo/Thiabendazole/060101 Human Health Risk Assessment D416471

Page 26 of 74 **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, soy

bean, 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 meta bolite in goat milk and tissues is the 5 - OH - TBZ compound (and its conjugates); BNZ and TBZ are also present. TBZ degrades predominantl y to 5 - OH - TBZ and its conjugates in hens. Varying amounts of BNZ and unchanged TBZ are also present in eggs and hen tissue s. The residues of concern in livestock commodities are thiabendazole, 5 - hydrox y - thiabendazole (free and conjugated), and benzimidazole. **5.1.2 Summary of Environmental Degradation**  Environmental fate studies show that thiabendazole is persistent and imm obile. Thiabendazole is stable to hydrol ys is and soil photolysis and degrades slowly in aerobic (half

- life ~ 700 day s) and anaerobic soil environments (>200 day s). Aquatic photoly sis, with a half - life of 1.2 day s in clear water, appears to be the only sign ificant 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 parti tioning coefficients (Koc s > 1,000 mL/g oc ), 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 weakl y 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 f rom 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 - hydrox y thiabendazole were identified. The major metabolite in livestock is the 5 - OH - TBZ compound (and its conjug ates); BNZ and TBZ are also present.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 27 of 74 **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 soy

bean, 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 - hydrox ythiabendazole were identified in these plant metabolism studies. [Note: The 5 - hydroxy thiabendazole metabolite was identified as a minor residue in rotational crops.] Post h arvest 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 so yb ean (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 b y 1.5x, 1.4x, 1.8x and 1.8x, respectively. The qualitative nature of the residue in animals is adequatel y understood based on acceptable ruminant and poultry

metabolism studies. The HED Metabo lism Committee determined that residues of concern in livestock for regulation and dietary risk assessment include thiabendazole, 5 - hydroxy

thiabendazole (free and conjugated), and benzimidazole. **Table 5.1.4 Summary of Metabolites and Degradates to be inc**  **luded in th e Risk**  **Assessment and Tolerance Expression**  Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop thiabendazole and benzimidazole (free and conjugated) thiabendazole and benzimidazole (free and conjugated) Rotational Crop thiabendazole and benzimidazole (free and conjugated) thiabendazole and benzimidazole (free and conjugated)

Livestock Ruminant thiabendazole, 5 - hydroxy thiabendazole (free and conjugated), and benzimidazole thiabendazole, 5 - hydroxy thiabendazole (free and conjugated), and benzimidazole Poultry thiabendazole, 5 - hydroxy thiabendazole (free and conjugated), and benzimidazole thiabendazole, 5 - hydroxy thiabendazole (free and conjugated), and benzimidazole Drinking Water thiabendazole Not ApplicableThiabendazole/060101 Human Health Risk Assessment D416471

Page 28 of 74 **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; Bras sica, head and stem, subgroup 5 A; vegetable, cucurbit group 9; alfalfa; spinach (includi ng bab y); and small grain s (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; Bras sica, head and stem, subgroup 5 A; 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 so yb eans, in response to a RED data requirement. The wheat and so yb ean field trial data submitted with this petition satisfy the RED data requirement for additional field trial data f

or wheat and soy

beans. Adequate wheat and so ybean processing studies were submitted, both reflecting a 5x application rate. The so yb ean processing study was submitted in response to a RED data requirement. The wheat samples treated at a 5x application rat e were processed into bran, flour, middlings, shorts and germ using simulated commercial procedures. Residues of thiabendazole were non quantifiable in wheat grain and all wheat processed commodities. The soybean samples treated at a 5x application rate w ere 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 soy beans and all soy

bean 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 so ybeans. 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 ty pical of seed treatment application rates, residues of thiabendazole and benzimidazole were non - quantifiable (<0.02 ppm total) in samples of lettuce, radish, and whe at commodities planted 30, 60, and 270 day s after treatment. This study satisfies the RED data requirement for rotational crop studies. **TABLE 5 .2**  **. Summary of Residue Data with Thiabendazole.**  Commodity Analyte Total Rate lb ai/A (g ai/ha) DAP

(days) Residue Levels (ppm) 1 n Sample Min. Sample Max. LAFT 2 HAFT 2 Median Mean Std. Dev. Al falfa Forage - 1 st Cutting Thiabendazole 0.02 - 0.05 (22 - 56) 45 - 253 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 12 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Al falfa Forage

– 2 nd Cutting Thiabendazole 0.02 - 0.05 (22 - 56) 70 - 292 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 12 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Al falfa Forage

– 3 rd Cutting Thiabendazole 0.02 - 0.05 (22 - 56) 110 - 323 10 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 10 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 10 <0.02 <0.02 <0.02 < 0.02 0.02 0.02 N/A Al falfa Hay

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

Page 29 of 74 **TABLE 5 .2**  **. Summary of Residue Data with Thiabendazole.**  Commodity Analyte Total Rate lb ai/A (g ai/ha) DAP

(days) Residue Levels (ppm) 1 n Sample Min. Sample Max. LAFT 2 HAFT 2 Median Mean Std. Dev. Cutting Benzimidazole (22 - 56) 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Combined Residues 3 12 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Al falfa Hay

– 2 nd Cutting Thiabendazole 0.02 - 0.05 (22 - 56) 70 - 292 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 12 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Al falfa Hay

– 3 rd Cutting Thiabendazole 0.02 - 0.05 (22 - 56) 110 - 323 10 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 10 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 10 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Al falfa Seed Thiabendazole 0.003 - 0.04 (3.4 - 45) 185 - 374 2 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 2 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 2 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Barley Hay Thiabendazole 0.03 - 0.20 52 - 242 12 <0.01 0.12 <0.01 0.12 0.010 0.023 0.032

Benzimidazole 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 12 <0.02 <0.13 <0.02 <0.13 0.020 0.033 0.032 Barley Grain Thiabendazole 0.03 - 0.20 83 - 256 12 <0.01 0.031 <0.01 0.029 0.010 0.012 0.005

Benzimidazole 12 <0.01 <0.01 <0.01 < 0.01 0.01 0.01 N/A Combined Residues 3 12 <0.02 <0.041 <0.02 <0.039 0.020 0.022 0.005 Barley Straw Thiabendazole 0.03 - 0.20 83 - 256 12 <0.01 0.085 <0.01 0.082 0.010 0.024 0.024

Benzimidazole 12 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 12 <0.02 <0.095 <0.02 <0.092 0.020 0.034 0.024 Wheat Forage Thiabendazole 0.08 - 0.14 (90 - 157) 39 - 236 19 <0.01 0.21 <0.01 0.20 0.010 0.025 0.044 Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.22 < 0.02 <0.21 0.020 0.035 0.044 Wheat Hay Thiabendazole 0.08 - 0.14 (90 - 157) 51 - 265 19 <0.01 0.066 <0.01 0.062 0.010 0.015 0.015 Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.076 <0.02 <0.072 0.020 0.025 0.015 Wheat Grain Thiabendazole 0.08 - 0.14 (90 - 157) 84 - 304 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Wheat Straw Thiabendazole 0.08 - 0.14 (90 - 157) 84 - 304 19 <0.01 0.078 <0.01 0.073 0.010 0.014 0.015 Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.088 <0.02 <0.083 0.020 0.024 0.015Thiabendazole/060101 Human Health Risk Assessment D416471

