Page 2 of 62 Pesticide Re-Evalu ation Division (7508P) Office of Pesticide Programs

Attached is the Health Effects Division’s (HED) human health ri sk assessment scoping document for thiophanate-methyl and its metabolit e, carbendazim, to support registration review.Page 3 of 62 Executive Summary

The Health Effects Division (HED) Thiophana te-Methyl/Carbendazim and the Antimicrobial Division (AD) Carbendazim Risk Assessment Team s have evaluated the database and the most recent human health risk assessments for the sy stemic benzimidazole fungicides, thiophanatemethyl (TM) and carbendazim (MBC). MBC is a pesticide active ingredient but is also a metabolite, environmental degradate and the pe sticidally active moiety of TM. The two compounds are therefore considered together in this document. HED performed this evaluation in order to determine the scope of work necessary to support the established tolerances (for TM only) and existing registrations fo r both active ingredients. The primary sources of information
were recent human health risk asse ssments written for TM (D330476, D330976 and D360951, 2009); the HED Chapter of the Reregistration Eligibility Decision (RED) document for TM (D275774, 2002); an updated hazard characte rization for TM and MBC (D340134, 2007), and HED’s revised residential exposure assessmen t for MBC in paint (D364554, 2009). Residue chemistry, dietary exposure and non-dietary exposu re assessments, and toxicology evaluations
were also considered.

The use patterns for these compounds are extens ive, and for TM include food uses. Their pesticidal activity derives from inhibition of fungal β -tubulin polymerization.

Thiophanate-methyl: TM is registered for use on a variety of fruits, nuts, ve getables and field crops, commercial treatment of a variety of s eeds including potato seed pieces and peanuts, greenhouses and nurseries (including bulb dip treatment). It is al so registered for use on turf, which includes sod farms, golf courses, athletic and recreational fields, ornamental grasses for landscapes and interiorscapes. E nd-use products are formulated as liquids, granules (G), water dispersible granules (WDG), wetta ble powders (WP), water solubl e bags (WSB) and dusts (for seed treatment). Products may be applied as a br oadcast foliar or soil directed spray by ground, aerial, or hand held equipment, granular spread er, and commercial and on-farm seed treaters. The personal protective equipment (PPE) for applic ators and other handlers consists of a range from baseline clothing (long-sleeved shirt, long pants, shoes plus socks) and chemical resistant gloves made of any waterproof material to the additional use of protective eyewear and an apron when mixing and loading.

The toxicology database for TM is largely comp lete for assessment of human health risk; however, additional toxicology data are require d. Based on the potential for applicator inhalation exposure during spray ap plication uses, a rat subchroni c inhalation study is required. A developmental thyroid study is also required to assess poten tial thyroid effects in early development from exposure to TM.

The main target organ is the liver in the rat, dog and mouse. There is evidence that TM causes disruption of thyroid homeostasis in the rat and dog, secondary to liver toxicity. Other effects included decreased body weight/weight gain, mild red blood cell effects at higher exposures and, in rats, renal and testicular toxicity. In th e rabbit, decreased food consumption was observed with dermal exposure.Page 4 of 62 Rat and rabbit developmental studies and a rat two-genera tion reproductive toxicity study
showed no evidence of increased susceptibility. No reproductive toxicity was observed in the rat. Liver and thyroid were examined at week 8 for parental and F1 an imals: effects were reported in both generations but at a lower inci dence in the F1 offspring. TM did not show evidence of neurotoxicity, and a developmen tal neurotoxicity study is not required.

TM is classified as “likely to be carcinogenic to humans,” based on thyroid tumors in rats and
liver tumors in mice and evidence of ane ugenicity, with a cance r potency factor (Q 1 *) based on
liver tumors in male mice.

In the most recent assessment (D360951 ; 6/24/2009), for chronic dietary and non-dietary (residential) exposure, the Food Quality Protectio n Act (FQPA) Safety Factor was reduced to a 3X due to a data gap for a developmental thyroi d study. A 3X factor (as opposed to the default 10X) was deemed adequate for the following reasons : 1) the toxicology data base is considered adequate to assess pre- and post-na tal toxicity; 2) there was no ev idence of increased susceptibity following in utero exposure to rat and rabbits and pre/pos t natal exposure to rats; 3) there was no concern for potential developmental neurotoxic ity, and a developmental neurotoxicity study is not required; and 4) the point of departure used risk assessmen t would adequately address any potential for the concern for thyroi d toxicity seen in the adult an imals. For acute dietary risk assessment, the FQPA safety factor was rem oved (i.e., 1X) because developmental thyroid effects would not be expected to result from a single dose and would therefore not affect the point of departure selected for acute dietary risk assessment. The developmental thyroid assay will address the concern for any potential thyroid e ffects that might occur during late gestational and early postnatal development a nd therefore will not have an impact on the point of departure or the endpoint of concern used fo r acute dietary risk assessment.

HED has not revised the endpoints, doses, and safety factors fo r the purpose of this scoping assessment for registration review. However, to ensure that future human health risk assessments are consistent with science policies in place at the time of registration review and take into consideration any fi ndings from the new studies, HED recommends reevaluation of: (1) endpoints selected for risk assessment and (2) reconsideration of the FQ PA safety factor.

The residue chemistry database supporting the re gistered uses of TM is complete, and no new residue chemistry data are requi red. A revised dietary risk assessment will be conducted to include updated percent crop tr eated estimates, monitoring data if available, changes in toxicological endpoints, and revi sed estimated drinking water con centrations. The most recent drinking water assessments used modeling to es timate surface water and groundwater residues. The dietary exposure database is adequate to support th e registration of TM. If the outstanding toxicity studies identify a more sensitive point of de parture than any used in the most recent risk assessment, or if the points of departure are re vised for any other reason, the revised values will be incorporated into the dietary risk assessment. Currently, the dietary (food and drinking water) risks are not of concern for the existing uses of TM.

The U.S. tolerance definition for TM differs from the Codex definition in that the Codex
definition includes residues of th e fungicide, benomyl. The structure of benomyl is similar to that of carbendazim. At one time, there were U. S. tolerances for benomyl, but these tolerancesPage 5 of 62 have been cancelled. Benomyl is still used in other countries and, as a result, Codex Maximum Residue Levels (MRLs) are still in effect. During registration review, HED will revisit
established tolerance levels and the toleran ce definition and, where possible, harmonize them
with Codex and Canadian MRLs and MRL definitions.

No new residential uses have been registered for TM since the RED (2005) . Residential handler and post-application scenarios did not result in ri sks of concern. However, since the most recent residential assessment, guidance for assessing re sidential exposure has been revised by the 2012 Standard Operating Procedures (SOPs) for Re sidential Pesticide Exposure Assessment, and updated cancer and non-cancer exposure and risk assessments will be needed. Furthermore, a rat subchronic inhalation exposure st udy is required. Since inha lation risks were previously assessed using an endpoint and dose from an or al study, revised residential handler exposure assessments (non-cancer) will be required under regi stration review to support use on residential turf, incorporating any new inhalation data as well as the 2012 SOPs.

An aggregate exposure assessment was perfor med for the 2005 TM RED document. Thisassessment combined exposure to TM and MBC and identified risks of concern for acute, shortterm and chronic non-cancer and cancer aggregate exposure to TM and MBC. The most recent aggregate exposure assessment was conducted in 2009 for proposed new uses of TM. The 2009 assessment considered TM and MBC separately, rather than combining exposures to the 2 actives. Aggregate short- and intermediate-ter m and cancer risks for TM alone were not of concern. [HED notes that the proposed TM uses were not granted becaus e they would have led to additional dietary exposure to MBC, for whic h residential risk estimates of concern were identified, and a safety finding could not be made under the FQPA]. A new aggregate assessment for TM will be required during registrati on review that includes current use patterns and incorporates any changes in endpoint selection, safety f actors, and updated dietary and residential exposure estimates.

Occupational handler and post-appl ication exposures were assessed in 2009 for proposed uses of TM on a variety of agricultural crops a nd non-crop land areas. The 2009 occupational assessment resulted in handler and post-applica tion exposure risks of concern for multiple crops resulting from the use a variety of formulations and application methods , including commercial and on-farm seed treatment. However, the uses were not registered due to risk estimates of concern for MBC. During registration review, new occupational handler and post-application assessments will be conducted for existing uses as necessary, based on updated doses, endpoints, and procedures for dermal and inhalation risk assessment. The exposure database for TM is considered complete, and addi tional data are not required.

Carbendazim: MBC (methyl 1H-benzimidazol-2-yl carbamate) is a systemic fungicide of the benzimadazole chemical class. Its pesticid al action derives from inhibition of fungal β -tubulin polymerization. MBC is also a metabolite of the fungicide TM in mammals and in the
environment.

MBC antimicrobial registered products are formul ated as in-can, ready-to-use and dry-film preservatives in adhesives (non-food), caulks, concrete, grouts, inks, paints, paper (non-food), plastic (including toys), roof co atings, sealants, stains, and tex tiles. Conventional use is forPage 6 of 62 seasonal suppression of fungus for ornamental trees, and the active is formul ated as ready-to-use capsules applied via tree injection. The products registered for tree injection are intended for use by professional applicator s only, including arborists.

The toxicology database for MBC is incomplete at this time. Under the revised 40 CFR Part 158 Guidelines (toxicology data re quirements), an immunotoxicity study is required. An extended one-generation reproductive toxicity study is cu rrently being conducted by the registrant to address the lack of an acceptable reproductive toxicity study, along with concern for evidence (quantitative and qualitative) of increased suscep tibility in the offspring, the occurrence of malformations in fetuses following in utero exposures, and the need for additional data to better characterize potential neurodevelopmental effect s observed in the pre-natal study with rats. During previous discussions with the Registrant on the study protocol, the Agency also requested
that a cohort of animals be included to eval uate immunotoxicity parame ters; this study could
therefore also address the im munotoxicity study requirement.

The available toxicological data indicate the live r and testes are the major target organs for MBC-induced toxicity; the latter was observe d following both oral and dermal exposure. Thyroid effects were not observed in the available studies, unlike TM. Olfactory degeneration of the nasal cavity and decreased body weight and wei ght gain were seen in a rat 90-day inhalation study conducted with the fungicide benomyl which is metabolized rapidly in vivo to MBC. No effects were reported at the e xposure concentrations tested in a rat 5-day inhalation study on

MBC.

Increased quantitative and qualitative suscepti bility was observed in de velopmental toxicity
studies with MBC in the rat and rabbit. A lthough developmental effects on the rat nervous system were reported, neurotoxicity is not observed in adult animals.

MBC was most recently classi fied as a Group C, or “possi ble human carcinogen” under the 1986 Agency cancer guidelines, based on liver tumors in female mice and aneugenic potential in genotoxicity studies. Cancer risk is assessed using a cancer potency (Q 1 *) value.

HED has previously recommende d retaining the 10X FQPA f actor for all non-occupational exposure scenarios due to the lack of data on developmental neurotoxicity. The endpoints, doses, and safety factors used in the most r ecent updated exposure assessment for MBC (D364554, 2009) are considered appropriate ba sed on the currently available da ta. To ensure that future
human health risk assessments are consistent with science policies in place at the time of registration review and take into consideration any findings from new studies, HED recommends reevaluation of: (1) endpoints selected for risk assessment and (2) reconsideration of the FQPA safety factor.

There are no food/feed uses for MBC and theref ore no residue chemistry data requirements. However, a dietary risk assessment is required b ecause residues in drinking water are possible as a result of degradation of TM in the environmen t, and because residues of MBC are expected in food as a result of application of TM to crops. The most recent dietary assessment for MBC was conducted in 2012 (D397646) and did not identif y risks of concern. However, during registration review, a new dietary risk assessm ent will be conducted incorporating the mostPage 7 of 62 current pesticide residue monitoring data, dri nking water and dietary models, along with any changes in endpoints, doses for risk assessment and safety factors.

Residential handler and post-app lication exposure may occur from antimicrobial uses of MBC (paint additive, treated items, tree injection) . The most recent residential assessment was conducted in 2009 using the reduced concentration of MBC in pain ts and a revised dermal dose of 20 mg/kg/day. All paint hand ler scenarios resulted in MOEs (ranging from 34 to 87) below the LOC of 1000. A paint bioava ilability study with MBC was submitted to refine the exposure estimates for residential painters, and the results of the study will be incor porated into a revised handler assessment for painters during registration re view. Post-applicatio n exposure from the paint use is expected to be low, and will not be re-assessed during registration review. Handler exposure from tree injection use has not been as sessed quantitatively in past risk assessments; however exposure is anticipated to be negligible. The tree injec tion product is formulated as ready-to-use, packaged in capsules which are insert ed into a feeder tube which is dispensed into the tree. Therefore, the handler has no direct co ntact with MBC. No additional review of this scenario is needed during regist ration review. Post-a pplication inhalation a nd dermal risks from exposure to MBC from treatment of turf with TM were not assessed because the exposures were considered to be negligible based on the reduction of th e turf application rate in conjunction with the RED, and on the results of the chemical-spe cific turf transferable residue (TTR) study; during registration review, HED doe s not anticipate assessing pos t-application exposure to MBC
as a result of TM use on turf.

Since the most recent residential assessment, guidance for assessing residential exposure has been revised by the 2012 Standard Operating Pr ocedures (SOPs) for Residential Pesticide Exposure Assessment. Therefore, during regist ration review, AD will conduct a new residential handler exposure assessment that will incorpor ate any new toxicological endpoints, points of departure and methods or policies for estimating exposure and risk associated with stain and paint products. In addition, AD anticipates cond ucting an exposure assessment for residential dermal and incidental oral post-application exposure for plastic t oys and textiles.

For occupational and residential exposure, paint product use inform ation is required (i.e., pouring liquid/solid material preservative formulation) to refine the da ily amount handled; in addition, a description of the pouring operations should be s ubmitted. Furthermore, for purposes of refining residential post-application exposure, chemical -specific indoor surface residue dissipation data and a description of human ac tivity practices will be require d for risk assessment purposes.

The most recent aggregate assessment for MBC was conducted in 2002 for the TM RED (D275774). During the course of evaluating proposed uses of TM in 2009, risk estimates of
concern were identified for MBC for residential painters, based in part on new toxicology data. Once these risks were noted, HED did not c onduct a full aggregate assessment for MBC including exposure from food and drinking water (from TM use). A new aggregate assessment will be conducted during registration review that includes current use patterns and incorporates any changes in scientific policy, new toxicol ogy and residential exposu re data, dose/endpoint selection and safety factors, as well as updated dietary exposure estimates.Page 8 of 62 Introduction

This document summarizes HED’s and AD’s eval uation of the data available for assessing human health risk from exposure to TM and M BC, as well as any data needed to support registration review. HED revi ewed the conventional uses of both TM and MBC, while AD
reviewed the antimicrobial uses of MBC [note: although HED evaluated the paint use in the 2009 assessment, during registration review the use pattern will fall under the purview of AD]. TM and MBC are systemic fungicides of the benz imidazole class, with a pesticidal mode of action of inhibition of tubulin formation in fungi. MBC is a metabolite of TM in mammals and a primary degradate identified in drinking water and residues of crops tr eated with TM. Both compounds are therefore being evaluated together in this scoping document, with each chemical discussed individually. The structures of TM and MBC may be found in the Chemical Identity Table (Attachment 1).

In conducting this evaluation, HED and AD have c onsidered the most recent human health risk assessments, HED and OPPIN/PRISM databases, open literature (via Google Scholar) and the latest Agency science policie s and risk assessment methodologi es. HED and AD have evaluated
this information for TM and MBC in association w ith the updates to their toxicity, exposure, and usage databases to determine if sufficient data are available and if furt her updates are needed to support registration review.

There are food and residential uses for TM. Pr oducts registered for use include dust (D), granular (G), wettable powder (WP), water-dispe rsible granular (WDG), flowable concentrate (FIC) and emulsifiable concentrat e (EC) formulations. TM is currently registered for use on numerous fruit, vegetable, nut and field crops. Residential non-dietary exposure may occur from
treatment of turf.

MBC is not registered for food uses at this time, but dietary exposure may occur due to contamination of drinking water as well as residu es in food commodities due to applications of TM. It is currently registered for antimicrobi al use patterns that ma y result in residential exposure. Registered products include in-can and dry-adhesive formulations for ornamental tree injection and as a preservative in various products that incl ude non-food adhesives, caulks, concrete, grouts, inks, paints, paper, plastic, r oof coatings, sealants, st ains and textiles.

THIOPHANATE-METHYL

Hazard Identification/Toxicology

A summary of the available toxi city data on TM is provided in Attachment 3a. Since the previous human health risk assessment, conducted in 2009 (D330476), no additional toxicity studies have been submitted to the Agency. Th e database is largely complete, but under the revised 40 CFR Part 158 guidelines for toxicology data, a subchronic inhalation toxicity study in the rat is required based on the potential for inha lation exposure from nu merous uses and portal of entry effects observed in a non-guideline i nhalation study. A developm ental thyroid study is also required to evaluate poten tial thyroid toxicity during earl y development based on thyroid
effects in adult animals and re sidual uncertainties for the rela tive sensitivity of the young.Page 9 of 62 However, an immunotoxicity study is not requ ired for TM, based on weight of evidence considerations (HASPOC memorandum, TXR# 0056916, U. Habiba, meeting of February 27, 2014; HASPOC Meeting memorandum, L. Hansen, 12/18/2008).

TM is of low or minimal acute oral and dermal toxicity (Categories III or IV) but of moderate acute inhalation toxicity (Category II ). It is not irritating to the eye or skin (Category IV) and is
a dermal sensitizer.

Metabolism data in the rat indicate that TM is well absorbed from the gastrointestinal tract, extensively metabolized and excreted primarily in the urine following a single low dose, but primarily via the feces following a single high dose, or following repeated dosing. Sixteen metabolites (12 identified) were observed with the major urinary metabolite being 5-hydroxy(2- methoxycarbonylamino) benzimidazolyl sulfate. MBC was also identified as a metabolite in both the urine and feces. Unchanged parent co mpound was identified with a single high dose or repeated low doses, primarily in the feces. Radi oactivity was widely distributed but there was not significant accumulation, with the highest leve ls observed in the liver and thyroid. More than 90% of the administered radioactivity was excreted within 24 hours of dosing. The residues of concern for dietary exposure have been accounted for in the ra t toxicity studies.

The liver is the major target organ for multiple species following oral exposure to TM. Hepatocellular hypertrophy and increased liver wei ght were observed in all species tested, along with effects on clinical chemistry parameters such as cholesterol, serum albumin, alkaline phosphatase and circulating thyroi d hormones. Thyroid effects in rats, dogs and mice included enlargement, hypertrophy and follicular hyperplasia. Additional studies in the rat showed an increase in liver enzyme (UDPGT) activity along with effects on circulati ng thyroid hormones.

In addition to liver and thyroid effects, TM al so caused mild red blood cell effects at the higher dose levels in rats, dogs and mice following subchr onic or chronic exposure. In rats, TM caused toxicity to the kidney as i ndicated by increased urinary pr otein (in males), lipofuscin pigmentation, and increased severity of nephr opathy following chronic administration. An increase in systemic calcificati on was observed in males and to a lesser extent in females and was probably secondary to hype rparathyroidism. Decreased body weight/weight gain was
observed in both sexes. Effects on the testes were seen in rat chronic studies (one study showed decreased spermatogenesis; the othe r, testicular hyperplasia). Ma le rats appeared to be more sensitive than females overall based on greater severity of effects a nd high mortality at the highest dose tested (6000 ppm or 280.6 mg/ kg/day, males and 334.7 mg/kg/day, females). Beagle dogs also showed decreased body weight. In the mouse carcinogenicity study, increased heart weight (females) and incidence of atrial thrombosis were observed.

TM is a carbamate, but only limited data are avai lable on its potential to inhibit cholinesterase (ChE). As a class of compounds, thiocarbamate s do not produce consistent cholinesterase inhibition patterns. In the rat subchronic toxicity study, serum cholinesterase activity was
increased in males but decreased in females. In the rat chronic toxi city/ carcinogenicity study,
males showed increases in serum ChE whereas at 24 months, it was decreased. ChE activity in females was slightly decreased at 6 and 12 m onths. RBC and brain ChE activities were not evaluated, and ChE was not measured in the subchronic or ch ronic dog studies.Page 10 of 62 Dermal exposure to TM for three weeks (5 applications per week ) caused decreased food consumption in females and, at a higher dose, in males. Because this decrease was reported in both sexes and a dose-response was observed in females, it is considered treatment-related although no other signs of toxicity were observed. Comparison of the NOAEL/LOAEL of this study with those of oral studies provided an estimated dermal absorption value of 7%, based on maternal food consumption changes in the rat de velopmental toxicity study. Dermal irritation
was observed at the site of application in all dose groups.

The only inhalation toxicity study submitted was a rat14-day inhalation toxicity study on a formulation containing 5.2% TM . Local pulmonary effects we re observed at the LOAEL and decreased body weights at the HDT. In addition to testing a formulati on and not the technical a.i., this study did not evaluate all of the standard parameters and therefore, was considered inadequate for assessment of inhalation toxicity for risk assessment purposes.

In the rat and rabbit developmental toxicity studies and the rat two- generation reproductive toxicity studies, there was no evidence of increased prenatal susceptibility. There was no evidence of reproductive toxicity in any of the studies. A limite d evaluation of thyroid effects was performed on parental (P0) and first generati on (F1) animals at 8 weeks of age in the twogeneration reproductive toxicity study, along with assessment of se veral structural and functional developmental tests during lactati on. Offspring had t hyroid effects at comparable to parental
animals but at lower incidence. There were no treatment-related effect s on the developmental
tests. The data did not indicat e increased developmental suscepti bility; however, an examination of offspring thyroid function duri ng late gestation/lactation and/ or early post-weaning times was not performed.

TM did not show evidence of ne urotoxicity. Transient tremor s following capsule dosing were observed in the first weeks of the chronic dog stu dy, but at dose levels that caused significant toxicity and were not seen at later times, and were not observed in the subchronic dog study. In the rat acute neurotoxicity study, decreased landing foot splay at the time of peak effect was observed, but not at later times or in the subc hronic neurotoxicity study, and did not show a dose-response. These findings were therefore no t considered indicative of neurotoxicity. A developmental neurotoxicity study is not required.

In the most recent assessment (D360951 ; 6/24/2009), for chronic dietary and non-dietary (residential) exposure, the Food Quality Protectio n Act (FQPA) Safety Factor was reduced to a 3X due to a data gap for a developmental thyroi d study. A 3X factor (as opposed to the default 10X) was deemed adequate for the following reasons : 1) the toxicology database is considered adequate to assess pre- and post-natal toxicity; 2) there was no evidence of increased susceptibility following in utero exposure to rat and rabbits a nd pre/post natal exposure to rats; 3) there was no concern for potential devel opmental neurotoxicity, and a developmental neurotoxicity study is not requir ed; and 4) the point of depart ure used risk assessment would adequately address any potential for the concern fo r thyroid toxicity seen in the adult animals. For acute dietary risk assessment, the FQPA safety factor was removed (i.e., 1X) because developmental thyroid effects w ould not be expected to resu lt from a single dose and the
additional data would not affect th e point of departure selected for acute dietary risk assessment.Page 11 of 62 The developmental thyroid assay will address the concern for any potential thyroid effects that might occur during late gestational and early postn atal development and therefore will not have an impact on the point of departure or the e ndpoint of concern used for acute dietary risk

assessment.

TM is classified as “likely to be carcinogenic to humans” under the Agency’s final guidelines for carcinogenicity assessment (2005), based on an increas ed incidence of liver tumors in mice and thyroid follicular cell adenomas/carcinomas in rats. Although there is evidence of antithyroid activity via increased hepatic UDP-glucuronosyl transferase (UDPGT) act ivity, the data to support a threshold antithyroid mode of action for thyroid tumors was considered inconclusive. The available genotoxicity data indicate aneugeni c potential; therefore, a default quantification of cancer risk was performed using linear-low dose extrapolation based on the incidence of liver tumors in male mice, with a cancer potency factor, Q 1 *, of 1.16 x 10 -2 (mg/kg/day) -1

.

Endpoints selected for the most recent human health risk assessment (2009) are shown in Attachment 2a. An acute dietary assessment is required only for females 13-49 years of age based on developmental effects, because an appropr iate single-dose endpoint was not identified for the general population. Non-dietary residentia l endpoints are required because there are turf uses of TM that may result in short- and inte rmediate-term handler or post-application dermal and inhalation exposure, as well as incidental or al exposure. HED will reevaluate endpoints and uncertainty factors (UFs) for risk assessment duri ng registration review, ta king into consideration the results of any new studies and current science policies at the time of the review.

Conclusions for Hazard Ident ification/Toxicology of TM

Additional toxicology data are required for TM, based on the recently revised data requirements for food use pesticides in 40 CFR Part 158. A s ubchronic toxicity study in the rat (870.3465) is required to support registration review, based on th e potential for significant inhalation exposure for occupational uses of TM and evidence for pote ntial portal of entry e ffects. In addition, a developmental thyroid study is required to eval uate potential secondary effects of thyroid hormone alteration during late pre-natal and early post-natal development. An immunotoxicity study is not required, based on l ack of evidence of potential imm unotoxicity at relevant dose
levels.

During registration review, HED recommends reev aluation of the following points, which should
take into consideration the resu lts of the additional data studies received for TM and ensure consistency with science policies in effect at the time of review: (1) endpoints for risk assessment and (2) reconsiderati on of safety/uncertainty factor s, including the FQPA safety
factor.

Dietary Exposure

The residue chemistry database is adequate to support current regist ration review data requirements (D308747, 3/19/2009; D335849, 5/12/2009). The 2002 residue chemistry chapter
of the RED cited numerous data deficiencies for the analytical methods a nd field trial studies.Page 12 of 62 The registrant submitted data in response to the cited deficiencies, and HED concluded the data were adequate.

Tolerances for TM have been established for numerous crops. In plant and livestock commodities, the residues of concern for tolerance enforcement are TM and MBC, calculated as the stoichiometric equivalent of TM. For risk assessment, the residues of concern in plants are TM, MBC, and the metabolite 2-AB. In livestock commodities, the residues of concern are TM, MBC, and the metabolites 4-OH-MBC, 5-OH-M BC, and 5-OH-MBC-S. The degradates of concern in drinking wate r are TM and MBC only.

In 2009, HED performed a human health risk asse ssment for proposed uses of TM on numerous commodities (D330467). Although there were no aggr egate risk estimates of concern for TM alone, there were residential e xposure estimates of concern for MBC and, therefore, the proposed uses were not granted. In support of the 2009 assessment, HED conducted acute, chronic, and cancer dietary exposure assessments. A partially refined acute probabi listic dietary exposure analysis was performed for the population subg roup females 13-49 only, and was based on field trial and residue monitoring data [Pesticide Data Program (PDP) monitori ng data]; percent crop treated estimates for many commodities, and a modeled drinking water estimate. Acute exposure and risk for females 13-49 years old were not of concern to HED (8.6% acute Population Adjusted Dose, or aPAD) . A refined chronic dietary an alysis was also conducted for
this assessment in order to address both the non- cancer and cancer risk assessments. The chronic analysis included residue refinements from fi eld trials and PDP, pe rcent crop treated and projected percent crop treated estimates, and mode led drinking water estimates. The resulting chronic dietary risk estimate for Children 1- 2 years old, the most hi ghly exposed population subgroup, was not of concern at 3.6% chronic P opulation Adjusted Dose (cPAD). The cancer
risk estimate was 4.7 x 10 -6 . However, when the proposed use on citrus was excluded, the cancer
risk estimate decreased to 3.3 x 10 -6

.

The Environmental Fate and Effects Division (E FED) recommended that modeled estimates of residues in drinking water be used in the most recent dietary risk assessment. EFED is requesting updated environmental fate studies because the submitted studies do not meet current
standards. These studies indicate that five degradates might be of concern if they are found to be major degradates. HED’s Residues of Con cern Knowledgebase Subcommittee (ROCKS) has determined that these degradates would probably be considered to be of equal toxicity to the parent compounds. Once the updated studies are received and reviewed, HED and EFED will determine whether or not the additional degradates are of concern. As a re sult, it’s likely that HED and EFED will determine that an updated dri nking water assessment is needed, and if this is the case, the results will be included in HED’s preliminary risk assessment to support registration review. A new dietary assessment will include the most recent consumption data and the most current version of the dietary exposure model.

Conclusions for Dietary Exposure

The dietary exposure database is adequate to support the existing registrati ons and tolerances. No new residue chemistry data are required. Ho wever, a new dietary risk assessment will be conducted during registration review to include updated percent cr op treated estimates, residuePage 13 of 62 monitoring data if available, changes in toxi cological endpoints, update d consumption data, and the revised estimated drinking water concentrations.

Residential Exposure

Handler Exposure

TM is registered for use on residential turf, golf courses, athletic and recreational fields, ornamental grasses, and landscapes . The products registered for resi dential use are formulated as liquids, granules (G), water dispersible gran ules (WDG), wettable powders (WP) and water soluble bags (WSP) and may be applied by a va riety of hand held equipment and granular spreaders.

The primary source of information used to eval uate residential handler exposure was the HED
Human Health Risk Assessment for th e RED (D275774, 2002). Although a revised residential assessment was performed in 2009, the residential handler section was based on the
2002 RED assessment. The TM RED assessed shor t-term residential non-cancer and cancer handler dermal and inhalation exposure resultin g from use of hand held equipment (i.e., hoseend, back-pack, and manually pressurized ha ndwand sprayers) for liquid formulations on ornamental plants (i.e. includi ng backyard orchards) and push -type spreader for granular formulations on lawns. Furthermore, in orde r to mitigate handler risks identified in the assessment, the principal Registrants agreed to remove the use of hand or belly grinder applications from the labels of products that may be purchased by residents. The Registrants also agreed to restrict the use of ready-to-use liquids to spraying of orna mentals. The RED also
indicates that there is a WP formulation for use on turf and ornamentals; however, it is not
intended for residential use and was therefore consid ered unlikely to be sold to the general public
and was not evaluated. Since there are concer ns that such label language is not legally enforceable (unless the active ingredient is cons idered to be a restricted use pesticide), HED typically assesses potential exposure to residentia l users in the event th at they are able to purchase and apply the product. Since TM is not restricted use, HED will conduct a handler assessment for the wettable powder on turf and ornamentals during regist ration review. Shortterm risk estimates for residential handlers did not exceed HED’s level of concern (LOC = margins of exposure (MOEs) > 300) for any scen ario. Handler total MOEs ranged from 1,900 to 35,000. Cancer risk estimates were less than 10 -7 for all scenarios.

No new or additional residential uses have been registered for TM since the 2005 RED. However, since the most recent residential assessment, guidance for assessing residential exposure has been revised by the 2012 Standard Operating Procedures (SOPs) for Residential Pesticide Exposure Assessment. Furthermor e, in accordance with the Part 158 Data Requirements for conventional pesticide active i ngredients a 28-day inhala tion exposure study is now required. Since inhalation ri sks were assessed using the e ndpoint and dose from an oral study, a revised residential handler exposure asse ssment (non-cancer and cancer) will be required under registration review for all formulations of products used on resi dential turf. This assessment will incorporate the additional TM inhalation toxicology studies, updated human exposure factors assumptions (e.g., body weight), and the 2012 SOPs for Residential Pesticide Exposure Assessments.Page 14 of 62 TM Post-application Exposure

The primary source of information used to evalua te residential dermal post-application exposure and risk resulting from the use of TM on tu rf was the 2009 assessment entitled “Revised Residential Exposure Assessment for Use of TM on Turf” (D360623, 2009). In the revised version, HED reassessed the 2002 residentia l turf exposure asse ssment (Revised TM Occupational and Residential Exposure Assessmen t and Recommendations for the Reregistration Eligibility Decision Document (RED), D279269, 2009) to reflect a reanalysis of the dermal and oral post-application exposure a nd risk resulting from use on turf. In accordance with the updated Part 158 data requirements (2007), a tu rf transferable residue (TTR) study for occupational (e.g., sod farms, golf co urses, parks and recreational area s) or residential turf uses was submitted for TM (Dissipation of transferab le turf residues of 3336WP 50 percent TM, MRID 45000701). HED averaged the daily predic ted chemical-specific TTR values over 14 days which is in accordance with the minimum retreatment interval specified on the product labels to determine non-cancer dermal post-appli cation exposure and risk. All adult and children residential lawn and golf dermal scenarios resulted in risk estima tes which were not of concern.
All incidental oral scenarios resulted in risk estimates greater than the LOC and therefore posed
no risk of concern. To determine residential post-application cancer ri sk to homeowners and golfers exposed to treated turf , HED used a draft approach to estimate a range of available
residues based on retreatment intervals of 14 da ys in combination with a range of possible number of applications per year and a chemical specific TTR study to better refine cancer risk.
HED’s calculations indicated resi dential post-application cancer risk resulting from exposure to turf ranged from 4.5 x 10 -8 to 3.2 x 10 -7 for 5 applications.

Since the most recent residential assessment, guidance for assessing residential exposure has been revised by the 2012 Standard Operating Pr ocedures (SOPs) for Residential Pesticide Exposure Assessment. Therefore, a revised re sidential post-applica tion exposure and risk assessment (non-cancer and cancer) for turf will be required duri ng registration review for all formulations of products used on comm ercial and residential treated turf.

Spray Drift and Volatilization

Residential exposures resulting from off-site tr ansport (e.g., spray drift or volatilization) may occur as a result of applications of TM. The Ag ency is in the process of evaluating these types of exposures and may, as appropriate, develop pol icies and procedures to identify the need for and, subsequently, the way to inco rporate these post-application expos ures into the Agency's risk assessments. The need for spray drift and vol atilization risk assessments for TM will be examined during Registration Review

.