Page 30 of 74 **TABLE 5 .2**  **. Summary of Residue Data with Thiabendazole.**  Commodity Analyte Total Rate lb ai/A (g ai/ha) DAP

(days) Residue Levels (ppm) 1 n Sample Min. Sample Max. LAFT 2 HAFT 2 Median Mean Std. Dev. Carrot roots Thiabendazole 0.0003 - 0.007 (0.34 - 7.8) 79 - 134 8 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 8 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 8 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Radish roots Thiabendazole 0.002 - 0.004 (2.2 - 4.5) 26 - 60 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 5 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Radish tops Thiabendazole 0.002 - 0.004 (2.2 - 4.5) 26 - 60 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 5 <0.01 <0.01 <0.01 < 0.01 0.01 0.01 N/A Combined Residues 3 5 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Cantaloupe Thiabendazole 0.002 - 0.008 (2.2 - 9.0) 62 - 119 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 6 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Cucumber Thiabendazole 0.005 - 0.012 (5.6 - 13.4) 49 - 81 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 6 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/AThiabendazole/060101 Human Health Risk Assessment D416471

Page 31 of 74 **TABLE 5 .2**  **. Summary of Residue Data with Thiabendazole.**  Commodity Analyte Total Rate lb ai/A (g ai/ha) DAP

(days) Residue Levels (ppm) 1 n Sample Min. Sample Max. LAFT 2 HAFT 2 Median Mean Std. Dev. Summer Squash Thiabendazole 0.001 - 0.007 (1.1 - 7.8) 33 - 62 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 5 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Cabbage heads w/wrapper leaves Thiabendazole 0.00025 - 0.00077 (0.28 - 0.86) 4 84 - 190 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 6 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Broccoli head and stem Thiabendazole 0.00019 - 0.0008 (0.21 - 0.90) 73 - 137 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 6 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Spinach Leaves Thiabendazole 0 .001 - 0.014 (0.8 - 15.7) 47 - 89 8 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 8 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 8 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Immature (Baby) Spinach Leaves Thiabendazole 0.001 - 0.014 ( 0.8 - 15.7 ) 43 - 54 2 <0.01 <0.01 <0.01 < 0.01 0.01 0.01 N/A Benzimidazole 2 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 2 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Soybean Forage Thiabendazole 0.012 - 0.024 (13.5 - 26.9) 46 - 94 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Soybean Hay Thiabendazole 0.012 - 0.024 (13.5 - 26.9) 46 - 94 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Soybean Seed Thiabendazole 0.012 - 0.024 (13.5 - 26.9) 109 - 153 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 19 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 19 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A Dry Bulb Onion Thiabendazole 0.001 - 0.003 (1.1 - 3.4) 113 - 252 8 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Benzimidazole 8 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A Combined Residues 3 8 <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A 1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. N/A = Not Applicable 2 LAF T = 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

Page 32 of 74 n o 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 soy bean use rate increase. Surface water estimates were higher than ground water estimates. The highe st 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 anal ys es, respectively . See Table 5.3 below for details . **Table 5.3**  **. Summ**  **ary of Tier 1 Estim ated 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 2.40 1 1.55 1 Groundwater Highest Daily Concentration Average Concentration after Breakthrough New Uses (0.15) PRZM - GW 0.46 - Wheat (0.20) PRZM - GW 0.62 - 1 The highest EDWCs in surface water for thiabendazole were previously prepared for the 2002 Reregistration Eligibility D ecision (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 fo r 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 befor e 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/ .Thiabendazole/060101 Human Health Risk Assessment D416471

Page 33 of 74 **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 soy beans. Established/recommended tolerances were used for cereal grains (corn tolerance at the method limit of quantitation; estimated at 1⁄2 L OQ), citrus oil/peel, dried beans, soy beans 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 bab y 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 n ot 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 reasonabl e 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 - hydrox ythiabendazole (free and conjugated). All estimates were supported by available ruminant metabolism data. DEEM default processing factors were use d for all commodities except potato chips /granules/flakes and wheat processed commodities which relied on empirical data demonstrating that residu es 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 soy beans and wheat (SLUA report 2/22/13) were used in the acute (maximum %CT for both <2.5) and chronic (average %CT for bo th <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.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 34 of 74 **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 soy beans 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 : soy

beans 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 currentl y registered for thiabendazole : soy beans 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 harves t 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 c ombined acute dietary exposure from food and drinking water at the 99.9 th percentile of exposure is estimated at 0.012953 mg/kg/day

for the general population, equival ent to 26 % of the aPAD. The population subgroup with the highest estimated acute dietary exposure is children 1 - 2 years , with an estimated exposure at the 99.9 th percentile of 0.034322 mg/kg/day , equivalent to 69 % of the aPAD. **5.4.4 Chronic Dietary Risk Assessment**  Chronic dietary

exposure estimates for food and drinking water are well below HED’s level of concern (<100% CPAD) for all population subgroups. The dietary exposure is estimated at 0.000379 mg/kg/day

for the general population ( 1.1 % of the cPAD) and 0.00 1562 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 thyr oid hormonal balance but **not likely** to be carci nogenic 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 lev els at which thy roid hormone balance is impacted and consequentl y is also being protective of potential carcinogenic effects. Therefore, a cancer dietary assessment was not performed.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 35 of 74 **5.4.6 Summary Table**  **Table 5**  **. 4**  **6 Summ**  **ary of Dietary** (Food and Drinking Water) **Exposure and Risk for Thiabendazole. Population Subgroup**  **Acute Dietary (99.9 Percentile)**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD*** **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population 0. 0 129 53 26 0.0003 79 1. 1 All Infants (<1 year old) 0.021 098 42 0.00061 2 1.9 N/A N/A **Children 1 -**  **2 years old*** **0.034 322**  **69 0.00156**  **2 4.**  **7** Children 3 - 5 years old 0.0282 11 56 0.00108 1 3.3 Children 6 - 12 years old 0.01786 5 36 0.000 597 1.8 Youth 13 - 19 years old 0.0090 42 18 0.00029 5 0.9 Adults 20 - 49 years old 0.0075 28 15 0.0002 67 0.8 Adults 50 - 99 years old 0.0077 86 1 6 0.00027 6 0.8 Females 13 - 49 years old 0.0077 89 16 0.00025 6 0.8 *T he population subgroup (s) with the highest risk estimates. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  (AD memo of 6/23/10, T. Leighton, D379421) The proposed seed treatment uses of thiabendazole are not expected to result in residential (non occupational) exposures . However, residential exposure is possible via antimicrobial uses in products such as paints and sponges. The Antimicrobials Division has previously conducted an assessment of these uses (D379421, T. Leighton, 6/23/10). No risks of concern were identified. There are several thiabendazole uses which may result in residential exposures