Conclusions for Residential Exposure

No new or additional residential uses have been registered for TM since the 2005 RED. Furthermore, no additional data are required at this time. Ther efore, the resi dential exposure database is adequate to support the registration review process fo r TM. However, since the most recent residential assessment, guidance for assessi ng residential exposure has been revised by the 2012 Standard Operating Procedur es (SOPs) for Residential Pe sticide Exposure Assessment.Page 15 of 62 Therefore, revised residential handler and post- application exposure and risk assessments (noncancer and cancer) will be required during registra tion review for all formulations of products used on commercially treated and residential tu rf. This assessment should incorporate, as necessary, the additional TM inhalation toxi cology study, updated human exposure factors assumptions (e.g., body weight) and the 2012 SO Ps for Residential Pesticide Exposure

Assessments.

Aggregate Risk Assessment

In accordance with the FQPA requirements for f ood use chemicals, when there are potential residential exposures to a pesticid e, an aggregate risk assessment must consider exposure from three major routes: oral, dermal, and inhalation. There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exposures
from relevant sources are added together and compared to quanti tative estimates of hazard (e.g.,
a no-observed-adverse-effect-level , NOAEL or PAD), or the risks th emselves can be aggregated. When aggregating exposure and risk from va rious sources, HED considers both the route and duration of exposure. In the most recent risk assessment, HED provided updated aggregate exposure and risk estimates (D330476, 2009). Th e aggregate risk assessments that were performed were for acute, short- and intermediate-term, chronic and cancer risk scenarios for
adults and children.

Dietary (food and water) consumption is the only s ource of exposure to TM that is expected to result in acute exposure. Therefore, the acu te aggregate exposure and risk estimates are equivalent to the acute dietary exposure and ri sk estimate discussed above and were not of concern. The exposures resulting from short- an d intermediate-term residential uses must be aggregated with the dietary (food and water) exposures. Short- and intermediate-term aggregate
risk estimates for adults and children were not of concern.

Both cancer and non-cancer aggregate risk esti mates were conducted. Non-cancer chronic aggregate risk is equivalent to non-cancer diet ary exposure from food an d drinking water, which
was not of concern for TM as discussed above.

A cancer aggregate risk assessment was performe d for the general U.S. population. Aggregate cancer risk is comprised of the risk from dietary sources (food a nd drinking water) and the risk from residential handler and pos t-application uses on lawns and golf courses. The aggregate cancer risks were all in the range of 10 -6 or below.

Conclusions for Aggregate Assessment

HED anticipates that a new aggregate assessment will be required for TM during registration review. Additional toxicology data on TM ma y change the endpoints selected for risk assessment, and could impact the selection of safe ty and uncertainty factors. Because of updated science policies, new residential and dietary exposure estimates will result in the need for new aggregate exposure and risk assessments.Page 16 of 62 Occupational Exposure

Occupational Handler Exposure

TM is registered for use on a variety of fruits, nuts, vegetables and field crops, treatment of a variety of seeds (e.g., cotton, corn, vegetables , soybean, wheat and sunflower) including potato seed pieces and peanuts, greenhous es and nurseries (including bulb dip treatment). It is also registered for use on turf, which includes sod farms, golf courses, athletic and recreational fields, and ornamental grasses for la ndscapes and interiorscapes.

TM end-use products for occupa tional use are formulated as liquids, granules (G), water dispersible granules (WDG), we ttable powders (WP), water soluble packets (WSP), and dust for seed treatment. Products may be applied as a br oadcast foliar or soil directed spray by ground, aerial, by hand held equipment, and granular spr eaders or commercial or on-farm seed treaters. The PPE for applicators and other handlers cons ists of a range from baseline clothing (longsleeved shirt, long pants, shoes plus socks) and chemical resistant gloves made of any waterproof
material to the additional use of protective eyewear and apro n when mixing and loading.

The primary source of information used to eval uate occupational handler exposure, including commercial and on-farm seed treatment, was fr om the most recent occupational exposure assessment written for this chemical (D335120, 2009). However, this document did not include
a revised commercial handler assessment for tu rf uses. Since no chemical-specific data for assessing human exposures during pesticide handling activities were submitted to the Agency in support of the registration of TM, HED used su rrogate data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 (PHED Surrogate Exposure Guide, 8/98) to assess exposures for crop protection uses. Standard assumptions established by the HED Science Advisory Council for Exposure were used for acre s treated per day and body weight. For seed treatment uses, handler assessments were base d on the unit exposure data from the Science Advisory Council for Exposure (Exposure SAC) Policy #14: Standard Operating Procedures (SOP) for Seed Treatment (May 1, 2003) and on the treating/planting data from the Exposure SAC Policy #15: Amount of Seed Treated or Planted Per Day (March 2, 2004).
Risks of concern were identif ied for non-cancer handlers mixing /loading wettable powder, dry flowable and liquid formulations for aerial, chemigation, ground boo m and airblast applications for a variety of proposed uses, which weren’t re gistered due to risk estimates of concern identified for MBC. Since the most recent occupational exposure assessment, the standard values recommended for use in predicting handler exposure, known as “unit exposures,” have been updated in the new “Occupational Pesticid e Handler Unit Exposure Surrogate Reference
Table i ”; in addition, standard body weights for determ ining risk estimates have been updated. Furthermore, HED is in the process of revisi ng seed treatment Policies 14 and 15 with updated inputs and assumptions from additional seed tr eatment studies and survey information. Therefore, an updated non-cancer and cancer occ upational handler exposure assessment will be required for registered agricultural, seed treat ment, and commercial turf (i.e. golf course maintenance) uses during registration review.

i Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdfPage 17 of 62 TM Occupational Post-application Exposure

As indicated previously, a quant itative dermal post-applicatio n exposure assessment was most recently performed in 2009. The estimations of post-application exposures were based on the chemical specific dislodgeable foliar residue (D FR) data obtained from three studies: (1) an apple DFR study (MRID 44876301), (2) a strawberry DFR study (MRID 44866201), and (3) a grape DFR Study (MRID 46388701). Therefore, no addi tional data are needed at this time. Non-cancer dermal post-application exposure es timates were assessed based on predicted DFR data on day 0 (day of application), and risks of c oncern were identified for certain activities in a number of crops. Cancer dermal post-applica tion exposure was assessed based on average DFR data in the range of day 1 to day 14, since TM la bels permit reapplication at 14-day intervals. The dermal cancer risk estimates ranged from 1.6 x 10 -5 ~ 1.5 x 10 -7 . It should again be noted that a post-application exposure assessment for commercial turf (i.e., golf course maintenance) use was not included in the 2009 assessment, si nce it was not a new us e under consideration.

A quantitative post-application inhalation exposure assessment was not performed for TM based on the Agency's current practices. However, ther e are potential sources of inhalation exposure to workers performing post-applicati on activities in previously tr eated fields. These potential
sources include volatilization of pesticides and re-suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on i ssues related to volatilization of pesticides from its Federal Insecticide, F ungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/ meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post-applicat ion inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, s ubsequently, the way to incorporate occupational post-application inhalation exposur e into the Agency's risk asse ssments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for TM.

Since the 2009 assessment, HED has revised various transfer coefficients within the Outdoor Residential Exposure Task Force (ORETF) and th e Agricultural Re-entry Task Force (ARTF) databases, with data from new exposure mon itoring studies. Therefor e, updated non-cancer and cancer occupational post-application exposure as sessments will be required for registered agricultural and commercial turf us es during registration review.

Conclusions for Occupational Exposure

The occupational exposure database for TM is comp lete and no additional data are needed at this time. However, since the most recent occupatio nal exposure assessment, the standard values recommended for use in predicting handler expos ure, known as “unit exposures,” have been updated in the new “Occupational Pesticide Hand ler Unit Exposure Surrogate Reference Table ii

, and updated body weight assumptions are typicall y used for determining risk estimates. Furthermore, HED is in the process of revisi ng seed treatment Policies 14 and 15 with updated inputs and assumptions from additional seed tr eatment studies and survey information.

ii Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdfPage 18 of 62 Therefore, updated non-cancer and cancer occu pational handler exposure assessments will be required for agricultural, seed tr eatment, and commercial turf us es during registration review. Furthermore, HED has revised various transfer coefficients within the Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Re-entry Task Force (ARTF) databases. Therefore, updated non-cancer and cancer occu pational post-application exposure assessments will be required for agricultural and commercial turf uses during registration review. HED will also consider the impact of new policies and procedures, such as a ddressing volatilization exposure, as well as the potenti al for exposure from spray drift during registration review.

Tolerance Assessment and International Harmonization

Tolerances for residues of TM in or on agricultural commodities are established in 40CFR §180.371. For plant commodities, the tolerances ar e established as follows: “Tolerances are established for residues of TM, dimethyl(( 1,2-phenylene) bis (iminocarbono-thioyl)) bis (carbamate), including its metabolites and degradat es, in or on the commodities in the following table. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only the sum of TM, dimethyl((1,2- phenylene) bis (imino carbono-thioyl)) bis (carbamate), and its metabolite, methyl 2-be nzimidazoyl carbamate (MBC), calculated as the stoichiometric equivalent of TM, in or on the commodity.”

Maximum residue limits (MRLs) for residues of TM have been established by Codex and Canada, but not by Mexico. The Codex MRLs ar e expressed in terms of the sum of benomyl, MBC, and TM, expressed as MBC, and are, theref ore, not compatible with U.S. tolerances. Codex MRLs range from 0.05 ppm for wheat grain to 5 ppm for head lettuce. As with the U.S. tolerances, the Canadian MRLs are establishe d based on residues of MBC and TM; however, in Canada, MRLs are expressed as MBC, rather than TM. Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.

All benomyl uses have been cancelled in the U.S. As a result, the U.S. tolerance definition for
TM differs from the Codex MRL definition. Alt hough the U.S. tolerances and Canadian MRLs include the same two compounds, the MRLs are not expressed in terms of the same compound. During registration review, HED will revisit th e tolerances and tolerance definitions, and
harmonize them with the Codex and Canadian MR Ls and MRL definitions, when possible. The
international residue limit status sh eet can be found in Attachment 5.

Data Requirements

The following toxicology st udies are required for TM:

870.3465 Subchronic inhalation study in the rat . This study is require d to assess occupational
and residential handler inhala tion exposure, based on high ap plication rates and potential inhalation exposure during spray ap plication uses, and ev idence of portal of en try effects in a 14- day inhalation study on a 5% TM formulation.

Developmental thyroid study in the rat . This study is required to evaluate potential developmental effects from pert urbation of thyroid levels.Page 19 of 62 No new residue chemistry, residential or occupa tional exposure data requirements have been identified for TM to support registration review.

MBC

Hazard Identification/Toxicology

The toxicology database for MBC is not complete for assessment of human health risk. There are currently data gaps fo r an immunotoxicity study (870.7800), a rat two-generation reproductive toxicity study (870.3800) and a rat developmental neurotoxicity study (870.6300). However, an extended one-generation reproductiv e toxicity study is currently in progress in response to the data requirements in the RED, which may satisfy the requirement for these studies. Additionally, the Agency requested duri ng review of this study protocol that a cohort for immunotoxicity should be included which ma y satisfy the gap for the immunotoxicity study. A 21/28-day dermal toxicity study in the rat has been submitted (MRID 47341601) since the previous assessment and satisfies the requirement from the post-RED DCI of January 4, 2005. In the rat, MBC has been shown to be rapidly absorbed and extensively metabolized. Urine is the primary route of excretion at lower doses , but at higher doses it becomes saturated and accounts for only 41% of the excretion. Distributi on of MBC or its metabolites to tissues is limited and radioactivity was not retained (less than 1% was detected in the liver and carcass). The primary routes of metabolism involved oxida tion of the phenyl ring followed by sulfate or glucuronide conjugation of 5-hydroxyMBC and 5,6-dihydroxyMBC. Phenyl ring oxidation and
N-oxidation at the imidazole N were also observed, especially in female rats.

MBC is of low to minimal acute toxicity (Categ ory III - IV) by all routes. It is minimally irritating to the eye (III), slightly irritating to the skin (IV), and is not a derm al sensitizer. It does not cause delayed neurotoxicity in the hen.

Liver and testes are the major target organs of MBC toxicity. The mammalian mechanism of toxicity of MBC has not been fully characteri zed, although some effects such as aneuploidy and testicular toxicity may be derived from its ability to disrupt tubulin polymerization. Liver effects include cirrhosis, swelling and necrosis, and changes in alkaline phosphatase, serum glutamic pyruvic transaminase (SGPT), albumin and choles terol levels in plasma. Unlike TM, thyroid effects have not been reported.

Testicular degeneration was obser ved in subchronic and chronic dog studies, although not in the
subchronic and chronic rat studies. Guideline reproductive toxicity data are not available at this time, but other studies indicate a dverse reproductive effects on the testes in the rat (premature release of immature germ cells, slight atrophy of seminiferous tubules). Seminiferous tubule degeneration and hypospermia were reported in th e rat following a 28-day dermal treatment at 720 mg/kg/day, with a NOAEL of 20 mg/kg/da y. Because of the large dose spacing, a benchmark dose, lower confidence limit 10% (BMDL 10 ) of 68 mg/kg/day was calculated for short-term exposure, which may be used for short-term exposure. A dermal absorption factor of 3.5% was determined using data obtained from benomyl, now a cancelled pesticide, whichPage 20 of 62 metabolizes in vivo to MBC; this factor was used to asse ss cancer risk associated with dermal

exposure.

A 90-day inhalation study in the rat on benomyl showed olfactory degeneration of the nasal cavity and, at higher doses, decreased body weight a nd weight gain in males. No effects were reported in the rat following five days of e xposure to MBC via nose-onl y inhalation exposure.

Increased susceptibility of offspr ing is observed in developmental toxicity studies. In the rat,
fetuses showed skeletal variations associated wi th delayed growth. At doses below maternally toxic levels, fetuses showed decreased body wei ght and an increase in skeletal variations (bipartite ossification, dumbbe lled vertebral centra). Because some of the malformations reported at the high dose were s een at the developmental LOAEL and not in control or low dose animals, it was considered a possible threshol d level for developmental malformations. At maternally toxic levels, dams showed decrease d body weight gain and in creased liver weight. Fetal effects included decreases in live fetuses, increased early and late resorptions and decreased fetal weight, along with an increase in fetuse s/litters with malformations that included exencephaly and domed head, small or no eyes, clubbe d paws, and various skelet al effects. It is also noted that benomyl, for which MBC is a ma jor metabolite, also produced central nervous system (CNS) abnormalities in rat developmental studies. In the rabbit, increased resorptions, decreased implantations and reduced live litter si zes were observed at doses below maternally toxic levels. At maternally t oxic levels, decreased maternal food consumption and weight loss during treatment were observed. Fetal effect s included fused ribs and malformed cervical vertebrae, which may have been secondary to ma ternal stress. Although MBC is associated with developmental effects on the rat nervous system, no evidence of neurotoxicity has been observed
in studies on adult animals.

MBC was most recently classified under the Agency 1986 cancer guidelines as a Group C, or “possible human carcinogen” based on the presen ce of hepatocellular ad enoma and/or carcinoma in female CD-1 mice and aneugenic potential observed in genotoxicity studies. A cancer potency factor (Q 1 *) of 2.39 x 10 -3 (mg/kg/day) -1 based on liver tumors in female mice is used to
estimate cancer risk.

Endpoints selected for the most recent MBC human health risk assessment (2009) are shown in Attachment 2b. Non-dietary residential endpoints are required because antimicrobial uses may result in residential exposures. HED recomm ends re-evaluation of the endpoints for risk assessment during registration review, taking into consideration the results of new studies and current science policies at the time of the review.

It is noted that there is currently an additiona l 10x uncertainty factor (UF) for all endpoints due to the lack of data on developmental neurotoxic ity and reproductive toxicity. An extended onegeneration reproductive toxicity study is currently in progress to evaluate these effects. Uncertainty factors should also be re-evaluated during registra tion review, based on the findings and acceptability of this study.Page 21 of 62 Conclusions for Hazard Identification/Toxicology

Based on the recently revised pes ticide data requirements (40 CFR Part 158), an immunotoxicity study (870.7800) is required. An extended one ge neration reproductive toxicity study, which
includes additional measures of neurobehavioral parameters, is being conducted and may address uncertainties regarding reproducti ve toxicity and developmental neurotoxicity. Additionally, the Agency requested that the study include a c ohort evaluating immunotoxicity of MBC, which could be used to satisfy the immunotoxicity study requirement.

During registration review, HED recommends reev aluation of the following points, taking into
consideration the results of th e additional studies received fo r MBC and ensuring consistency with science policies in effect at the time of re view: (1) endpoints for risk assessment and (2) selection of the FQPA safety factor for rele vant populations (i.e., infants and children).

Dietary Exposure

MBC is not registered for use on food in the US; th erefore, no tolerances are established for its residues. However, dietary exposure to carbend azim residues can result fr om use of TM in food crops or from contamination of drinking water sources from the us e of TM. Therefore, a dietary exposure assessment will be required.

In 2012, HED performed acute, chronic, and cancer dietary exposure assessments for
carbendazim to determine the effect of the inclusion of residues in orange juice on the dietary risk estimates (D397646). These assessments we re done because it was discovered that some shipments of imported oranges into the U.S. contained residues of carbendazim, although a
tolerance was not established for residues in oran ges. The analyses were based on the previous assessment of carbendazim exposure resulting from existing uses of TM. Two separate assessments were performed based on different s ources of the drinking water concentrations. In the first assessment, EDWCs provided by EFED were used. These EDWCs were based on the use pattern for TM, and included two major turf scenarios and numerous crop scenarios. There were acute, chronic, and cancer risks of concer n. However, when PDP monitoring data were used for residues in water, there were no acute , chronic, or cancer risks of concern. During registration review, HED and EFED will consider wh ether or not it is appropriate to use water monitoring data for dietary exposure assessmen t. At that time, a new dietary exposure assessment will be performed.

Conclusions for Dietary Exposure

HED anticipates performing a new dietary exposure assessment for carbendazim during registration review. The most current drinking wate r models will be used for this assessment. In addition, the most current versi on of the dietary model will be used, along with any potential changes in endpoints and doses for risk assessmentPage 22 of 62 Residential Exposure

MBC provides effective protection against decay fungi, and has antimicrobial (i.e., microbiocide) and conventional uses. The MBC antim icrobial registered us es are formulated as in-can ready to use and dry-film preservatives in adhesives (non-food), ca ulks, concrete, grouts, inks, paints, paper (non-food), pl astic, roof coatings, sealants, stains, and textiles. The MBC conventional use is for seasonal suppression of fungus for ornamental trees and is formulated as ready to use capsules. The products registered fo r use for tree injection are intended for use by professional applicators only, incl uding arborists, so residential ha ndler exposure is not expected for tree injection. MBC may be applied to orna mental trees in reside ntial and non-residential landscapes, exterior plantscapes, and other areas where ornamental trees are grown; however, it is not for use on ornamental trees grown for sa le. There is no residential post-application exposure expected for the tr ee injection use pattern.

MBC Handler Exposure

The primary source of information used to evaluate residential handler expo sure and risk for use of MBC was the 2000 occupational and resi dential exposure assessment for MBC (D265419, 2000) and the 2009 residential exposure a ssessment for use in paint (D364554, 2009).

Paint Additives

At the time the 2005 RED risk assessment was completed, MBC was added to paints at a maximum concentration of 0.5 % ai (5 lbs ai/1000 lb paint) and to sealants at 1.5% (15 lbs ai/1000 lb sealant). In an effort to mitigate human health risks of concern for residential painters posed by MBC from this use, the RED required that label amendments be submitted to reduce the concentration of MBC in paint from 0.5% a.i. to 0.35% a.i. based on dermal MOEs which exceeded the Agency’s level of concern (i.e., MOEs <1,000). In addition, the Agency required the registrant to conduct a dermal toxicity st udy with MBC. Since the 2002 RED, the most
recent residential risk assessment for MBC wa s conducted for the purpose of completing an aggregate exposure and risk assessment associ ated with newly proposed uses of TM (D364554, 2009). HED re-assessed the use of MBC in paints , coatings, plasters, and sealants from the following application methods: brush, rollers, lo w-pressure hand wand and airless sprayers. The short-term handler dermal exposure was recalcul ated using the reduced 0.35% concentration of MBC and the new dermal point of departure (POD) of 20 mg/kg/day, selected from the dermal toxicity study. Because of the effects observed in the dermal study (testicular degeneration), and because the rat extended reproductive toxicity st udy had not yet been completed, HED concluded that an additional 10X FQPA fact or should be retained as a da tabase uncertainty factor (UF DB ) for all residential scenarios. Therefore, the LOC for risk assessment continued to be MOEs
<1000. All dermal handler risk scenarios resulted in MO Es well below 1000 (MOEs ranging from 34 to 87) and were of con cern. Short-term handler inhalati on exposure scenar ios were also recalculated using the oral NOAEL of 10 mg/kg/ day and resulted in MOEs greater than 1000 and
were not of concern. All residential handler cancer risk estimates associated with painting were

below 3 x 10 -6

.

Since the 2009 assessment, AD identified one label (EPA Reg # 365-80) that still has a
concentration of MBC at 0.5 % a.i. and contacte d the registrant who indicated that they willPage 23 of 62 reduce the rate to 0.35% a.i. AD anticipates the need to reassess reside ntial handler paint use scenarios during registration review to ensure applic ation rates are acceptable. In order to further refine exposure estimates, AD will require new exposure data for residential handlers applying paints and stains, as well as chemical specific product use information. The revised assessments will incorporate updated toxicological endpoints and new exposure data.

Tree Injections

The registered tree injection pr oduct labels state that they ar e intended for use by professional applicators including arborists. Therefore, a quantitative assessment for residential handler exposure resulting from the use of MBC for tree injection was not previously performed (G. Bangs, D265419, June 21, 2000). However, since these are not restricted use products, the “professional applicator” wording on registered la bels is not considered enforceable, and HED assumes there is potential for homeowners to pur chase and use these products. Currently, HED does not have unit exposure data to assess reside ntial handler exposure associated with this use pattern. Furthermore, these products are formulat ed as ready to use and packaged in capsules
which are inserted into a feed tube and dispensed into the tree . Therefore, the potential for handler exposure to MBC from tree injection is c onsidered to be negligible. During registration review, no additional data or assessments are required for this use.

MBC Post-application Exposure

The primary source of information used to evalua te residential post-appli cation exposure and risk for use of MBC was the 2000 occupational and residential exposure assessment for MBC (D265419, 2000) and the 2009 residential exposure a ssessment for use in paint (D364554, 2009).

Paint Additive

Post-application exposure (non-canc er and cancer) to MBC-treated pa ints, coatings, and sealants was anticipated to be only by the inhalation route, as the treated materials will have dried and will be relatively inert. It was anticipated that only very low exposures to MBC would be obtained from inhalation of vapor s in a treated room; in additi on to the calculated inhalation MOE of 30,000 for applying paint (2 gallons) with a brush, MBC has a very low vapor pressure (1.0×10 -7 mmHg). However, a quantitative assess ment of potential inhalation exposure was conducted by modeling the emission rate of the ac tive ingredient from the product. The MultiChamber Concentration and Exposure Model (MCCE M) was used to estimate post-application inhalation exposures for occupants after painting one room (2 gallons of paint) in a home. The inhalation post-application risk estimates for toddlers and a dults were MOEs of 1.1 x 10 6 and 4.6

x 10 6 respectively. The cancer risk estimate for adults was 3.6 x 10 -10

.

Based on the Agency’s current practices, a qu antitative post-applica tion inhalation exposure assessment for paint is not required due to MBC’s low vapor pressure and low potential for aerosol generation. As a result, a post-application exposure assessment for paint vapors will not be required during re gistration review.Page 24 of 62 Plastic Toys and Textiles

Previous residential exposure assessme nts (D273465, 2001 and D364554, 2009) did not assess the new uses of plastic toys a nd textiles impregnated with MBC. Based on the use of MBC as a material preservative to treat text iles and plastics, there is potentia l for dermal and incidental oral exposure resulting from contact with treated cl othing and toys made of plastic. During Registration Review, AD will conduct an exposure screening risk assessment using default assumptions (i.e., 100% and 5% transfer rates) for treated textiles using the most recent toxicological endpoints. If th e residential risks are not of concern using the 100% default transfer rate assumption, resident ial post-application residue data for treated textiles will not be needed. However, if the risks are not acceptable, post-application residue data will be required. To support the Agency’s assumption of a 5% tran sfer rate, an indoor su rface residue dissipation study is required.

Tree Injection

A quantitative post-application exposure assessment has not been performed for the use of MBC tree injections to ornamental tr ees. However, the potential for post-application exposure is anticipated to be negligible due to the method of applicati on, previously explained, the low application rate, and due to th e tree tissue incorporat ion of the product thus preventing its release. No additional exposure assessments are anticipated during registration review for this

use.

Conclusions for Residential Exposure

Additional residential exposure data are require d for MBC. During registration review, AD will conduct a new residential handler exposure as sessment that will incorporate any new toxicological endpoints, and me thods or policies for estimating exposure risk estimates associated with the registered paints and stains products. In order to further refine exposure estimates, AD will require new handler exposure da ta for applying paints and stains (see data requirements, below) as well as chemical speci fic product use information. AD also anticipates
the need to conduct a residential dermal and incidental oral pos t-application exposure assessment for plastic toys and textiles. In order to support the us es of MBC in textiles (e.g. clothes) and plastics (e.g. toys), AD will require a chemical-s pecific indoor surface residue dissipation study.

Aggregate Risk Assessment

The last aggregate risk assessment of MBC was conducted in 2002 for the TM RED, which examined MBC both as a degradate of TM and as an active ingredient. This assessment combined exposures to TM and MBC, consideri ng total aggregate exposure from food, drinking
water and residential sources of exposure from uses of both TM and MBC. In this assessment, risk estimates were conducted for exposure to TM and MBC from use of TM, and from all uses of TM and MBC combined. TM and MBC, along w ith other metabolites of concern, were added together for total risk estimates, based on both sh owing liver toxicity and developmental effects, and on simultaneous exposure to both com pounds in a given food commodity. The acute aggregate risk was based on evaluation of diet + drinking water only and for uses of TM andPage 25 of 62 MBC combined exceeded the LOC for infants le ss than one year of age, but not other subpopulations. Short-term aggregate risk estim ates were not conducted for TM and MBC from
TM uses because the risks from MBC alone exce eded HED’s level of concern. Specifically,
HED identified risks of concern for residential painters. Chronic non-cancer aggregate exposure to all uses of TM and MBC exceeded the level of concern for infants and children 1-6 years of age. Aggregate cancer risk was 1.1 x 10 -6 for combined TM and MBC from all food and
residential uses.

For future aggregate risk assessments, the risk s for TM and MBC will not be combined because although both compounds share a comm on target organ (liver), thei r overall toxicological profile differs. An updated aggregate risk assessment is anticipated during registra tion review that will take into account changes in endpoint selection a nd safety factors and scie ntific policies at the time of registration review.

Conclusions for Aggregate Exposure

A new aggregate risk assessment is anticipated du ring registration review that will reflect current scientific and exposure assessment policies. Ad ditional toxicity studies received by the Agency may result in revised doses and endpoints and safety factors. The Agency will likely have to address acute, short-term and intermediate-ter m, chronic, and cancer risks for registration
review.

Occupational Exposure

Handler Exposure

Registered MBC formulations in clude soluble concentrates/solid, emulsifiable concentrates, ready-to-use solutions, wettable powders and wa ter dispersible granules. Products may be applied using a paint brush/roller, low pressure sp rayer or airless sprayer, and ready-to-use tree injectors. The primary source of information used to evaluate occupational handler exposure and risk for use of MBC was the 2000 MBC occupationa l and residential exposure assessment and the 2001 assessment of TM/MBC for the RED (D265419, 2000 and D273465, 2001). All occupational handler scenarios for paint and stain products resulted in risk estimates greater than the LOC (LOC=MOEs equal to or greater than 100) at baseline (single layer clothing) and were not of concern, with one exception. The mixing/lo ading of wettable powders (0.5% a.i.) scenario
resulted in an inhalation risk estimate of concer n (MOE=8) at a baseline level of protection. In an effort to mitigate human health risks of c oncern posed by MBC, the RED required that label
amendments should be submitted to reduce the concen tration of MBC in paint from 0.5% a.i. to
0.35% a.i. based on dermal MOEs which exceeded the Agency’s level of concern (i.e., MOEs <100). AD identified that one label (EPA Reg # 365-80) was still at 0.5 % a.i. and contacted the registrant who indicated that th ey will reduce the rate to 0.35% a. i. AD anticipates the need to reassess this scenario during re gistration review to determine whether or not the rates are acceptable with updated toxicological endpoints and exposure data.

As indicated previously in the residential se ction, a quantitative asse ssment for residential handler exposure resulting from the use of MBC for tree injection was no t previously performedPage 26 of 62 (D265419, 2000). Currently, HED does not have unit exposure data to assess residential handler exposure associated with this use pattern. Furthe rmore, these products are formulated as ready to use and packaged in capsules which are inserted into a feed tube and di spensed into the tree. Therefore, the potential for occupational handler exposure to MBC from tree injectio n activities is negligible and no further data or assessments will be required for this use during registration
review.

MBC Occupational Post-application Exposure

Dermal post-application occupati onal exposure to dried or “cured” paint containing MBC is not expected to be of concern. Ha ndlers of MBC or MBC-treated mate rials are anticipated to have a greater exposure to MBC than any post-app lication occupationally-e xposed group. Given the uncertainty and lack of information about post-a pplication exposure to MBC, it is assumed that the handler risk estimates represent the high-e nd for possible post-appli cation exposure. Postapplication inhalation concerns are expected to be minimal based on the low MBC vapor pressure (1 x 10 -7 mm Hg at 20  C) and the small amount of active ingredient in the ready-to-use product (maximum 3.5%). Based on the Agency 's current practices, a quantitative postapplication inhalation exposure assessment is not expected for re gistration review.

The potential for post-application exposure resulting from tree injection of MBC is anticipated to be negligible due to the method of application, previously expl ained, the low application rate, and due to the tree tissue incorporation of the product thus preventing its release. No additional exposure assessments are anticipated duri ng registration review for this use.

Conclusions for Occupational Exposure

During registration review, AD anticipates the need to conduct updated handler dermal and inhalation exposure risk assessments for the pain t use with updated toxicological endpoints and updates to the Agency’s standard assumptions for conducting handler exposure assessments, including revised unit exposure data. AD will also address whether any scenarios require additional PPE (i.e., gloves, dust mist respirato r) or engineering contro ls (i.e., water soluble packets). Based on the Agency's current prac tices, a quantitative post -application inhalation exposure assessment was not performed for MBC, a nd is not expected for registration review.

Tolerance Assessment and International Harmonization

There are currently no food uses for MBC. See the tolerance harmonization discussion in the
TM section of this document.

Data Requirements

The following studies are required for MBC:Page 27 of 62 Toxicology

870.7800 Immunotoxicity. This study is required per the revised pesticide registration data requirements (40 CFR Part 158, 2009). The Agency has previously discussed inclusion of a cohort in the rat extended one-g eneration reproductive toxicity study, currently in progress, evaluating immunotoxic parameters which may satisfy this guideline requirement.

Residue chemistry

There are no food uses for MBC. No new re sidue chemistry data requirements have been
identified for MBC to s upport registration review.

Exposure

Occupational Handler

875.1200/875.1400 (Exposure Data):

 Occupational handler dermal and inhalation exposu re applying paints/stains, slurries (airless sprayer, low pressure handw and and brush/roller);

875.1200/875.1400 (Exposure Data):

 Occupational dermal and inhalation for pouring liquid and or solid ma terial preservatives formulations (paints/stains, slurries); and

875.1700 Product use information

 For occupational exposure assessments product us e data are required for pouring liquid/solid material preservative formulation. The Agency needs to refine the daily amount handled for these procedures and a description of th e pouring operations. The occupational data requirements may be conducted by the registrants or they may cite the completed or planned Antimicrobial Exposure Assessment Task Force (AEATF) studies.

Residential Handler

875.1200/875.1400 (Exposure Data):

 Residential handler dermal and inhalation exposure applying pa int/stain (airless sprayer and brush/roller).

875.1700: Product Use Information:

 Product use for applying paints/stains

 Product use information for pouring liquid/solid material preservative formulation

Residential Post-application

875.2300: Indoor Residue Exposure Data

 Indoor surface residue dissipation da ta for plastic toys and textilesPage 28 of 62 875.2700: Product Use Information:

 For material preservative uses (plastic toys and textiles) in residential products

The residential exposure section indicates new residential risk assessments are anticipated for registration review. The need for additional exposu re data was confirmed by the EPA’s Scientific Advisory Board (SAP) in 1997. The residential data requirements may be conducted by the registrants or they may cite the completed or planned Antimicrobial Exposure Assessment Task Force (AEATF) studies.

CONSIDERATIONS FOR BOTH TM AND MBC

Public Health and Pesticide Epidemiology Data

For this evaluation, both the O PP Incident Data System (IDS) and the Centers for Disease
Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupati onal Risk-Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredients TM and MBC (PC codes: 102001, 128872). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effect s attributed to TM exposure. TM is not included in the AHS, and therefore this study does not provide information for this report.

OPP’s IDS includes reports of alleged human h ealth incidents from various sources, including mandatory Federal Insecticide, Fungicide and Ro denticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state hea lth and environmental agencies, and individual consumers. Since 1992, OPP has compiled these repor ts in IDS. The IDS contains reports from across the U.S., and most incidents have all re levant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report.

IDS records incidents in one of two modules: Main IDS and Aggregate IDS:

Main IDS contains incidents resulting in higher severity outcomes and provides more detail with regard to case specifics. This sy stem stores incident data for death, major and moderate incidents, a nd it includes information about the location, date and nature of the incident. Main IDS incidents involving only one active ingredie nt (as opposed to pesticide products with multiple active ingred ients) are considered to provide more certain information about the potential e ffects of exposure from the pesticide.

Aggregate IDS contains inci dents resulting in less seve re human incidents (minor, unknown, or no effects outcomes). These are re ported by registrants only as counts in what are aggregate summaries.