– exposures to adults and/or children in residential settings. Two antimicrobial exposure scenarios have been assessed for residential exposures. The two uses include treated paint and impregnated sponges. Other antimicrobial uses of thiabendazole are not expected to cause exposure in residential settings. These uses are use on carpet backing, canvas textiles, wallboard and ceiling tiles, poly urethane foam, pla stics and rubber, paper, and coatings and filters used in HVAC sy stems. 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 to ys . Residential exposure and risk to residential handlers of thiabendazole - treated paints, using brush/roller application and airless sprayer application was assesse d. 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 f or airless sprayer applications, respectivel y, 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 subsequentl y ingested. A screening -Thiabendazole/060101 Human Health Risk Assessment D416471

Page 36 of 74 level assessment was conducted b y assuming exposures would be similar to a hard surface sanitizer. I f 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 condu cted assuming that 100% of the thiabendazole on a treated sponge is transferred to surfaces over 20 day s 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 generall y be used much longer than 20 day s; (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 unlikel y that 100% of any released thiabendazole would be transferred to countertops because th is 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 Exposu**  **re/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 sourc es are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7. 1**  **Acute Aggregate Risk** The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of thiabendazole (food and drinking water). The acute dietary risk estimates are not of concern to HED (<100% aPAD) at the 99.9 th exp osure 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 subgroup s. **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 populati on 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 risk s 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 asses sment was conductedThiabendazole/060101 Human Health Risk Assessment D416471

Page 37 of 74 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 Exposure**  **1 mg/kg/day**  **Aggregate MOE (food and**  **residential) 2**  General U.S. Population 0. 000379 0.0046 2000 Youth 13 - 19 yrs 0.0002 95 2000 Adults 20 - 49 yrs 0.000 267 2000 Adults 50+ yrs 0.000 276 2000 Females 13 - 49 yrs 0.000 256 2000 1 Residential Exposure = [Dermal exposure + Inhalation Exposure]. 2 Aggregate MOE = [NOAEL (10 mg/kg/day ( Avg F o o d & W at er E xp o s ure + Re s i d e nt i al E xp o s ure ) ] **Table 7.2. Short -**  **and Intermediate -**  **Term Aggregate Risk Calculations -**  **LOC =300 Population**  **Subgroup Average** 

**Food & Water Exposure**  **mg/kg/day Residential**  **Exposure 1**  **mg/kg/day Aggregate MOE** 

**(food and residential)**  **2 Fraction of Thiabendazole Transferred Daily From Sponge to Surface = 100%**  Children 1 - 2 0.001562 0.11 3 90 General Population 0.000379 0.02 490 **Fraction of Thiabendazole Transferred From Sponge to Surf**  **ace = 5%** Children 1 - 2 0.001562 0.0055 3 1400 General Population 0.000379 0.001 7300 1 Residential Exposure = [ Incidental Oral Exposure ]. 2 Aggregate MOE = [NOAEL (10 mg/kg/day / (Avg Food & Water Exposure + Residential Exposure)] 3 These exposure values have been adjusted from the original AD memo to reflect the current, more protective, assumptions for child body weight (11 kg, rather than the 15 kg used previously). **7. 3**  **Chronic Aggregate Risk** The chronic aggregate risk assessment takes into account exposure estimates from dietary consumption of thiabendazole (food and drinking water). The chronic dietary risk estimates are not of concern to HED (<100% aPAD) at the 99.9 th exposure percentile for the general U.S. population and all other population subgroups. Therefore, the chronic aggregate risk associated with the proposed uses of thiabendazole is not of concern to HED for the general U.S. population or any population subgroups.Thiabendazole/060101 Human Health Risk Assessment D416471

Page 38 of 74 **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 toxici ty finding as to thiabendazole and any other substances and thiabendazole does not appear to produce a toxic metabolite produced b y 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 informatio n 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 determ inations 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 t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protecti ve gear or controls used by a handler can cause exposure levels to differ in a manner specific to each app lication 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 (m ixing, loading, appl yi ng liquid formulations; b agging treated seed; s ewing bags; and multiple activities ) . In addition, occupational handlers may experience short - and intermediate - term e xposure 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 interm ediate - term exposure durations, short - term exposure and risk estimates are considered to be protective of intermediate term exposure. While the number of day s treating the proposed seed crops could potentially exceed the typical intermediate - term duration used in HED’s occupational assessments, HED ha s no information to indicat e that the same chemical is used consecutivel y for a long - term duration . Therefore, chronic occupational handler exposure for seed treatment was not assessed . Dermal and inhalation risk estimate s 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 2,2 00,000 for seed treaters and 1,600 to 220,000 for seed planters. (Tables 9.1.1 and 9.1.2).Thiabendazole/060101 Human Health Risk Assessment D416471

Page 39 of 74 **Table 9**  **.1.1 Summary of**  **Short -** **/Intermediate -**  **Term Handler Exposures/Risks for**  **Thiabendazole Seed Treatment Seed**  **Type Max** 

**Application Rate**  **1 Unit Exposure**  **2**

**(m g/lb ai)**  **Am ount** 

**of Seed Treated**  **3 Absorbed Dose** 

**(m g/kg/day)**  **4 MOE**  **5 Total**  **MOE 6**  **lb ai/lb seed Derm**  **al Inhal**  **. lb**  **seed/day Derm**  **al Inhal**  **. Derm**  **al 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 soy bean 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 soy bean 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 soy bean 0.00024 281,250 3.8E - 05 1.3E - 04 260,000 74,000 58,000 **MULTIPLE ACTIVITIES (com** **bination 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 1,400Thiabendazole/060101 Human Health Risk Assessment D416471

Page 40 of 74 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 soy bean 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 Advi sory 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 = 3 00. 6 Total MOE = 1 ÷[(1 ÷ Dermal MOE) + (1 ÷ I nhalation MOE)]Thiabendazole/060101 Human Health Risk Assessment D416471

Page 41 of 74 **Table 9**  **.1.2. Summary of Secondary Handler (Planter)**  **Exposures and Risks for Thiabendazole (**  **Single Layer , No Gloves**  **during Loading Only)** . **Seed Type Max** 

**Application Rate**  a **Unit Exposure b** 

**(m g/lb ai)**  **Am ount of** 

**Seed Planted**  **Per Day** c **Absorbed Dose**

**(m g/kg/day)**  **d MOE**  e **Total MOE**  **f lb ai/lb seed**  **Derm al**  **Inhal. lb seed/day**  **Derm al**  **Inhal. Derm**  **al 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 5,2 30 8.7E - 04 3.9E - 04 11,000 26,000 7,900 soy bean 0.00024 33,3 00 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 glove s. 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 (m g/ lb ai) × ap plication 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; inhalatio n = 10 mg/kg/day for short - /intermediate - term) ÷ Absorbed Dose (mg/kg/day) . LOC = 300. f Total MOE = 1 ÷ [ (1 ÷ Dermal MOE) + (1 ÷ I nhalation MOE)]Thiabendazole/060101 Human Health Risk Assessment D416471

Page **42** of **74 9.2**  **Short -** **/Intermediate Post** **- Application**  **Risk** HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. The potential for dermal and inhalation post - a pplication exposures following the planting of thiabendazole - treated seeds is unlikely because s ustained 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 prac tice 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 se ed 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 p ost - 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 Soy bean. 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 Thy roid Assay s in Pregnant Animals, Fetuses, Postnatal Animals, and Adult Animals. Hummel, S. 12/13/13. D410807, D410833, D313507. Thiabendazole. PP# 3F8166. New Seed Tre atment 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 bab y); and small grains (wheat , barley , oats, rye, and triticale). Summary

of Anal ytical 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. Thia bendazole: Antimicrobial Residential Uses for Consideration in the Aggregate Assessment to be Developed b y 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 Alfal fa, Brassica , Bulb Vegetables, Cucurbits, Root Vegetables, Small Grain Cereals, Spinach and Soy beans. 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

Page **44** of **74 A** **ppendix 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

Page **45** of **74 A.2**  **Toxicity Profile s**  **Table A.2.1 Acute Toxicity Profile**  **- Thiabendazole**  **Guideline No**  **. Study Type**  **MRID # Results**  **Toxicity Category**  870.1100 Acute Oral Toxicity

– rat 46556301 LD 50 >5000 mg/kg IV 870.1200 Acute Dermal Toxicityrabbit 46556302 LD 50 >5000 mg/kg IV 870.1300 Acute Inhalation

Toxicity

– rat 47321101 LC 50 > 0.53 mg/L (both sexes) III 870.2400 Acute E ye Irritation 46556303 Reversible within 48 hours I II 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 Ty pe MRID No. (year)/ Classification /Doses Results 870.3100 3 - month oral toxicity study - rats (gavage) 429428 01 (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 hy pertrophy), thy

roid ( follicular cell hy

perplasia), kidney s (h yp erplasia of transitional epithelium , tubular degeneration) and spleen (congested and pigmented). **NOAEL** = 25 mg/kg/day 870.3100 3 - month oral toxicity study - rats (gavage) 429428 0 2 (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 hyp erplasia), liver ( centrilobular hy

pertrophy), thyr oid ( follicular cell hy pertroph y) 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 In creased emesis and gall bladder epithelial cy toplasmic vacuolation at the mid and high dose. **LOAEL** is equivocal because th e toxicological significance of emesis and gall bladder epithelial cy toplasmic 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 sy stemic toxicity = >1000 mg/kg/day **NOAEL** for sy stemic toxicity = 1000 mg/kg/day **LOAEL** for dermal toxicity = >1000 mg/kg/day **LOAEL** for sy stemic toxicity = 1000 mg/kg/dayThiabendazole/060101 Human Health Risk Assessment D416471

Page **46** of **74 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile** Guideline No./ Study Ty pe 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 . **D evelopmental 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 significantl y (p ≤0.05 ) reduced (5 - 6%) in females and were slightly

but significantly

(p ≤0.05 ) reduced in m ales (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, day s 6 - 19) and reduced feed consumption ( ↓ 6 - 30%, day s 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 incompletel y ossified metacarpals in the fetal (28.1% vs. 8.5% for controls) and litter incidence (56.2% vs. 16.7% for controls) as wel l 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 bo dy

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 .Thiabendazole/060101 Human Health Risk Assessment D416471

Page **47** of **74 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile** Guideline No./ Study Ty pe 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 , F 0 males ; 7 - 18%, p ≤0 .05 , F 1 males) and food consumption (3 - 4%, p ≤0 .05 , F 0 males ; 4 - 5%, p ≤0 .05 , F 1 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 N**  **OAEL** = 90 mg/kg/day . **Development al toxicity LOAEL**  = 90 mg/kg/day based on reduced body weights in the offspring during lactation in both sexes of the F 1 ( ↓ 5 - 8%, day s 4 - 21, p ≤0 .05 ) and F 2 ( ↓ 7 - 10%, day s 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 Thy roids had v ery slight follicular enlargement in high dose females, while very

slight to slight follicular cell hy pertrophy was observed in high - dose males and females . 870.4100 24 - Month Chronic/Carcinog enicity - Rats Dietary 43593201 ((1993)

**Acceptable/Guideline** 0, 1 0.1, 30.2, 91.8 mg/kg/day **LOAEL** = 30 mg/kg/day based on reduced body weight and body weight gains and liver hy pertrophy (males). **NOAEL** = 10 mg/kg/day Thiabendazole induce d thy roid adenomas in male rats at dosages of ≥30 mg/kg/day . 870.4200 24 - Month Carcinogenicity in Mice , Dietary 00031447 (1980)

**Acceptable/Guideline** 0 , 31 - 42 (reduced to 5.6 - 8.3 on 7 th week) , 63 - 121, 184 - 372 mg/kg/day

for males and 0,,94 - 131 ( reduce to 5.7 - 9.9 on 7 th week) ,209 - 368, and 534 - 1005 mg/kg/day for females **LOAEL** = 209 - 368 mg/kg/day for ♀, 63 - 21 mg/kg/day for ♂ based on decreased body weight gains and increased liver weights. **NOAEL** = 5.7 - 9.9 mg/kg/day for ♀, 5.6 - 8.3 mg/kg/day for ♂ There were no treatment - related neoplastic lesions detected in the animals when compared to controls.Thiabendazole/060101 Human Health Risk Assessment D416471

Page **48** of **74 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile** Guideline No./ Study Ty pe 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 l ocomotor 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

w eights, 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 S almonella typhimurium strains and Esch erichia 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 cy totoxicity 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 ly mphoma cells (mammalian cell gene mutation assay) 46561901 (2005)

**Acceptable/Guideline** Excessive cy totoxicity 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 Cy togenetics (Chromosomal Aberration Assay in Human Peripheral Blood Lymphocy

tes) 4656190 2 (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 ly mphocy tes induced by thiabendazole over background in the presence or absence of S9 - activation.Thiabendazole/060101 Human Health Risk Assessment D416471

Page **49** of **74 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile** Guideline No./ Study Ty pe 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 body weight . Bone marrow was sampled 6, 24, and 48 hours after treatment. All mice survived to their scheduled term ination 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 s ampling time. The positive control induced significant increases in cells with chromosome aberrations.

870 - 5385 In vitro mammalian cell cy togenetic assay in human embryo fibroblasts 00098002 (1977)

**Acceptable/non**   ** Guideline** The test is negative up to the highest dose tested (50 μ g/mL) without S9 activation.

870 - 5385 in vitro mammalian cell cy togenetic assay in W1 - 38 human fibroblasts 00125297 (1977)

**Acceptable/non**   ** Guideline** The test is negative up to precipitating levels (1000 μ g /mL) without S9 activation.