For the Main IDS, from January 1, 2008 to Se ptember 11, 2013, there were 5 incidents reported for single chemical only in the database. There were 3 additional incidents reported involving
more than one chemical. One incident was classi fied as major severity (Table 1). The other incidents reported were classi fied as moderate severity.Page 29 of 62 In Aggregate IDS, from January 1, 2008 to Se ptember 11, 2013, there were 14 reported incidents involving TM and MBC. Overall, there are fe w incidents involving TM and MBC reported to

IDS.

Table 1. Major Severity Inci dent Descriptions for TM

Human Incident Chemical: TM PC Codes: 102001, 128872

Incident Package Report Incident

Date Location Reg
Number Product Name Exposure Severity Incident Description

020111
- 00270 1/1/2008 NC 000538-

00088 LAWN
FUNGUS
CONTROL Major One individual chronically exposed in the home to a low level reported the following symptoms: tingling, numbness in feet, hands and toes, pain and progressing burning sensation in both arms and muscle twitches in legs. She also reported headaches and nausea. No one else in the family experienced
any symptoms.

The SENSOR-Pesticides database covers 11 st ates from 1998-2009, although reporting varies
from state to state. Cases of pesticide-related illnesses are asce rtained from a variety of sources, including: reports from local Poison Control Ce nters, state Department of Labor workers’ compensation claims when reported by physicia ns, reports from State Departments of Agriculture, and physician reports to state Departments of Hea lth. Although both occupational and non-occupational incidents ar e included in the database, SE NSOR-Pesticides is focused on occupational pesticide incidents, and is of part icular value in providing that information. The state coordinator at each of the 11 respective st ate Departments of Health conducts case followup activities such as obtaining medical records to verify symptoms and severity. Using standardized protocol and case definitions de rived from poison center reporting, the state
SENSOR-Pesticide coordinator enters the incident information into the state-based system which is sent to NIOSH annually to be aggregated. A query of SENSOR-Pesticides 1998-2009 finds 28 cases involving TM and MBC. Of these, nine cases involved a single activ e ingredient. Five of the nine cases were work-related. All nine cases were low in severity. Case symptoms are summarized in Table 2.Page 30 of 62 Table 2. SENSOR-Pesticides 1998-2009: Reported
Health Effects for TM Cases

Health Effect # of Times Reported

Dermal 3

Ocular 0 Respiratory 2

Gastrointestinal 4

Renal 0
Nervous System 5

Cardiovascular 0

Miscellaneous 1 * Cases may report multiple health effects

Based on the low frequency and severity of inci dent cases reported for both TM and MBC in both IDS and SENSOR-Pesticides, ther e does not appear to be a conc ern at this time that would warrant further investigation. Th e Agency will continue to mon itor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

AD conducted a review of the incident data associ ated with antimicrobial use of MBC in OPP’s Incident Data System (IDS) for the time peri od spanning 1997 to 2013. There were only 2 minor human incidents involving MBC reported in OPP’s Incident Da ta System. Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that
would warrant furthe r investigation.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the human-health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/ guidance/justice/e o12898.pdf). The OPP typically considers the highest potential exposures from the le gal use of a pesticide when conducting human-health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diet s within the U.S., and people who might be exposed when harvesting cr ops. Should these highest exposures indicate potential risks of concern, OPP further refines th e risk assessments to ensure that the risk
estimates are based on the best available information.

Cumulative Risk Assessments

TM and MBC are carbamates and members of the benzimidazole chemical group of fungicides, and is the pesticidally active moiety for TM. The Agency has not determined whether TM andPage 31 of 62 MBC and share a common mechanism of toxicity w ith other chemical substances. Prior to a final registration review decision for TM and MBC, the Agency will determine if there is any new information, such as new hazard or exposur e data or information on changes to the use pattern, which would affect the need for a cu mulative risk assessment. Should the Agency
determine that new information on TM and MBC is available that could potentially trigger the
need for a cumulative risk assessment and result in a risk of concern, the Agency will revisit the
cumulative risk assessment.

Conclusions for Cumulative

A cumulative assessment is not needed at this tim e for TM and MBC, but may be required in the future if a cumulative assessment group (CAG) fo r benzimidazole fungicides is identified and the hazard or exposure data indicate that it is appropriate to include TM and MBC in that group.

For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to ev aluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concer ning common mechanism determinations and procedures for cumulating effects from subs tances found to have a common mechanism on EPA’s website at http://www.ep a.gov/pesticides/cumulative/.

Human Studies

Past TM and MBC risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pest icide to determine their dermal and inhalation exposure. Many such studies, i nvolving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pestic ide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Databa se. EPA has reviewed all the studies supporting these multi-pesticide generic exposure databa ses, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevai ling at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subj ects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on
these studies.Page 32 of 62 References for TM and MBC

U. Habiba, TXR #0056916, in preparation. Thiopha nate-Methyl and Carbe ndazim: Summary of Hazard and Science Policy Council (HASPO C) Meeting of February 27, 2014:
Recommendations on the Need for Subchronic Inhalation, Immunotoxicity and Developmental Thyroid Toxicity Studies on Thiophanate Methyl and Immunotoxicity Study on Carbendazim.

S. Recore, D416734, December 17, 2013. Thiophanate -methyl and Carbendazim: Tier I Review
of Human Incidents.

S. Piper, D397646, January 17, 2012. Carbendazim: Dietary Exposure and Risk Assessments for the Fungicide Carbendazim (MBC), Including Potential Residues in Orange Juice.

J. Liccione, D366268, September 28, 2009. Carbe ndazim: Review of a Benchmark Dose (BMD) Analysis of the Subchronic Dermal Toxicity Study in Rats.

D. Dotson, D330476, June 24, 2009. Thiophanate-methyl. Human Health Risk Assessment for the Proposed Uses on the Caneberry Subgroup, th e Bushberry Subgroup, Citrus, Ginseng, Leafy

Brassica Greens, Turnip Greens, Mushroom, Mustar d, Pistachio, Sunflower, Tomato, Tomatillo, Tree Nuts, Tuberous and Corm Vegetables (PP#6E7075), Cotton (PP#6F7069), and Sweet Corn (PP#2E6478)

A. Parmar, D360625, June 24, 2009. Thiophanate-met hyl. Acute Probabilistic, Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Bushberry (Crop Subgroup 13-07B), Caneberry (Crop Subgroup 13-07A), Canola, Citrus (Crop Group 10), Cotton, Ginseng, Juneberry, Lingonberry, Leafy Brassica Greens (Crop Subgroup 5-B), Mushroom, Mu stard, Pistachio, Salal, Sunflower, Sweet Corn, Tuberous and Corm Vegetables (Crop Subgroup 1-C) Turnip Greens, Tomato, Tomatillo and Tree Nut (Crop Group 14).

L. Hansen, D357221, June 17, 2009. Thiophanate-met hyl. HED Response to the Registrant’s Rebuttal to the 2007 Updated Hazard Characteri zation Regarding Retention of the 10X FQPA Factor and Requirement of a De velopmental Neurotoxicity Study.

S. Dapson, D350585, April 28, 2009. Carbendazim, Re view of a Subchronic Dermal Toxicity Study in Rats.

J. Stokes, D308747, 3/19/2009. Thiophanate-methyl. Topsin ® M 70WP (EPA Reg. No. 73545- 11) and Topsin M ® 4.5FL (EPA Reg. No. 73545- 13). Addition of Uses on Bushberries, Juneberry, Lingonberry, Salal, Caneberries, Citr us, Ginseng, Leafy Brassica Greens, Turnip Greens, Mushroom, Mustard, Pistachio, Sunflower, Tomato, Tomatillo, Tree Nuts, and Tuberous and Corm Vegetables (PP#6E7075). Topsin ® M 70WP (EPA Reg. No . 73545-11), Topsin M ® 4.5FL (EPA Reg. No. 73545-13), Topsin ® M WSB (EPA Reg. No. 73545-16), and Topsin ® MPage 33 of 62 70 WDG (EPA Reg. No. 73545-18). Addition of Use on Cotton (PP#6F7069). Summary of Analytical Chemistry and Residue Data.

P. Savoia, D335849, May 12, 2009. Thiophanate-Methy l. Required Data Provided to Support the October 2005 Reregistration El igibility Decision. Summary of Analytical Chemistry and
Residue Data.

M. Collantes, D364554, May 1, 2009. Revised Reside ntial Exposure and Ri sk Assessment for
Use in Residential Paint.

M. Collantes, D360623, March 4, 2009. Revised Re sidential Exposure Assessment for Use of Thiophanate-methyl on Turf.

S-C. Wang, D335120, February 26, 2009. Thiophanate-Methyl : Occupational Exposure/Risk Assessment of Thiophanate-Methyl for Crop Protection Uses on Cotton, Canola, Berries, Various Vegetable Crops, Citrus, Pistachios, Tree Nuts and Mushroom, and for Seed Treatment Uses on Cotton, Sweet Corn, Leafy Brassica Greens, and Sunflower.

L. Hansen, HASPOC memorandum, January 20, 2009. Thiophanate methyl: Summary of HASPOC Meeting of December 16, 2008. Discussi on of FQPA Factor Retention and DNT Study Requirement in Response to the Registra nt’s Rebuttal to the Agency’s 2007 Hazard

Assessment.

L. Hansen, D340134, September 12, 2007. Thiophanate Methyl. Updated Hazard
Characterization: Toxicol ogy Summary for Proposed New Us es (Including Summary of Carbendazim Toxicity).

L. Hansen, HASPOC memorandum, June 4, 2007. Thiophanate-Methyl and Carbendazim (MBC): Summary of HASPOC Meetings of May 9 and May 16, 2007: Recommendations on
the Use of a Cumulative Assessment for Human Health Risk.

October, 2005. Thiophanate-Methyl Reregi stration Eligibility Decision, October 2005.

D. Smegal, D275774, April 25, 2002. Human Health Risk Assessment for the Registration Eligibility (RED) Document.

J. Morales, D279270, April 3, 2002. Thiophanate-m ethyl. Revision of the Residue Chemistry Chapter for the Reregistration Eligibility Document, PC Code 102001.

G. Bangs, D273465, March 21, 2001. Revised Occupational and Residential Exposure
Assessment and Recommendations for the Risk Assessment Document for Carbendazim (MBC ).

G. Bangs, D271922, March 16, 2001. REVISE D Thiophanate-methyl: Occupational and Residential Exposure Assessment and Recomme ndations for the Reregistration Eligibility
Decision.Page 34 of 62 G. Bangs, D265419, June 21, 2000. Occupational and Residential Exposure Assessment and
Recommendations for the Risk Assessme nt Document for Carbendazim (MBC).

Attachments

Attachment 1. Chemical Identity Tabl e for Thiophanate-methyl and Carbendazim Attachment 2a. Thiophanate-met hyl Endpoint Selection Tables
Attachment 2b. Carbendazim Endpoint Selection Tables Attachment 3a. Summary of Acute, Subchroni c and Chronic Toxicity Profile, Toxicological Doses for Thiophanate-methyl for Use in Human Health Risk Assessments. Attachment 3b. Summary of Acute, Subchronic and Chronic Toxicity Profile, Toxicological
Doses for Carbendazim for Use in Human Health Risk Assessments.
Attachment 4. Internati onal Residue Limit StatusPage 35 of 62 Attachment 1. Chemical Identity Tabl e for Thiophanate-Methyl and Carbendazim

Thiophanate-Methyl Nomenclature.
Compound

Common name Thiophanate-methyl

IUPAC name dimethyl 4,4 ′ -(o-phenylene)bis(3-thioallophanate)

CAS name dimethyl [(1,2-phenylene)bis(imi nocarbonothioyl)]bis(carbamate)
CAS registry number 23564-05-8
End-use products 70% WP formulation (Topsin® M 70WP; EPA Reg. No. 73545-11); 4.5 lb/gal SC formulation (Topsin® 4.5FL; EPA Reg. No. 73545- 13); 70% WP formulation (Topsin® M WSB; EPA Re g. No. 73545-16); 70% WDG formulation (Topsin® M 70 WDG; EPA Reg. No. 73545-18); 30% SC formulation (Tops® 30 Flowable Fungicide; EPA Reg. No. 264-990)
Regulated Metabolite

Common name MBC, carbendazim

CAS name methyl 1H-benzimidazol-2-ylcarbamate
CAS registry number 10605-21-7

Metabolite to be
included in risk assessment for plant
commodities

Common name 2-AB

Chemical name 2-aminobenzimidazole
CAS registry number 934-32-7 N H

S O CH 3

O N H S

N H

N H O CH 3 O

N

N H NH O CH 3 O

N

N H NH 2Page 36 of 62 Attachment 2a. Summary of Toxicological Doses and Endpoints for Thiophanate-Methyl
for Use in Human Health Risk Assessments

Table 2a.1. Summary of Toxicological Doses a nd Endpoints for Thiophanate-methyl for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,
Level of
Concern
for Risk
Assessment Study and Toxicological Effects

Acute Dietary (Females 13- 49 years of age) NOAEL= 20 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x aPAD =0.2 mg/kg/day Developmental toxicity oral (gavage) study in the rabbit (1997 study) LOAEL = 40 mg/kg/day based on supernumerary ribs in fetuses and decreased fetal body weight

Acute Dietary (General population including
infants and children) An appropriate endpoint was not selected. This risk assessment is not required.

Chronic Dietary (All Populations) NOAEL= 8 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 3x cPAD = 0.027 mg/kg/day Chronic oral (one-year capsule) toxicity study in the dog LOAEL = 40 mg/kg/day based on thyroid effects and decreased body weight.

Incidental Oral
Short- and
IntermediateTerm (1-30 days and 1-6 months, respectively) NOAEL= 10 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 3x Residential
LOC for MOE

= 300 Developmental toxicity oral (gavage) study in the rabbit (1997 study) LOAEL = 20 mg/kg/day based on decreased maternal body weight and food consumption.

Dermal Shortand
IntermediateTerm (1-30 days and 1-6 months, respectively) NOAEL= 100 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 3x Residential
LOC for MOE

= 300 Twenty-one day dermal toxicity study in
the rabbit LOAEL = 300 mg/kg/day based on decreased food consumption and body weight gain.

Dermal LongTerm (>6 months) NOAEL=8 mg/kg/day.

(dermal absorption rate
= 7% relative
to oral absorption) UF A = 10x

UF H =10x FQPA SF= 3x Residential
LOC for MOE

= 300 Chronic oral (one-year capsule) toxicity study in the dog LOAEL = 40 mg/kg/day based on thyroid effects and decreased body weight.Page 37 of 62 Table 2a.1. Summary of Toxicological Doses a nd Endpoints for Thiophanate-methyl for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,
Level of
Concern
for Risk
Assessment Study and Toxicological Effects

Inhalation
Short- and
IntermediateTerm (1-30 days and 1-6 months, respectively) NOAEL=10 mg/kg/day

(inhalation absorption rate
= 100%
relative to oral absorption) UF A = 10x

UF H =10x FQPA SF = 3x Residential
LOC for MOE

= 300 Developmental toxicity oral (gavage) study in the rabbit (1997 study) LOAEL = 20 mg/kg/day based on decreased maternal body weight and food consumption.

Inhalation Long-Term (>6 months) NOAEL= 8 mg/kg/day

(inhalation absorption rate
= 100%
relative to oral absorption) UF A = 10

UF H =10 FQPA SF = 3x Residential
LOC for MOE

= 300 Chronic oral (one-year capsule) toxicity study in the dog LOAEL = 40 mg/kg/day based on thyroid effects and decreased body weight.

Cancer (oral, dermal, inhalation) N/A N/A Q 1 * = 0.0116 (mg/kg/day) -1 78-week mouse dietary carcinogenicity study, based on increased incidence of
liver adenoma/and/or carcinoma and/or hepatoblastoma combined tumor.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 data (i.e., lack of a critical study). FQPA SF = FQPA Sa fety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 2a.2. Summary of Toxicological Doses and Endpoints for Thiophanate-methyl for Use in Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty

Factors Level of Concern
for Risk
Assessment Study and Toxicological Effects

Dermal Shortand
IntermediateTerm (1-30 days and 1-6 months, respectively) NOAEL=100 mg/kg/day UF A =10x

UF H =10x

UF DB = 3x Occupational
LOC for MOE =

300 Twenty-one day dermal toxicity study in
the rabbit LOAEL = 300 mg/kg/day, based on decreased food consumption and body weight gain.Page 38 of 62 Table 2a.2. Summary of Toxicological Doses and Endpoints for Thiophanate-methyl for Use in Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty

Factors Level of Concern
for Risk
Assessment Study and Toxicological Effects

Dermal LongTerm (>6 months) NOAEL = 8 mg/kg/day

(dermal absorption
rate = 7%
relative to
oral absorption) UF A =10x

UF H =10x

UF DB = 3x Occupational
LOC for MOE =

300 Chronic oral (capsule) toxicity study in the dog LOAEL = 40 mg/kg/day based on thyroid effects and decreased body weight.