870 - 5385 In vivo cy togenetic assay 00098002 (1977)

**Acceptable/Guid eline**  The test was negative in Wistar rats administered single doses of 10 - 1000 mg/kg b y oral gavage or 30 - 300 mg/kg once daily for 5 consecutive day s. Lethality was seen in the high - dose group but there was no evidence of bone marrow cy

totoxicity . The study

is classified as Acceptable and satisfies the 870 - 5550 In vitro Alkaline/Elution in rat hepatocy

tes 41170103 (1989) **Acceptable/Non**   ** guideline** Thiabendazole did not induce DNA strand breakage in primary rat hepatocy

tes 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**  **adequ ate high dose**  **was used** . Reportedly negative for the induction of dominant lethal in mice treated for 5 day s up to 500 mg/kg/day . However, no clinical or reproductive effects at HDT (TXR 0010290)Thiabendazole/060101 Human Health Risk Assessment D416471

Page **50** of **74 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile** Guideline No./ Study Ty pe MRID No. (year)/ Classification /Doses Results 870.7485 Metabolism and pharmacokinetics (Rat) 42114701 (19 90)

**Acceptable/Guideline** phenyl - U 14 C thiabendazole (99.1% a.i.) was administered to five Crl:CD BR strain rats/sex/dose by gavage as a single dose at 25 or 400 mg/kg or as a single dose at 25 mg/kg following a 14 - day pretreatment with unlabeled thiabendazole at 25 mg/kg. 14 C - thiabendazole was readily absorbed by

male and female rats following oral dosing. The rate of urinary excretion for both sexes in the high dose groups was lower during the initial 24 hours compared to the low dose groups. For all tes t 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 - hydroxy thiabendazole, followed by conjugation to form glucuronide and sulfate conjugates of 5 - hydrox ythiabendazole. 870.7600 Dermal penetration (Rat) 47705 131 (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

Page **51** of **74 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile** Guideline No./ Study Ty pe MRID No. (year)/ Classification /Doses Results Non - guideline Special study : Thy roxine clearance (male rat) 43593202 (1995)

**Acceptable/non**   ** guideline** 0, 10, 90, 270 mg/kg/day

for 13 weeks followed b y 14 week recovery **LOAEL** = 90 mg/kg/day based on centrilobular hepatocellular hy pertrophy and thyroid follicular cell hyperplasia **NOAEL** = 10 mg/k g/day The data support the hyp othesis that thiabendazole alters thy roid hormone homeostasis in male rats resulting in hy pothy roidism. The study

authors contend that the primary effect of thiabendazole is on the liver, resulting in hepatocellular hyp ertrop hy [microsomal enzy

me induction presumed, but not measured in the study]. Enhanced hepatic metabolism of the thy roid hormones leads to decreased serum levels. The decreased serum levels of the hormones cause an increased release of TS H . The higher serum TS H levels, in turn, causes thy roid h ypertrophy 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: 489963 10 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% carbox ym ethylcellulose at doses of 0, 50, 200, or 2000 mg/kg bw and observed for 14 day s. 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 tim e 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 examinati on. 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 t ransient 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; l acrimation, slightly drooping eyelids, increased time to first step, andThiabendazole/060101 Human Health Risk Assessment D416471

Page **52** of **74** a “slightl y 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 statisticall y 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 (Day s 0 - 15) was significantl y reduced in males ( ↓33%), but not females, at 2000 mg/kg bw. Daily body weight gains over day s 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. Reduc tions 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 day s 0 - 1 in males and females at 200 mg/kg bw. The transient decrease in food consumption and body

weight gain that occurred over day s 0 - 1 in males and females at 200 mg/kg bw are considered an adverse effect of tre atment 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 Spra gue - 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 LOAELof 200 mg/kg Uncertainty Factor (UF ): 10 00 (10x for interspecies extrapolation , 10x for intraspecies variation and 10x data base uncertainty factor for lack of a developmental thy roid study) . Comments about Study

/Endpoint : The observed effects occurred after a single oral exposure . This endpoint i s appropriate for the acute dietary exposure risk assessment.

= ( ) = 50	mg/kg	(NOAEL) ( ) = 0.05	mg/kgThiabendazole/060101 Human Health Risk Assessment D416471

Page **53** of **74 A**  **.3. 2**  **Chronic Reference Dose (RfD)**  **– General Population**  Study Selected: C hronic/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, 1 0.1, 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, urinaly sis, or gross pathology . Body weights and body

weight gains were generally

lower ( ↓7 - 30%) throughout the study for the mid - and high - dose males and high dose females. Reduced body weight gains ( ↓15, ↓28, and ↓19%, p≤0.05) for the mid - and high dose males and high - dose females, respectively , compared to the controls were observed at week 103. A reduced body weight gain ( ↓10%, not statistically significant) was also noted at this time for the mid - dose females. Significant increases ( ↑36 - 79%, p ≤0.05) in total serum cholesterol observed in the high - dose group were judged to be treatment - related. In the high - dose males, increased ( ↑29%, p≤0.05) relative (to body) liver weights and an increased incidence of centrilobular hepatocellular hy pertrophy (28/50 treated vs 0/50 controls) were also detected. Centrilobular hepatocellular hy pertrophy was al so observed in 7/50 mid - dose males. In the high - dose females, an increased ( ↑45%, p≤0.05) relative thy roid weights and increased incidences of thyroid focal cystic follicular cell hyperplasia (6/50 treated/2/50 controls) and diffuse follicular cell hy pertroph y (2/50 treated vs 0/50 controls) were observed. Thy roid diffuse follicular cell hy pertrophy was also observed (4/50 treated vs 0/50 controls) in the high - dose males . The sy stemic LOAEL is 30 mg/kg/day

based on reduced body weights and body weight gains and liver hy pertrophy (males). The sy stemic 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 ): 3 00 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicody namic reasons (rats eliminate thy roxine (a thy

roid hormone) at a higher rate than humans) and 10x for intraspecies variation and 10x data base uncertainty factor for lack of a comparative thy roid 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. 4294280 2) 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, splenicThiabendazole/060101 Human Health Risk Assessment D416471

Page **54** of **74** erythropoiesis and hemosiderosis in both sexes at 40 mg/kg/day . Th yroids had very slight follicular enlargement in high - dose females, while very slight to slight follicular cell hy pertrophy was observed in high - dose males and females (dogs) .

= = 10	mg/kg/day	(NOAEL)

( ) = 0.033	mg/kg/day **A .**  **3 .**  **3 Incidental Oral E**  **xposure ( S**  **hort -**  **and I**  **ntermediate -**  **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 biologicall y (> 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%, respectivel y). 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%, respectivel y). Cli nical pathology

revealed treatment - related changes in hematology and clinical chemistry , but not in the urinaly ses. 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 thy roid weights with increasing dose. Stati stically

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 a bsolute thy

roid weights were observed in females dosed at 160 mg/kg/day and higher and relative thy roid weights in males and female rats dosed at 160 mg/kg/day and higher. Histopathological examination revealed treatment - related changes in the liver, thy r oid, bone marrow, spleen, and kidney . At 40, 160, and 320 mg/kg/day , centrilobular hy pertrophy was observed in the livers of males (7/10, 9/10, and 9/10, respectivel y) and females (1/10, 9/10, andThiabendazole/060101 Human Health Risk Assessment D416471

Page **55** of **74** 9/10, respectivel y). At these same doses, follicular cell hy pertrophy was observed in the thy

roids of males (1/10, 2/10, and 6/10, respectivel y) and females (3/10, 10/10, and 10/10, respectivel y). Very slight ery

throid hy perplasia was observed in the bone marrow of 5/10 females dosed at 40 mg/kg/day

8/10 female s 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 LO AEL 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 NOAELis 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 ): 3 00 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicody namic reasons (rats eliminate thy roxine (a thy

roid 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 studie s. **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 .Thiabendazole/060101 Human Health Risk Assessment D416471

Page **56** of **74** Uncertainty Factor (UF ): 3 00 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicody namic reasons (rats eliminate thy roxine (a thy

roid 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 L OAEL (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 o f 0.5% should be used for this risk assessment. The reduced body weight gains and histopathological changes in the bone marrow, liver, and thy roid 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): 3 00 (3x for interspecies extrapolation (an interspecies scaling factor of 3x, lowered from 10x for toxicody namic reasons (rats eliminate thy roxine (a thy

roid 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 toxicody namic reasons (rats eliminate thy roxine (a thy

roid hormone) at a higher rate than humans) and 10x f or 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 LOAE L (40 mg/kg/day); and, 2) the duration of this study is appropriate for this e xposure period of concern (1 - 6 months). The reduced body weight gains and histopathological changes in the bone marrow, liver, and thy roid 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 toxicody namic reasons (rats eliminate thy roxine (a thy

roid hormone)Thiabendazole/060101 Human Health Risk Assessment D416471

Page **57** of **74** 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 hy pertrophy 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 hy

perplasia of transitional epithelium were observed in the kidney s of 5 - 8/20 females, and very slight tubular degeneration was observed in the kidney s of 15/20 rats per sex. Relative kidney weights were increased 32 - 40%. Slight to moderate follicular cell hy perplasia was observed in the thy roids of 18 - 19/20 rat s per sex; absolute and relative thy

roid weights were increased 56 - 64% and 104 - 136%, respectivel y. 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 o f the stomach included very slight acanthosis or degeneration of the nonglandular mucosa (3/20 males, 7/20 females), very slight focal cy

toplasmic 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 ery throcyte 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 hy pertrophy was observed in the livers of 2/20 males and 5/20 females; follicular cell hyp erplasia was observed in the thy roids of 8/20 males and 8/20 females; and calculus (1/20 males, 5/20 females) and hy perplasia of transitional epithelium (1/20 males, 2/20 females) were observed in the kidney s. The spleens of 7/20 males and 2/20 females were congested, and of 2/20 females were pigmented. Absolute liver weights (females onl y) and relative liver, kidney , and thy roid weights were increased 10 - 29%. At 13 weeks, cholesterol levels of males and females were 19 and 69% higher, respectivel y, than the controls. In addition, rats (2/20 males, 4/20 females) had increased incidence in alopecia/thin fur of the hindquarters. In the 25Thiabendazole/060101 Human Health Risk Assessment D416471

Page **58** of **74** 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 spl een. 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 ea ch 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 biologicall y (> 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%, respectivel y). 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 fem ales (38 and 57%, respectivel y). Clinical pathology

revealed treatment - related changes in hematology and clinical chemistry , but not in the urinaly ses. 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 thy roid 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 female s. Statistically significant increases in absolute thy roid weights were observed in females dosed at 160 mg/kg/day and higher and relative thy roid weights in males and female rats dosed at 160 mg/kg/day and higher. Histopathological examination revealed treatment - related changes in the liver, thy roid, bone marrow, spleen, and kidney . At 40, 160, and 320 mg/kg/day , centrilobular hy pertrophy was observed in the livers of males (7/10, 9/10, and 9/10, respectivel y) and females (1/10, 9/10, and 9/10, respecti vel y). At these same doses, follicular cell hypertrophy was observed in the thyroids of males (1/10, 2/10, and 6/10, respectivel y) and females (3/10, 10/10, and 10/10, respectivel y). Very slight ery

throid hy perplasia 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 sexThiabendazole/060101 Human Health Risk Assessment D416471

Page **59** of **74** were very slightly to slightly

pigmented with hemoglob in 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 NOAELis 10 mg/kg/day . **870.3100 90**  **- Day Oral Toxicity**  **- Mouse**  No ne. **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 , urinaly sis or electrocardiographic parameters; all animals survived to terminal sacrifice. Thiabendazole produced concentration - dependent increases in the inciden ce 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 cy toplasmic 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 cy

toplasmic vacuolation. The gallbladders of 2/4 males and 3/4 females treated at 75 mg/kg/day

exhibited very

slight epithelial cy

toplasmic vacuolation. The toxicological significance of this finding could not be determined. No neoplastic lesions were observed. **The LOAEL for this study is equivocal b ecause 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 satisfie s the Subdivision F guideline requirement for a subchronic toxicity study (82 - 1b) in non - rodents.Thiabendazole/060101 Human Health Risk Assessment D416471

Page **60** of **74 870.3200**  **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 day s/week for either 21 or 22 days. No treatment related mortality was ob served. No s ys temic or dermal toxicities were noted at doses up to 1000 mg/kg/day (Limit dose). Therefore, the LOAELfor s ys temic toxicity is > 1000 mg/kg/day . The sy stemic NOAEL is 1000 mg/kg/day . The dermal toxicity L OAEL ≥ 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 b y 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 significantl y (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 b y 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 day s 6 through 18 of gestation.Thiabendazole/060101 Human Health Risk Assessment D416471

Page **61** of **74** Maternal toxicity

was noted at 600 mg/kg/day as a treatment - related reduction in body weight gain during treatment ( ↓69%, p≤0.05, day s 6 - 19) with a statistically significant rebound in the post - treatment interval ( ↑47%, p≤0.05, day s 19 - 28). In addition at 600 mg/kg/day , treatment related decreases in feed consumption were observed during treatment ( ↓6 - 30%, day s 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 oc curred 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, bl ood 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 significantl y (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 incompletel y 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 contro ls (9 and 19%, respectivel y). 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:I CR mice/dose at dose levels of 0, 25, 100, or 200 mg/kg/day

from day s 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 1 00 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 b y significant (p ≤0.05) reductions in feed consumption b y 9 - 13% at 200 mg/kg/day

during gestational day s 6 - 8, 12 - 14, 14 - 16, and 16 - 18, and at 100 mg/kg/day , by

13% during gestational day s 12 - 14. No treatment - related changes in body weightThiabendazole/060101 Human Health Risk Assessment D416471