Inhalation
Short- and
IntermediateTerm (1-30 days) NOAEL=10 mg/kg/day

(inhalation absorption
rate = 100%
relative to
oral absorption) UF A =10x

UF H =10x

UF DB = 3x Occupational
LOC for MOE =

300 Developmental toxicity oral (gavage) study in the rabbit (1997 study) LOAEL = 20 mg/kg/day based on decreased maternal body weight and food consumption.

Inhalation Long-term (1-6 months) NOAEL=8 mg/kg/day

(inhalation absorption
rate = 100%
relative to
oral absorption) UF A =10x

UF H =10x

UF DB = 3x Occupational
LOC for MOE =

300 Chronic oral (capsule) toxicity study in the dog LOAEL = 40 mg/kg/day based on thyroid effects and decreased body weight.

Cancer (oral, dermal, inhalation) N/A N/A Q 1 * = 0.0116 (mg/kg/day) -1 78-week mouse dietary carcinogenicity study, based on increased incidence of
liver adenoma/and/or carcinoma and/or hepatoblastoma combined tumor. Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Page 39 of 62 Attachment 2b. Summary of Toxicological Doses and Endpoints for Carbendazim for Use
in Human Health Risk Assessments

Table 2b.1. Summary of Toxicological Doses and Endpoints for Carbendazim (MBC) for Use in Dietary and Non-Occupational (Res idential) Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,
Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (Females 13- 49 years of age) Oral NOAEL= 10 mg/kg UF A = 10x

UF H =10x FQPA SF= 10x aPAD =0.01 mg/kg Developmental toxicity oral (gavage) study in the rat with MBC Developmental toxicity LOAEL = 20 mg/kg/day based on increases in skeletal variations and a possible threshold for
malformations in fetuses and decreased fetal body weight.

Acute Dietary,
General Population (including
infants and children) Oral LOAEL = 50 mg/kg (NOAEL not established) UF A = 10x

UF H =10x

UF L = 3x

FQPA SF= 10x
infants and children only aPAD=0.017 mg/kg, infants and children;

aPAD = 0.17 mg/kg, general population Single dose rat study with MBC (Nakai
et al. , 1992) LOAEL = 50 mg/kg based on adverse testicular effects including sloughing (premature release) of immature germ cells seminiferous tubules in one testicle, significant decrease in seminiferous tubule diameter and slight abnormal growth of the efferent ductules at 70 days post-exposure.

Chronic Dietary (All Populations) Oral NOAEL= 2.5 mg/kg/day UF A = 10x

UF H =10x FQPA SF = 10x cPAD = 0.025 mg/kg/day 2 year chronic oral toxicity study in the dog with MBC

LOAEL = 12.5 mg/kg/day based on decreased body weight and food consumption.

Incidental Oral Short-Term (1- 30 days) Oral NOAEL= 10 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x Residential
LOC for MOE

= 1000 Developmental toxicity oral (gavage) study in the rat with MBC Developmental toxicity LOAEL = 20 mg/kg/day based on increases in skeletal
variations and a threshold for
malformations in fetuses and decreased fetal body weight.

Incidental Oral
IntermediateTerm (1-6 months) NOAEL = 11 mg/kg/day (rounded to 10 mg/kg/day) UF A = 10x

UF H =10x FQPA SF= 10x Residential
LOC for MOE

= 1000 90-day dog dietary study with MBC LOAEL = 35 mg/kg/day based on
adverse liver effects.Page 40 of 62 Table 2b.1. Summary of Toxicological Doses and Endpoints for Carbendazim (MBC) for Use in Dietary and Non-Occupational (Res idential) Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,
Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Dermal Shortand
IntermediateTerm (1-30 days and 1-6 months, respectively) Dermal

NOAEL= 20 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x Residential
LOC for MOE

= 1000 28-day dermal toxicity study in rats
based on seminiferous tubule degeneration and hypospermia observed at the LOAEL of 120 mg/kg/day.
( Note: results of this study have not yet been incorporated into an updated
revised hazard char acterization for

MBC. A BMDL 10 has also been calculated)

Dermal LongTerm (>6 months) Oral

NOAEL=2.5 mg/kg/day.

(dermal absorption rate
= 3.5%
relative to oral absorption) UF A = 10x

UF H =10x FQPA SF= 10x Residential
LOC for MOE

= 1000 2 year chronic oral toxicity study in the dog with MBC

LOAEL = 12.5 mg/kg/day based on decreased body weight and food consumption.

Inhalation Short-Term (1- 30 days) Oral NOAEL =10 mg/kg/day (assume 100% absorption
relative to oral absorption) UF A = 10x

UF H =10x FQPA SF= 10x Residential
LOC for MOE

= 1000 Developmental toxicity oral (gavage) study in the rat Developmental toxicity LOAEL = 20 mg/kg/day based on increases in skeletal variations and a possible threshold for
malformations in fetuses and decreased fetal body weight.

Inhalation
Intermediateand LongTerm (1-6
months and > 6 months) Inhalation

NOAEL= 0.96 mg/kg/day (10 mg/m 3 ) UF A = 10x

UF H =10x FQPA SF= 10x, Residential
LOC for MOE

= 1000 90-day rat inhalation study with benomyl LOAEL = 4.8 mg/kg/day (50 mg/ m 3) based on olfactory degeneration in the nasal cavity.

Cancer (oral, dermal, inhalation) N/A N/A Q1* = 2.39 x

10 -3 (mg/kg/day) -1 Two-year mouse dietary carcinogenicity study, based on increased incidence of hepatocellular (adenoma/and/or carcinoma) tumors. The 10X FQPA factor was retained fo r all acute, short- and intermediate-term dietary and residential exposure scenarios (except general population acute dietary). The factor has been retained due to concern for potential neurodevelopmental toxicity raised by the observations of increased offspring sensitivity, CNS abnormalities from prenatal exposure and aneugenic poten tial. A 10X FQPA factor was not reta ined for chronic exposure because the windows of developmental sensitivity are no t expected to be of chronic duration. Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 keyPage 41 of 62 date (i.e., lack of a critical study). FQPA SF = FQPA Sa fety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Page 42 of 62 Table 2b.2. Toxicological Doses and Endpoints for MBC for Use in Occupational Human
Health Risk Assessments Exposure
Scenario Dose Used in Risk Assessment, UF FQPA SF* and Endpoint for Risk
Assessment Study and Toxicological Effects

Dermal Shortand
Intermediate Term (1-30 days and 1-6 months, respectively) Oral NOAEL =10 mg/kg/day

(dermal absorption rate =
3.5% relative to oral absorption) LOC for MOE = 100 for occupational workers Rat Developmental Study Developmental LOAEL= 20 mg/kg/day based on decreased fetal body weight and
increases in skeletal variations and a possible threshold for malformations in fetuses of exposed dams

Dermal, LongTerm (>6 months) Oral NOAEL =2.5 mg/kg/day (dermal absorption rate =
3.5% relative to oral absorption) LOC for MOE = 100 for occupational workers 2 year dog study LOAEL= 12.5 mg/kg/day based on histopathological lesions of the liver characterized as swollen, vacuolated hepatic cells, hepatic cirrhosis and chronic hepatitis in both sexes of dogs. Inhalation, Short-term (1- 30 days) Oral NOAEL =10 mg/kg/day

(assume 100% absorption relative to oral absorption) LOC for MOE = 100 for occupational workers Rat Developmental Study Developmental LOAEL= 20 mg/kg/day based on decreased fetal body weight and
increases in skeletal variations and a possible threshold for malformations in fetuses of exposed dams Inhalation,
Intermediateand Long Term (1-6 months and >6 months) Inhalation

NOAEL=
0.96 (10 mg/m 3 ) LOC for MOE = 100 for occupational workers 90 day rat inhalation study with benomyl LOAEL= 4.8 mg/kg/day (50 mg/m 3 ) based on olfactory degeneration in the nasal cavity.

Cancer Q1* = 2.39x10 -3 (mg/kg/day) -1 (dermal absorption rate =3.5% relative to oral absorption; inhalation absorption
rate=100% relative to oral absorption) N/A 2 year mouse study based on hepatocellular (adenoma and/or carcinoma) tumors in
female CD-1 mice

UF = Uncertainty Factor
LOC= Level of Concern MOE = Margin of ExposurePage 43 of 62 Attachment 3a. Summary of Acute, Subchr onic and Chronic Toxicity Profile, Toxicological Doses for Thiophanate-Methyl fo r Use in Human Health Risk Assessments.

Table 3a.1. Acute Toxicity Profile of Thiophanate-methyl (tech. a.i.)

Guideline

No. Study Type MRID # Results Toxicity Category
870.1100 Acute Oral, Rat 41644301 LD 50 >5000 mg/kg, both sexes IV 870.1200 Acute Dermal, Rabbit 41644302 LD 50 >2000 mg/kg, both sexes III 870.1300 Acute Inhalation, Rat 41482804 LC 50 = 1.7 mg/L, males 1.9 mg/L, females II

870.2400 Primary Eye Irritation, Rabb it 40095501 Slight ocular irritant IV 870.2500 Primary Skin Irritation, Rabbit 40095502 Not a dermal irritant IV 870.2600 Dermal Sensitization, Guinea Pig 41482805 Is a dermal sensitizer N/A
N/A: Not applicable to this guideline study

Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90-Day dietary toxicity (rat) 42001701 (1990) Acceptable/guideline Males 0, 13.9, 155.0, 293.2, 426.9 or 564.7 mg/kg/day Females 0, 15.7, 173.4, 323.0, 478.8 or 647.3 mg/kg/day

Tech., 96.55% a.i. NOAEL = 15.7 mg/kg/day LOAEL = 155.0 mg/kg/day, based on anemia,
increased serum cholesterol and calcium (males), increased liver and thyroid weights, increased kidney (males) weight and increased incidence of thyroid hyperplasia/hypertrophy, liver swelling and lipofuscin deposition, and glomerulonephrosis (males) were observed. At higher dose levels, effects included increased serum cholinesterase (males), increased thymus weight (females), increased incidence of glomerulonephritis (females) and fatty degeneration of the adrenal cortex were also reported.

870.3150 90-Day oral (capsule) toxicity (beagle dog) 41982203 (1992)

Acceptable/guideline

0, 50, 200 or 800 mg/kg/day in gelatin capsules (HDT lowered to 400 on day 50 due to excessive toxicity)

Tech., 96.55% a.i. NOAEL < 50 mg/kg/day LOAEL (threshold) = 50 mg/kg/day, based on slight thyroid hypertrophy in 1 male and 1 female. At 200 mg/kg/day, thin/dehydrated appearance, tarry stools, decreased body weight/weight gain, decreased food consumption, slight anemia, increased serum cholesterol, decreased serum T3/T4 (females), increased liver and thyroid weights, thyroid follicular cell hypertrophy and hyperplasia, hypoplasia/atrophy of the prostate, thymic involution/atrophy (males) and depletion of spleen lymphoid cells were observed. At 800/400 mg/kg/day, mortality (1 male), increased platelet count were also observed.Page 44 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3200 21/28-Day dermal toxicity (NZW rabbit) 42110801 (1991)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day, moistened with water (5 days/week, 6 hrs/day) Tech., 96.55% a.i. Systemic toxicity NOAEL = 100 mg/kg/day Systemic toxicity LOAEL = 300 mg/kg/day, based on decreased food consumption in females. At 1000 mg/kg/day, consumption also
decreased in males.

Slight dermal irritation was observed at all dose
levels.

870.3465 14-Day inhalation toxicity (rat) 42527601 (1992)

Unacceptable/nonguideline

0.0, 0.00514, 0.0151 or 0.247 mg/L

Tech., 5.2% a.i. (Tops® 5 formulation) NOAEL = 0.00514 mg/L LOAEL = 0.0151 mg/L, based on increased incidence of alveolar macrophages, pneumonocyte hyperplasia of the lung and nonsuppurative alveolitis. At 0.247 mg/L, decreased body weight gain (females) and increased incidence of lung microgranulomas (both sexes) were also observed.

870.3700a Prenatal developmental in (rat) 00106090 (1981)

Unacceptable/guideline (report lacking information on dosing solution analyses, maternal clinical sign and food consumption data, and individual litter data) 0, 100, 300 or 1000 mg/kg/day (gavage in 5% aq. gum arabic)

tech., 97.2% a.i. Maternal NOAEL = 300 mg/kg/day Maternal LOAEL = 1000 mg/kg/day, based on decreased body weight gain.

Developmental NOAEL ≥ 1000 mg/kg/day Developmental LOAEL >1000 mg/kg/day

870.3700a Prenatal developmental in (rat) 00146643 (1985)

Acceptable/nonguideline 0, 18, 85, or 163 mg/kg/day (0, 250, 1200 or 2500 ppm in diet) tech., 95.3% a.i. Maternal NOAEL = 18 mg/kg/day Maternal LOAEL = 85 mg/kg/day, based on decreased food consumption.

Developmental NOAEL =163 mg/kg/day (HDT) Developmental LOAEL none established

870.3700b Prenatal developmental in (NZW rabbit) 45051001 (1997)

Acceptable/guideline 0, 5, 10, 20, or 40 mg/kg/day (gavage in 1% aq. methyl cellulose) tech., 97.28% a.i. Maternal NOAEL = 10 mg/kg/day Maternal LOAEL = 20 mg/kg/day, based on decreased body weight gain and food consumption

Developmental NOAEL= 20 mg/kg/day Developmental LOAEL = 40 mg/kg/day, based on increased supernumerary ribs and decreased fetal weightPage 45 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3700b Prenatal developmental in (NZW rabbit) 40028801, 41056701 (1986)

Unacceptable/nonguideline 0, 2, 6 or 20 mg/kg/day (gavage in 1% aq. methyl cellulose)

tech., 96.2% a.i. Maternal NOAEL = 6 mg/kg/day Maternal LOAEL = 20 mg/kg/day, based on transiently decreased body weight gain,
increased abortion/total litter loss

Developmental NOAEL ≥ 20 mg/kg/day Developmental LOAEL = none

870.3800 Reproduction and fertility effects (rat) 42899101 to -05 (1993);

43624401 (1995)

Acceptable/guideline

Males 0, 13.7, 43.3 or 138.9 mg/kg/day; Females 0, 15.5, 54.0 or 172.0 mg/kg/day (in diet)

tech., 95.9% a.i. Parental systemic NOAEL <13.7 mg/kg/day Parental systemic LOAEL = 13.7 mg/kg/day, based on hepatocellular hypertrophy and thyroid hypertrophy/hyperplasia in males (females affected at mid and high dose). At

≥ 43.3 mg/kg/day, slightly decreased body weight gains in males and at 138.9 mg/kg/day, increased liver and thyroid weights (both sexes). Slight increase in TSH of P animals at
Week 8.

Reproductive NOAEL ≥ 138.9 mg/kg/day (HDT) Reproductive LOAEL > 138.9 mg/kg/day

Offspring NOAEL = 13.7 mg/kg/day Offspring LOAEL = 43.3 mg/kg/day, based on slightly reduced body weights of the F2b offspring during lactation. Thyroid hypertrophy/hyperplasia seen at 138.9 mg/kg/day in males (F1 examined). Slight
increase in TSH at Week 8 in F1 males. 870.3800 Reproduction and fertility effects (CD rat) 00117870 (1972)

Unacceptable/guideline (upgradable with
submission of test material purity) 0, 2, 8 or 32 mg/kg/day (estimated from ppm in diet)

purity a.i. not stated Parental systemic/r eproductive NOAEL ≥ 32 mg/kg/day Parental systemic/rep roductive LOAEL >32 mg/kg/day. Thyroid/liver not evaluated.

Offspring NOAEL = 8 mg/kg/day Offspring LOAEL = 32 mg/kg/day, based on slightly decreased mean litter weights.

870.4100a Chronic toxicity (rat) See 870.4300 See 870.4300Page 46 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4100b Chronic toxicity (beagle dog) 42311801 (1992)

Acceptable/guideline 0, 8, 40 or 200 mg/kg/day in gelatin capsules Tech., 96.55% a.i. NOAEL = 8 mg/kg/day LOAEL = 40 mg/kg/day, based on decreased body weight/weight gain, markedly increased serum TSH (1 male) and decreased T4 (males), increased serum cholesterol (males), increased abs/rel thyroid weights (both sexes) and thyroid follicular cell hypertrophy (females). At 200 mg/kg/day, tremors in all dogs 2-4 hrs postdosing (most on day 1; sporadically through day 17), slight anemia, increased serum alkaline phosphat ase and cholesterol, increased relative liver weight, thyroid follicular cell hypertrophy in males and hyperplasia (both sexes) were also observed.

870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300

870.4200b Carcinogenicity (mouse) 42607701 (1992)

Acceptable/guideline

Males 0, 23.7, 98.6,

467.6 or 1078.8 mg/kg/day; Females 0, 28.7, 123.3,

557.9 or 1329.4 mg/kg/day

Tech., 95.93% and
96.55% a.i. Systemic toxicity NOAEL = 23.7 mg/kg/day Systemic toxicity LOAEL = 123.3 mg/kg/day, based on hepatocellular hypertrophy in females.

At ≥ 98.6 mg/kg/day, decreased body weights,, sporadic effects on ci rculating T4 and TSH, increased thyroid and liver weights, increased heart weight (females), increased hepatocellular hypertrophy and increased atrial thrombosis were also observed. At the HDT, mortality was
increased in both sexes.