Page **62** of **74** gain or feed consumption were noted at 25 mg/kg/day compared to controls. **The maternal L OAEL 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/da y, 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 adminis tered 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 F 0 generation animals began at 8 weeks of age and lasted for 9 weeks prior to mat ing to produce F 1 pups. At weaning, F 1 pups (25 males and 27 females/dose level) were selected to become the parents of the F 2 generation and were given the same concentration test diets as their dam. F 1 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 F 0 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 F 1 generation males as treatment - related decreases in body weight gains (7 - 18%, p ≤0.05) and food consumption (4 - 5%, p ≤0.05) v s. controls. At 90 mg/kg/day , parental toxicity was demonstrated during the pre - mating and post cohabitation intervals in F 0 generation males as treatment - related decreases in body weight gains (29 - 46%, p ≤0.05) and food consumption (11 - 13%, p ≤0.05), and i n F 1 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 F 0 generation and (14%, p ≤0.05) in the F 1 generation vs. controls. Food consumption for females during the pre - mating interval was decreased (12%, p ≤0.05) in the F 0 generation. In addition, a decrease was noted in body weight gains (8%, p ≤0.05) vs. control s in the F 0 generation during gestation with a subsequent 3.5 fold increase during the lactation period. No change in body weight gains occurred in the F 1 generation during gestation; however, an increase (18 g) at 90 mg/kg/day vs. a decrease (5 g) for co ntrols was noted during the lactation period. Although not statistically significant, food consumption was decreased vs. controls during gestation in the F 0 (4 - 16%) and F 1 (4 - 10%) generation females.Thiabendazole/060101 Human Health Risk Assessment D416471

Page **63** of **74** No sy stemic toxicity

was observed at 10 mg/kg/day . **Th e 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 F 1 (5 - 8%, day s 4 - 21, p ≤0.05) and F 2 (7 - 10%, day s 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 offsp**  **ring 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 orall y 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 hematol ogy parameters; clinical chemistry

and urinaly sis 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 pol yc hromasia 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 significantl y (p ≤0.05) higher in mid - (14 and 20%, respectively , combined sexes) and high - (37 and 41%, respectively , combined sexes) dose animals. In high dose animals, absolute thyroid weights were increased b y 22% (not significant), while relative thy roid weights were increased b y 33% (p ≤0.05).Thiabendazole/060101 Human Health Risk Assessment D416471

Page **64** of **74** Histopathological evaluatio ns 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. Thy roids had very

sl ight follicular enlargement high - dose females (1/4), while very slight to slight follicular cell hy pertrophy 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 cy toplasmic lipid vacuolation and discolored foci of the mucosa; dose - related increases in severity (very slight to marked) were observed. The kidney s of mid - (3/4) and high - (4/4) dose females showed very slight to slight distal tubule vacuolation, compare d 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 cy toplasmic inclusions; this finding was also observed in 3/4 males and 2/4 females in the mid - dose group. The toxicolog ical significance of the above findings could not be determined. Spleens exhibited very slight to slight increases in ery

thropoiesis in mid - (1/4 males; 1/4 females) and high - (2/4 males; 3/4 females) dose animals; hemosiderin deposits were observed in mi d - (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**  Ina 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 survi val, clinical signs, food consumption, ophthalmoscopic findings, urinaly sis, or gross pathology . Body weights and body

weight gains were generally

lower ( ↓7 - 30%) throughout the study for the mid - and high - dose males and high dose females. Reduced body we ight gains ( ↓15, ↓28, and ↓19%, p≤0.05) for the mid - and high dose males and high - dose females, respectively , compared to the controls were observed at week 103. A reduced body weight gain ( ↓10%, not statistically significant) was also noted at this time for the mid - dose females. Significant increases ( ↑36 - 79%, p ≤0.05) in total serum cholesterol observed in the high - dose group were judged to be treatment - related. In the high - dose males, increased ( ↑29%, p≤0.05) relative (to body) liver weights and an inc reased incidence of centrilobular hepatocellular hy pertrophy (28/50 treated vs 0/50 controls) were also detected. Centrilobular hepatocellular hy pertrophy was also observed in 7/50 mid - dose males. In the high - dose females, an increased ( ↑45%, p≤0.05) rel ative thy roid 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. Thy roid diffuse follicular cell hy pertro phy was also observed (4/50 treated vs 0/50 controls) in the high - dose males. The sy stemic LOAEL is 30 mg/kg/day

based on reduced body weights and body weight gains and liver hypertrophy (males). The sy stemic NOAEL is 10 mg/kg/day .Thiabendazole/060101 Human Health Risk Assessment D416471

Page **65** of **74 870.4200b Carcinogeni**  **city (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 significantl y 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 rec eived 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 adequat e 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 l ymphoma cells (MRID 46561901)  Chromosome aberration, human peripheral blood lymphocy tes (MRID 46561902)  Two in vitro mammalian cy togenic assay - human embryo fibroblasts (MRID 00098002, MRID 00125297)  in vivo cy

togenetics, bo ne marrow chromosome aberration assay in male mice (MRID43328304)  in vivo cy

togenic assay

in male rats (MRID 00098002)  in vitro alkaline/elution in rat hepatocy tes (MRID 41170103) Results in all eight studies were negative for genotoxicity .Thiabendazole/060101 Human Health Risk Assessment D416471

Page **6 6**  of **74 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 or al dose of thiabendazole (99.3 % a.i., batch/lot # HK 1998/011) in 0.5% carbox ym eth yl cellulose at doses of 0, 50, 200, or 2000 mg/kg bw and observed for 14 day s. 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

day s 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 s ys tem 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 count s (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 “ slightl y 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 n o 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 statisticall y 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 (Day s 0 - 15) was significantl y reduced in males ( ↓33%), but not females, at 2000 mg/kg bw. Daily body weight gains over day s 0 - 1 were sign ificantly 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 m ales 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 day s 0 - 1 in males and females at 200 mg/kg bw. The transient decrease in food consumption and body

weight gain that occurred over day s 0 - 1 in males and females at 200Thiabendazole/060101 Human Health Risk Assessment D416471

Page **67** of **74** 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 p erformed 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/se x/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 sy stem tissues. Treatment with 15 00 ppm adversely affected body weight, body weight gain, and food consumption in both males and females. Mean absolute body weight was statisticall y significantl y (p<0.05) decreased compared to controls in males on day s 84 and 92 ( ↓11% for both day s) and i n 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 b y 18% and 36% in males and females, respectivel y. Reduc tions in body

weights and body

weight gains were accompanied by reduced food consumption. Food consumption was statistically significantl y reduced in males over several weeks ( ↓11 - 17%) and in females at all weekl y intervals ( ↓13 - 22%), with overall food co nsumption reduced b y 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 re sult 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 b rain 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).** Thiabendazole/060101 Human Health Risk Assessment D416471

Page **68** of **74 870.6300 Developmental Neurotoxicity Study**  Not required (TXR No. 0013601). **A.4.8 Metabolism**  **870.7485 Metabolism**  **- Rat**  In a rat metabolism study (MRID 42114701), [phenyl - U 14 C]thiabendazole (99.1% a.i.) was administered to five Crl:CD BR strain rats/sex/dose by gavage as a single dose at 25 or 400 mg/kg or as a single dose at 25 mg/kg following a 14 - day pretreatment with unlabeled thiabendazole at 25 mg/kg. [ 14 C]Thiabendazole was readil y absorbed b y male and female rats following oral dos ing. 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 uri ne, 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, kidney s, 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

enzy matic reactions as the glucuronide conjugate of 5 - hydroxy

thiabendazole (7.3 - 21.3% of dose) and the sulfate conjugate of 5 - hydrox y 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 - hydrox ythiabendazole (HTBZ) were present in urine from rats from all dose groups. HPLC analy ses 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 - hydroxy

thiabendazole, followed by conjugation to f

orm glucuronide and sulfate conjugates of 5 - hydroxy

thiabendazole. This metabolism study

in the rat is classified **acceptable (§85 -**  **1)** and satisfies the guideline requirement for a metabolism study .Thiabendazole/060101 Human Health Risk Assessment D416471