Increased incidence of hepatocellular adenomas
in males at ≥ 467.6 mg/kg/day (control to high dose, 9%, 17%, 15%, 42% and 57%) and in
females at ≥ 123.3 mg/kg/day (0%, 0%, 8%, 24% and 56%). Both sexes showed significant increasing trends and pair wise increases at the highest two dose levels.Page 47 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4300 Combined chronic toxicity/carcinogen icity (rat) 42896601 (1993)

Acceptable/guideline

Males 0, 3.3, 8.8, 54.4 or

280.6 Females 0, 3.8, 10.2, 63.5

or 334.7

Tech., 96.55% a.i. NOAEL = 8.8 mg/kg/day LOAEL = 54.4 mg/kg/day, based on decreased body weight/weight gain (males; marginal in females), decreased food efficiency (males; marginal in females), sporadic effects on circulating T3/T4 and TSH, increased serum cholesterol and creatinine, decreased serum cholinesterase in females, increased liver, thyroid and kidney weights, liver hypertrophy and lipofuscin accumulation, thyroid hypertrophy and hyperplasia and lipofuscin accumulation in the kidney. At ≥ 280.6 mg/kg/day, excessive mortality in males (2/50
survivors at termina tion), decreased body weight/weight gain in females, mild anemia, increased urinary protein, hyperparathyroidism (primarily in males), systemic calcification, increased severity of nephropathy and increased severity of liver and thyroid effects
were also observed. The HDT was considered
excessive in males.

Increased incidence of thyroid follicular cell adenoma in males (control to high dose, 2%, 0%, 0%, 6% and 27%) and females (0%, 0%, 0%, 2% and 4%). Significantly increased trend in both sexes; pair wise incidence in males at high dose. Follicular cell carcinomas also observed in high dose males at high dose (11% vs. 0% all other doses; significant trend and pair wise comparison). Combined incidence significantly increased at high dose (2%, 0%, 0%, 6% and 32%) with positive increasing
trend.

870.4300 Combined chronic toxicity/carcinogen icity (rat) 00017868 (1972)

0, 10, 40, 160 or 640 ppm (estimated at 0, 0.370, 1.54, 5.75 or 24.3 mg/kg/day, males and 0, 0.399, 1.62, 7.18 or 28.7 mg/kg/day, females)

Unacceptable/guideline (not upgradable) NOAEL = 5.75 mg/kg/day LOAEL = 24.3 mg/kg/day, based on decreased body weight/weight gain in males and females, increased thyroid epithelial cell columnar height, colloidal substance and hypertrophy in males and decreased spermatogenesis at termination in males. However, it was noted that testicular atrophy that was seen in some animals was not correlated with microscopic
lesions to the testes.

No evidence of carcinogenicity was observed but the overall number of surviving animals in the study was low.Page 48 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

Gene
Mutation

870.5100 Ames Assay ( S. typhimurium and E.
coli reverse gene mutation) 41608910 Acceptable/guideline 39.1 to 312.5 μg/plate without S9; 39.1 to 5000 μg/plate with S9 Not mutagenic with or without S9 activation in S. typhimurium

Gene
Mutation

870.5100 Ames Assay ( S. Typhimurium preincubation

reverse gene mutation) Published study (Zeiger et al. 1992, not submitted to Agency) Acceptable/nonguideline 0 to 10,000 μg/plate with
or without rat or hamster
liver S9. Tech., 95.1% Weak equivocal response: 2-fold increases in
revertant colonies of strains TA98 and TA100

at ≥ 3333.0μg/plate (precipitating concentration) with S9 and negative results in second assay. Negative response without S9.

Mammalian
Cell In Vitro Cytogenetics

870.5375 In Vitro
Mammalian Cell Cytogenetic Assay
in Chinese Hamster Ovary (CHO Cells) 40980101 (1988)

Acceptable/guideline

0 to 400 μg/ml culture
medium without rat liver S9 and 0 to 1000 μg/mL
with S9 Tech., 95% a.i. Negative for structural chromosomal aberrations. Mitotic delay increased at 100 μg/ml without S9 and 335 μg/mL with S9. Cytotoxicity/compound insolubility observed at 400 μg/mL without S9 and 750 μg/ml with S9.

Mammalian
Cell In Vivo Cytogenetics

870.5385 In Vivo Mouse

Bone Marrow
Micronucleus Assay Published study (Barale, 1993, not submitted to Agency) Acceptable/nonguideline 1 mg/kg body weight, single gavage dose Tech., 95% a.i. Borderline significant increase in polyploidy and hyperploidy. No increase in structural
chromosomal aberrations.

Unscheduled

DNA synthesis

870.5550 In Vitro
Unscheduled DNA Synthesis Assay in Primary Rat Hepatocytes 40095503 (1981)

Acceptable/guideline

0 to 1000 μg/mL culture
medium tech., 99.8% a.i. Negative for UDS induction at all doses tested. Cytotoxic at 1000 μg/mL.

Other Effects (no guideline number) In Vitro Cell
Transformation Assay in BALB/c
3T3 Cells Published report (Perocco

et al. , 1997; not submitted to the Agency)

Acceptable/nonguideline

0 to 200 μg/mL culture medium with rat liver S9; 0 to 25 μg/mL without S9

Tech., 99.5% a.i. Significant and reproducible increase in morphologically transformed foci at 25 μg/mL
without S9 and ≥ 20 μg/ml with S9. Cytotoxicity observed at ≥ 25 μg/mL (pronounced at ≥ 50 μg/mL) without S9; only weak cytotoxicity with S9 (most pronounced at 100-200 μg/mL).Page 49 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.6200a Acute neurotoxicity screening battery (Crl:CD(SD) rat) 48729901 (2005) Acceptable/guideline Initial study 0, 500, 1000 or 2000 mg/kg (gavage) Extension study 0, 50, 125, 500 or 2000 mg/kg (gavage) NOAEL = not established (<50 mg/kg/day) LOAEL = 50 mg/kg/day (lowest dose tested) based on decreased landing foot splay in males and females on the day of dosing at all doses
tested.

870.6200b Subchronic neurotoxicity screening battery (Crl:CD(SD) rat) 48729902 (2005) Acceptable/guideline 0, 100, 500 or 2500 ppm Males 0, 6.2, 30.3 or 149.6 mg/kg/day; Females 0, 6.8, 34.9 or 166.3 mg/kg/day Tech., 99.7% a.i. NOAEL = 30.3 mg/kg/day LOAEL = 149.6 mg/kg/day based on decreased body weight/weight gain and decreased food consumption in females and increased liver and thyroid weights (not examined microscopically).Page 50 of 62 Table 3a.2. Subchronic, Chronic and Other T oxicity Profile for Thiophanate-methyl

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.7485 Metabolism and pharmacokinetics (rat) 42474802, 42601601 (1992)

Acceptable/guideline

low oral radiolabeled 14 mg/kg; repeated oral unlabeled 14 mg/kg for 14 days, followed by single radiolabeled; high oral radiolabeled 170 mg/kg

Tech., 97.3%-98.5% radiochemical purity 14 Cthiophanate-methyl Thiophanate-methyl was rapidly absorbed,
metabolized and excreted at all dose levels (>90% within 24 hrs). Radioactivity did not accumulate in tissues (highest concentrations were in thyroid, 0.04-2.49 μg/g; liver, 0.17-2.15 μg/g; kidney 0.04-0.51 μg/g). Plasma half life for low, high and repeated doses was 2.8, 2.2 and 7.8 hrs, males and 2.5, 1.6 and 4.0 hrs,
females. T
max was achieved at 1-2, 2-3 and 4-7 hrs at single low, repeated low and single high doses, respectively. The primary route of excretion was urinary following a single low oral dose (70-72% of administered radioactivity) but was fecal after repeated low (48-49%) or single high (67-70%) doses.
Excretion in CO 2 was negligible. Metabolite profiles were qualitatively similar for all groups. Twelve identified and 4 unknown urinary metabolites were identified, including methyl 2-benzimidazolylcarbamate (MBC, 0.2 to 2.2% of recovered radioactivity) and other sulfate-conjugated and/or hydroxylated derivatives of the parent compound. The major urinary metabolite was 5-hydroxy(2- methoxycarbonylamino) benzimidazolyl sulfate (14-42%). Seven identified and 2 unknown fecal metabolites were identified; the major fecal metabolite was dimethyl[1,2-(4- hydroxyphenylene)]bis (iminocarbonothioyl)bis (carbamate) (3.5- 11%). MBC was also identified in feces (0.5- 2.7%). After a single low dose the parent compound was almost completely metabolized (1% of dose excreted), but it was the major excreted compound in f eces of the repeated low dose (21-24%) and single high dose (52-56%) groups. No significant differences in metabolism were reported between males and
females.Page 51 of 62 Table A.2.3: Special thyr oid and liver mechanistic st udies, supplement to chronic fe eding/oncogenicity study in rats (MRID 42896601b; 1996-Acceptable/Non-guideline) Guideline Purpose of study Doses Results None (1) Effect of short-term dietary administration of TM on liver and thyroid weights; circulating
T3/T4 and TSH and
serum cholesterol in
male F344 rats 0 or 6000 ppm for 2 or 8 days Tech., 96.55% a.i. (all experiments in this study)

Positive control groups: 500 ppm phenobarbital (liver enlargement) and 1000 ppm propylthiourea (PTU; antithyroid activity) TM caused liver and thyroid enlargement; increased serum cholesterol and TSH; decreased T3 and T4 (decreases marginal at day 8).

Phenobarbital (PB) caused liver enlargement and increased T3, T4, TSH and cholesterol at day 8. PTU caused thyroid and liver enlargement; increased TSH and cholesterol; decreased T3 and T4 (slight). (2) Reversibility of thyroid enlargement following termination of short-term dietary
administration of TM in
female F344 rats 0 or 6000 ppm for 8 days; half sacrificed on day 8 and half given basal diet for 8 additional days

Positive (liver)/negative (thyroid) control group: 500 ppm Phenobarbital Withdrawal of TM after 8 days’ treatment caused reversal of the thyroid enlargement.

Treatment with PB for 8 days’ and subsequent withdrawal and recovery had no significant effect on thyroid weight.

(3) Effect of T4 supplementation on thyroid and liver weights, TSH and serumcholesterol during shortterm dietary
administration of TM in
male F344 rats 0 or 6000 ppm for 8 days;
half of animals also received daily injections of 30 μg/kg L-thyroxine Supplementation with T4 prevented thyroid enlargement and increased TSH but not liver enlargement or increased serum cholesterol.

(4) Effect of TM on hepatic microsomal enzyme activities and protein concentration following short-term
administration of TM to male F344 rats (livers
collected from animals of study 1) 0 or 6000 ppm for 8 days

Positive control: 500 ppm PB for 8 days TM caused an increase in cytochromes p-450and b5, and a pronounced increase in UDPglucuronosyltransferase. Microsomal protein
was also increased.

PB caused an increase in cytochromes p-450 and b5, NADPH-cytochrome c reductase, UDP-glucuronosyltransferase and microsomal protein. (5) Effect of TM on porcine microsomal thyroid peroxidase activity 10 -3 to 10 -4 M, Guaiacol
method

Positive control: 10 -4 to
10 -6 PTU The ED 50 (effective dose to achieve 50% inhibition of thyroid peroxidase) for TM was 6

x 10 -4 M and no inhibition was reported at 8 x

10 -5 M (about 30-fold greater than PTU).

The ED 50 for PTU was 2 x 10 -5 M and no inhibition was reported at 4 x 10 -7 M.Page 52 of 62 Table A.2.3: Special thyr oid and liver mechanistic st udies, supplement to chronic fe eding/oncogenicity study in rats (MRID 42896601b; 1996-Acceptable/Non-guideline) Guideline Purpose of study Doses Results (6) Effect of TM on hepatocyte proliferation as measured by PCNA
immunohistochemical staining following
treatment with TM in
male F344 rats and ICR
mice 0 or 6000 ppm for 2 or 8 days

Positive control: 500 ppm
Phenobarbital In mice, TM caused a sustained increase in PCNA staining and liver enlargement after 2 and 8 days’ treatment. In rats, PCNA staining was increased at day 2 but not day 8; liver weights were increased at both times.

In mice, PB caused increased PCNA staining at days 2 and 8 but less pronounced at day 8 than day 2. In rats, PCNA staining was increased at day 2 but not day 8. Liver weights were increased at both times.Page 53 of 62 Attachment 3b. Summary of Acute, Subc hronic and Chronic Toxicity Profile, Toxicological Doses for Carbendazim for Use in Human Health Risk Assessments

Table 3a.1. Acute Toxicity of Ca rbendazim (purity as noted)

Guideline

No. Study Type % a.i. MRID Results Toxicity Category

870.1100 Acute Oral, Rat 98

00154508 LD 50 >10,000 mg/kg IV

870.1200 Acute Dermal, Rabbits 75 00154514,
00154515 LD 50 >2,000 mg/kg III

870.1300 Acute Inhalation, Rat 75 00154512,
00154513 LC 50 >5 mg/L III

870.2400 Primary Eye Irritation,
Rabbit >98
00154518 minimal to no
irritation III

870.2500 Primary Skin Irritation,
Rabbit 75
00154516 slight irritation at 24 hr, normal by 72 hr IV

870.2600 Dermal Sensitization, Guinea Pig 98
00154531 not a dermal
sensitizer N/A

870.6100a Delayed neurotoxicity,
hen Not given 00154520 NOAEL = 2500 mg/kg N/A

N/A Not applicable

Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3150 90-Day oral toxicity (dog) 00099130 (1970) Unacceptable/guideline 0, 100, 500 or 1500/2500 ppm in diet M: 0, 2.7, 14.4 or 40.7 mg/kg/day F: 0, 2.7, 11.3 or 35 mg/kg/day NOAEL = 11.3 mg/kg/day (F); 14.4 mg/kg/day (M) LOAEL = 35 mg/kg/day (F), 40.7 mg/kg/day (M), based on histopathology changes in liver (1/4 males and 1/4 females) and testes (1/4 males) and increased alkaline phosphatase,
cholesterol and SGPT. Liver effects included hepatic cirrhosis (hepatic cell necrosis, tubular collapse, and increased fibrous connective tissue around triads). Decreased testes weight in 3/4 males in the high dose.

Note: The HDT group was gradually given increasing amounts of MBC using the following schedule: 500 ppm (3 days); 1000 ppm (2 days); 1500 ppm (2 days); 2500 ppm
for a short time before the dose was lowered to 1500 ppm (week 3) due to decreased food consumption and weight loss.Page 54 of 62 Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3200 28-Day dermal toxicity (rat) 47341601 (2007) Acceptable/guideline 0, 20, 120, 480 or 720 mg/kg/day Systemic toxicity NOAEL = 20 mg/kg/day Systemic toxicity LOAEL = 120 mg/kg/day, based on seminiferous tubule degeneration and hypospermia. A BMDL 10 of 68 mg/kg/day
was determined.
Dermal irritation NOAEL ≥ 720 mg/kg/day Dermal irritation LOAEL > 720 mg/kg/day 870.3465 5-day inhalation toxicity (rat) 45849301 (2003) Acceptable/nonguideline

0, 0.17, 0.023 or 0.022 mg/L (4 hrs/day, 5 days)

Second exposure group, 0, 0.058 or 0.178 mg/L (4 hr/day, 5 days)

97% carbendazim NOAEL = 0.178 mg/L LOAEL = not determined (>0.178 mg/L)

870.3465 90-day inhalation toxicity (rat) 40399501 (1987) Acceptable/guideline

0, 0.01, 0.05 or 0.20 mg/L (4 hr/day, 5 days/week for 90 days)

95% benomyl (benomyl rapidly metabolizes to
carbendazim in vivo ) NOAEL = 0.01 mg/L LOAEL = 0.05 mg/L, based on olfactory degeneration in the nasal cavity in males.

At 0.20 mg/L, olfactory degeneration in females and decreased body weight and weight gain in males were also observed.

870.3700a Prenatal developmental in (rat), oral 40438001 (1987) Acceptable/guideline 0, 5, 10, 20 or 90 mg/kg/day (GD 7-16)
98.8% carbendazim Maternal NOAEL= 20 mg/kg/day, LOAEL = 90 mg/kg/day, based on increased absolute liver weight at 90 mg/kg/day

Developmental NOAEL = 10 mg/kg/day LOAEL = 20 mg/kg/day, based on decreased fetal body weight and increases in skeletal
variations and a threshold for malformations at 20 mg/kg/day. At 90 mg/kg/day, increased malformations of the head, eyes, paws and
skeleton were also seen.