Page **69** of **74 870.7600**  **Dermal Absorption -**  **Rat** Individual executive summaries of these studies are not available; onl y 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(I CR) 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 , respectivel y) for at least 28 day s. A concurrent positive control group rec eived 50 mg/kg/day cyclophosphamide monohydrate [CPS] once daily during study

day s 24 - 27 via IP injection. All animals were immunized via an intravenous injection with 0.2 mL of 1x 10 8 SRBC ( Sheep Red Blood Cell) in the tail vein on study

day 24. All animal s were observed twice dail y for mortality and moribundity . Clinical examinations were performed daily , and detailed phy sical examinations were performed weekl y. Indivi dual body weights were recorded twice weekly , and food consumption was recorded approxim ately weekly . On study

day 28, b lood samples for serum IgM antibody

anal ys is were collected from all animals from the caudal vena cava. The mesenteric l ymph node, Peyer’s patch, spleen, and thy mus were collected. In addition, organ weights for the spleen and thy mus were recorded at the schedule d 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 paramet ers 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 an d 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 N**  **OAEL for systemic toxicity is 1000 ppm (**  **205.6 mg/kg bw/day)**  **.** L ower (53%) tot al spleen activity (measured as AFC/spleen) was noted in the 5000 ppm group when compared to the vehicle group; however, there were no effects of thiabendazole on mean total spleen cell numbers or specific activity (measured as AFC /10 6 spleen cell s) 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) , l ower spleen cell numbers, specific activity (AFC/10 6 spleen cells), and total spleen activity (AFC/spleen) were note d when compared to the vehicle control group, which validated the functionality of the assay .Thiabendazole/060101 Human Health Risk Assessment D416471

Page **70** of **74** A review of previous thiabendazole regulatory toxicity studies in rats, mice, and dogs failed to show any treatment - related changes in a variety of indicat ors of potential Immunotoxicity (including leukocy

te counts, ly

mphocy te counts, globulin concentration, macroscopic findings [ly mph nodes, thy

mus, and spleen], organ w eights [spleen and thy mus], and microscopic findings [bone marrow, lymph nodes, spleen, and thy mus]). **Under conditions of this study, t**  **he 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 nom inal 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 thy roid onl y). During week 14 of the study , blood samples fro m 5 rats/dose were used for evaluation homeostasis of thy roid hormones and thy roid 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 pathologicall y (liver and thyr oid only). Mortality and clinical signs of treated animals were unaffected b y treatment. After 13 weeks of dosing, mean body weights of the mid - and high - dose animals were 12% and 32% lower than control s, respectivel y. 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 thy roid and liver showed increased absolute and relative organ weights and increas ed incidence of microscopic lesions. In the mid - and high - dose animals, absolute thy

roid weights were increased by 20 and 40%, respectively , and relative (to body) thy roid weights, b y 26% and 103%, respectivel y. Relative liver weights were also increased by 7% and 25%, in mid - and high - dose animals, respectively . Histopathological examination revealed dark foci in the thy roids of the 6/15 high - dose animals and very slight to slight diffuse follicular cell hyperplasia in the thy roid of 10/15 mid - and 12/1 6 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 thy roid and liver lesions were not observed in any of the low dose and control main study an imals or in any

of the recovery

phase animals. Thy roid homeostasis (serum T 3 , T 4 and TSH) was evaluated during treatment weeks 2, 4, 8, and 13 and weeks 6 and 13 of the recovery phase. T 3 levels decreased b y 5 - 10% in mid - dose and 11 - 19% in high - dose animals compared to controls; TSH levels were increased by 66 - 160% in mid dose and 65 - 189% in high - dose animals. Evaluations carried out during week 14 of the study , showed effects in mid - and high - dose animals. For high - dose animals, statistically significantThiabendazole/060101 Human Health Risk Assessment D416471

Page **71** of **74** increases in thy

roxine clearance (44%, p=0.001), volume of distribution (V d , 64%,p<0.001), rate of elimination ( kel , 13%, p<0.001), and half - life (T 1/2 , 16%, p<0.001). At the mid - dose significant increases in kel (18%, p<0.001), T 1/2 (23%, p<0.001) and in V d (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 compara ble to control values while T 3 serum levels were higher (9% - 19%). T 4 were comparable to controls throughout both the treatment and recovery

periods. These data support the hy pothesis that thiabendazole alters thy roid hormone homeostasis in male rats resulting in hypothyr oidism. The study authors contend that the primary effect of thiabendazole is on the liver, resulting in hepatocellular hy pertrophy [microsomal enzy

me induction presumed, but not measured in the study]. Enhanced hepatic metabolism of the thy roid 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 thy roid h ypertrophy and hy perplasia. The submitted special study is classif ied as **acceptable/non -**  **guideline .** Thiabendazole/060101 Human Health Risk Assessment D416471

Page **72** of **74 A** **ppendix B.**  **Chemical Names and Structures** Chemical Names and Structures Com pound

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

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

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

N O HThiabendazole/060101 Human Health Risk Assessment D416471

Page **73** of **74 Appendix C.**  **Physical/Chemical Properties T**  **able C1 .**  **Physicochemical Properties of the Technical Grade Test Compound: Thiabendazole.** Parameter Value Reference Melting point/range 304 - 305 °C Thiabendazole RED 10/02 pH 5.16 - 5.97 Thiabendazole RED 10/02 Density 25 - 30 cc (tapped) Thiabendazole RED 10/02 Water solubility 0.028 - 0.030 mg/mL at 25 °C Thiabendazole RED 10/02 Solvent solubility acetone benzene chloroform dimethylformamide dimethyl sulfoxide ethanol ethyl acetate methanol 25 oC

4.2 g/L 230 mg/L 80 mg/L 39 g/L 80 g/L 7.9 g/L 2.1 g/L (R.T.) 9.3 g/L The Pesticide Manual, 8 th edition

Vapor pressure 4 x 10 - 9 mm Hg at 25 °C Thiabendazole RED 10/02 Dissociation constant, pKa pKa1 = 4.73; pKa2 = 12.00 Thiabendazole RED 10/02 Octanol/water partition coefficient Log(KOW) = 240 - 285 at pH 7 Thiabendazole RED 10/02 UV/visible absorption spectrum Neutral solution 32,170 L/mol*cm 3 at 205.5 nm Ac idic solution 41,520 L/mol*cm 3 at 303.5 nm Neutral solution 40,553 L/mol*cm 3 at 215.5 nm MRID 46286801 1

1 Data were referenced in MRID 47705121.Thiabendazole/060101 Human Health Risk Assessment D416471

Page **74** of **74 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.