870.3700b Prenatal developmental in (rabbit) 00154466 (1985) Acceptable/guideline 0, 10, 20 or 125 mg/kg/day GD 7-19
98.7% carbendazim Maternal NOAEL = 20 mg/kg/day LOAEL = 125 mg/kg/day based on increased abortions and decreased maternal body weight. Developmental NOAEL = 10 mg/kg/day LOAEL = 20 mg/kg/day based on decreased implantations and litter size, and increased resorptions. Malformations (fused ribs, malformed cervical vertebrae) were noted at 125 mg/kg/day. Deficiencies: Terminal maternal body weights were not corrected by using empty uterine weight instead of gravid weights.Page 55 of 62 Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3800 Reproduction and fertility effects (rat) 00088333 (1972) Unacceptable/guideline (not upgradable) 0, 100, 500, 5000 or 2500/10,000 ppm in diet 0, 5, 25, 250 or 125/500 mg/kg/day
50 or 70% carbendazim NOAEL = 25 mg/kg/day LOAEL = 250 mg/kg/day based on decreased pup weight at weaning.

Deficiencies: Litter (or fetal) weights were not measured at birth, theref ore it is impossible to attribute weight decrease in 5000 and 2500/10000 ppm groups to prenatal or lactation period. Only 16 dams (20 dams for 5000 ppm), resulting in 10-16 litters per group were available, rather than the 20 litters recommended in the guid eline. There was no special attention for the testes, a known target organ, including organ weights measurements. Note: 2500 ppm group increased to 7,500 ppm at week 18 and to 10,000 ppm at week 20 to end of study. nonguideline Single dose study (rat), gavage Published study Acceptable/nonguideline
Nakai et al. (1992) 0, 50, 100, 200, 400 or 800 mg/kg NOAEL = not determined LOAEL = 50 mg/kg (lowest dose tested), based on premature release of immature germ cells two days post-exposure, and atrophy of a few seminiferous tubules and significant decrease inseminiferous tubule diameter 70 days’ postexposure. 870.4100a Chronic toxicity (species) See 870.4300

870.4100b Chronic toxicity (beagle dog) – two years, diet 00088333 (1972) Acceptable/guideline 0, 100, 500 and 1500/2500 ppm 0, 2.5, 12.5, or 37.5/62.5 mg/kg/day (doses adjusted for purity of a.i.)
53% a.i. carbendazim NOAEL = 2.5 mg/kg/day LOAEL = 12.5 mg/kg/day, based on swollen, vacuolated hepatic cells, hepatic cirrhosis and chronic hepatitis and biochemical alterations indicative of liver damage (i.e., increased cholesterol, total protein, SGPT and alkaline phosphatase levels, and decreased A/G ratio). At 37.5/62.5 mg/kg/day, anorexia, distended abdomens and poor nutritional condition were reported. 870.4100b Chronic toxicity, 1 year (beagle dog),
diet 00164304 (1986)

Acceptable/guideline

0, 100, 200, or 500 ppm in
diet F:0, 2.93, 6.43 or 16.54 mg/kg M: 0, 3.2, 7.19, 17.07
98.8% carbendazim NOAEL = 6.43 mg/kg/day (200 ppm) LOAEL: 16.54 mg/kg/day (500 ppm), based on possible transient increase in cholesterol (males and females) consistent with previous dog feeding studies.Page 56 of 62 Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4200b Carcinogenicity (mouse), oral 00154676, 0096513 (1982) Acceptable/guideline 0, 500, 1500 or 7500 (females) or 7500/3750 (males) ppm in diet 0, 75, 225, 1125 (females) or 1125/563 (males)
99.3% a.i. carbendazim NOAEL (non-cancer syst emic) = 75 mg/kg/day LOAEL (non-cancer systemic) = 225mg/kg/day, based on liver toxicity (hepatocellular necrosis and swelling), body weight decrease and lymphoid depletion. In both sexes, there was an increased incidence of liver tumors. In males, hepatocellular carcinomas were noted at 225 mg/kg/day, while
females exhibited carcinomas and adenomas at
all dose levels. Note: The 7500 ppm was reduced to 3750 ppm
at 66 weeks in males due to increased mortality. 870.4200b Carcinogenicity (mouse), oral 00154679 (1982) Unacceptable/guideline 0, 50, 150, 300 or 1000/5000 ppm (diet) 0; 5.8-7.1; 17.1 -21.2;
34.4 - 41.9 or 522 – 648 mg/kg/day
99% a.i. carbendazim NOAEL (non-cancer syst emic) = 34.4 - 41.9 mg/kg/day LOAEL (non-cancer systemic) = 522 – 648 mg/kg/day, based on increases the incidences of hepatic cell hypertrophy, clear cell foci and hepatocellular necrosis.
No increased incidence of carcinogenicity was
noted. Note: The 1000 ppm dose was increased to 2000 ppm after 4 weeks and to 5000 ppm after
an additional 4 weeks. Deficiencies: incomplete examination of most recommended tissues, blood and urine were not collected for analysis. 870.4200b Carcinogenicity (mouse), oral 00153420 (1976) Unacceptable/guideline 0, 150, 300 or 5000 ppm (diet) 0, 22.5, 45 or 750 mg/kg/day
99% a.i. carbendazim NOAEL = 45 mg/kg/day LOAEL = 750 mg/kg/day, based on hepatic
alterations which included increased relative liver weights in both sexes, increased number
of foci of cellular alterations in the liver in females, neoplastic nodules in females and hepatoblastomas in males Deficiencies: Brief methods, there were no historical data or microscopic or gross pathology reports for individual animals, and
there was no assurance that the diets were analyzed for compound homogeneity and stability. In addition, there were no hematology or clinical chemistry analysis, nor urinalysis. Only organs or lesions suspected of being tumors and livers (2 sections) were examined histologically.Page 57 of 62 Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4300 (870.4100a
and 870.4200a) Chronic oral toxicity/carcinogen icity (rat) 00088333 (1972) and 00068982 (1978) Acceptable/guideline 0, 100, 500, 5000 or 2500/10000 (8557) ppm 0, 5, 25, 250 or 125/500 (430) mg/kg/day
53% a.i. carbendazim NOAEL = 25 mg/kg/day LOAEL = 250 mg/kg/day, based on statistically significant decreases in red blood cell parameters (hematocrit, hemoglobin an red blood cells) in females and histological lesions in the liver (cholangiohepatitis and pericholangitis) in ma les and females. No evidence of carcinogenicity. Note: Dietary levels in 2,500 ppm were increased to 7,500 ppm at 18 weeks and to10,000 ppm from weeks 20-104 for a timeweighted average of approximately 8557 ppm (430 mg/kg/day). Deficiencies: Only 36 rats/sex/dose tested (only 20 rats/sex were in 250 mg/kg/day dose group). Lack of complete clinical chemistry data and histopathology examination. At 24 months, only liver evaluated in 5 and 25 mg/kg/day groups and only liver, kidney and testes evaluated in 250 mg/kg/day group.

Gene
Mutation

870.5265 Ames assay, S. typhimurium
bacterial reverse gene mutation Horst and Krahn (1980) Acceptable/guideline Up to 10,000 μg/plate Positive: TA1537, TA98: Doses: 5000 and 10,000 μg/plate with S9; Negative TA1535, TA1538, TA100 at 100-10,000 μg/plate -/+S9 and all nonactivated doses with TA1537, TA98.

Gene
Mutation

870.5265 Ames assay, S. typhimurium
bacterial reverse gene mutation 00154668 (1983) Acceptable/guideline 100-5,000 μg/plate Not mutagenic with or without S-9 activation in strains TA-1535, TA-97, TA-100, or TA-98

Gene
Mutation

870.5265 Ames assay, S. typhimurium
bacterial reverse gene mutation 00154669 (1983, 1986) Acceptable/guideline 100-5000 μg/plate Not mutagenic with or without S-9 activation in strains TA-1535, TA-97, TA-100, or TA-98

Gene
Mutation

870.5265 Ames assay, S. typhimurium
bacterial reverse gene mutation 00154753 (1983) Acceptable/guideline 100-10,000 μg/plate Not mutagenic with or without S-9 activation in strains TA-1535, TA-1537, TA-97, TA-100, or

TA-98

Gene
Mutation

870.5265 Ames assay, S. typhimurium and E.
coli bacterial

reverse gene mutation 43205504 (1992) Acceptable/guideline 5000 μg/plate Not mutagenic with or without S-9 activation in strains TA-1535, TA-1537, TA-100, or TA-98; Negative for E. coli WP2 uvrA +/-S9

Gene
Mutation

870.5265 S. typhimurium
host mediated assay (mouse) 00154670 (1977) Acceptable/guideline 500 or 2000 mg/kg once daily for 2 days by gavage Negative in ICR male mice administered 500 or 2000 mg/kg once daily for 2 days by oral gavage using strain S. typhimurium G46 (his -) as the indicator organism.Page 58 of 62 Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

Gene
Mutation

870.5265 Ames assay, S. typhimurium
bacterial reverse gene mutation 00154670 (1977) Acceptable/guideline

10-3000 μg/plate without S9; 10-1000 μg/plate with S9; HID: 1000 μg/plate without S9; 3000 μg/plate
with S9. Negative TA1535, TA1537, TA1538, TA98, TA100; E. coli WP2 hcr +/-S9

Gene
Mutation

870.5300 CHO/HGPRT forward gene mutation assay 00154671 (1980) Acceptable/guideline

3-628 μM (120 μg/mL) without S9; 3-654 μM (125 μg/mL)
with S9
100% a.i. Negative: Dose Range: 3-628 μM without S9 HID = 628 μM ( 120 μg/mL) without S9; Dose range with S9: 3-654 μM with S9 HID = 654 μM (125 μg/mL) with S9; ppt at ≥ 262 μM ( 50 μg/mL)+/-S9.

Gene
Mutation

870.5300 Mouse lymphoma L5178y TK +/-

Forward Gene Mutation Assay 00154673 (1980)

Acceptable/guideline

5-50 μg/ml without S9; 2-25 μg/ml with S9
98% a.i. Positive: (LED:50 μg/ml without S9); dose-dependent increases in mutation frequency over 8 concentrations of 12-25 μg/ml with S9. The response peaked at 25 μg/ml with S9, with a 7-fold increase in mutation frequency and 10% total growth. Colony sizing not performed. MBC was weakly mutagenic and two identified contaminants may be at least partially responsible for the mutagenic activity.

Gene
Mutation

870.5300 Mouse lymphoma

TK +/- assay Forward
Gene Mutation Assay 00159370 (1983) Acceptable/guideline

50-250 μM (about 10-50 μg/mL) without S9 25-250 μM (about 5-25 μg/mL) with S9 Negative at 50-250 μM (10-50 μg/mL) without S9. Positive at 75, 87.5, 100, 112.5, 125, 150, 200 and 250 μM with S9 but additional information sent by the registrant indicated that the mutagenicity was due to contaminants not

to MBC.

Cytogenetics

870.5375 CHO chromosomal aberrations study 43205505 (1990) Acceptable/guideline 38-300 μg/mL Negative with and without S9 activation up to a ppt and cytotoxic dose ( ≥ 300 μg/mL).

Mammalian
bone

marrow chromosoma
l aberrations

870.5385 In vivo mouse bone

marrow micronucleus 41051510 (1976) Acceptable/guideline 500 mg/kg (ip) or 50, 100, 500 & 100 mg/kg/day once daily for 2 days by oral gavage. Negative via ip; positive via oral gavage; doserelated increase in micronucleated polychromatic erythrocytes (MPEs) and micronucleated normochromatic erythrocytes (MNEs) at 100-1000 mg/kg-- no effect at 50 mg/kg but only sampled at 24 hours. MBC was a 2-5 times more potent inducer of micronuclei than benomyl.

DNA damage/repa ir, bacterial

870.5500 B. subtilis DNA damage/repair rec

assay 00154670 (1977) Acceptable/guideline Up to 1000 μg/plate Negative up to 1000 μg/plate without S9 B.
subtilis H17, M45Page 59 of 62 Table 3a.2. Subchronic, Chronic and Other Toxici ty Profile for Carbendazim (MBC)

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

Unscheduled

DNA synthesis

870.5550 In vitro
unscheduled DNA synthesis in mice 00154754 (1981) Acceptable/guideline 0.0125-12.5μg/mL (highest effective dose, HID) Not mutagenic for unscheduled DNA synthesis in primary mouse hepatocyte cultures.

Unscheduled

DNA synthesis

870.5550 In vitro
unscheduled DNA synthesis in rats 00154672 (1981) Acceptable/guideline 0.0125-12.5 μg/mL (highest effective dose, HID) Not mutagenic for unscheduled DNA synthesis in primary mouse hepatocyte cultures.

Unscheduled

DNA synthesis

870.5550 In vitro
Unscheduled DNA synthesis assay in
Human cells (explant from lung carcinomas) 43205506 (1992) Acceptable/guideline 0.3-300 μg/mL +/-S9 Negative up to a ppt ( ≥ 30 μg/mL) and cytotoxic doses ( ≥ 100 μg/mL).

In vitro
sister
chromatid exchange

870.5900 CHO cells in vitro
sister chromatid exchange 40801201 (1988) Acceptable/guideline 0.4 to 40 μg/mL without activation; 5 to 40 μg/mL with
activation
>99% a.i. Negative for SCEs in CHO cells at 0.4 to 40 μg/mL without activation, and at 5 to 40 μg/mL
with rat liver metabolic activation. MBC induced a high de gree of tetraploidy without activation (57-100%) at 1.33 to 40 μg/mL

Aneuploidy In vivo bone marrow erythrocyte
immunofluorescent
antikinetochore
micronucleus assay, BD-F1 mice 42911602 (1992) Acceptable/guideline 66, 1646 and 3293 mg/kg once by gavage Positive at 1646 & 3293 mg/kg in females (48 hrs.) and 3293 mg/kg in males (48 hrs); 83- 93% of micronuclei were kinetochore-positive at 3293 mg/kg; no effects at 1646 mg/kg (males) or 66 mg/kg (females).

870.7485 Metabolism and pharmacokinetics (rat) 41419201 (1990) Acceptable/guideline 50 or 1000 mg/kg single gavage dose; 50 mg/kg/day repeated
oral dose
94% a.i. carbendazim Carbendazim rapidly absorbed and extensively metabolized in CD/BR rats in all dose groups. Radioactivity excreted primarily via urine for low dose groups (54 to 66%) but at high dose only 41% was excreted in urine. Less than 1% retained in tissues (liver and carcass). Half life was about 12 hours, with 98% excreted by 72 hours postdosing. The primary routes of metabolism were oxidation of the phenyl ring, followed by conjugation to give sulfate and glucuronide conjugates of 5- hydroxycarbendazim and 5,6- dihydroxycarbendazim. Subsequent phenyl ring oxidation and N-oxidation at the imidazole nitrogen yielded 5,6-hydroxy-oxo-carbendazim N-oxide glucuronide conjugates, especially in
females.Page 60 of 62 Attachment 4. Thiophanate-Methyl In ternational Residue Limit Status

Thiophanate-methyl (102001; 11-4-2013)

Summary of US and International Tole rances and Maximum Residue Limits

Residue Definition:

US Canada Mexico 1 Codex 2,3,4

40 CFR 180.371 Plants: sum of thiophanate-methyl, dimethyl ((1,2-phenylene) bis (iminocarbonothioyl)) bis(carbamate), and its metabolite, methyl 2- benzimidazoyl carbamate (MBC),
calculated as the stoichiometric equivalent of thiophanate-methyl Carbendazim and Thiophanate-methylmethyl benzimidazol2-ylcarbamate (carbendazim) and1,2-di-(3-methoxycarbonyl-2- thioureido)benzene, expressed as
carbendazim Sum of benomyl, carbendazim,and thiophanatemethyl expressed as
carbendazim.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2,3,4

Almond 0.1 Almond, hulls 0.5 Apple 2.0 5 3 pome fruits 3,4 Apricot 15.0 5

Banana 2.0 Bean, dry, seed 0.2 1 beans 0.5 beans (dry) 4

Bean, snap, succulent 2.0 1 beans 0.5 common bean (pods
and/or other immature seeds)

4 0.02 garden pea,
shelled (succulent seeds)

4 Beet, sugar, roots 0.2 0.1 sugar beet 4 Cherry, sweet 20.0 5 cherries 10 cherries 4 Cherry, tart 20.0 5 cherries Grain, aspirated
fractions 12

Grape 5.0 5 3 3, 4
Onion, bulb 0.5 Onion, green 3.0

Peach 3.0 10

Peanut 0.1 0.1 4 Peanut, hay 5.0 3 peanut fodder 4 Pear 3.0 5 3 pome fruits 3,4Page 61 of 62 Summary of US and International Tole rances and Maximum Residue Limits

Residue Definition:

US Canada Mexico 1 Codex 2,3,4

Pecan 0.1
Pistachio 0.1

Plum 0.5 5

Potato 0.1 0.1 Soybean, hulls 1.5

Soybean, seed 0.2 1 beans 0.5 soya bean (dry) 4 Strawberry 7.0 5

Vegetable, cucurbit, group 9 1.0 0.5 cucumbers, melons. pumpkins, squash 0.5 squash

summer 4

Wheat, forage 1.1 Wheat, grain 0.1 0.05 3, 4 Wheat, hay 0.1 Wheat, straw 0.1 MRLs with NO US Equivalent

Blackberries 6 Boysenberries 6

Carrot roots 5
Citrus fruits 10

Mushrooms 5

Nectarines 10 Pineapples 1 Raspberries 6

Tomatoes 2.5
Berries and other small fruits (except grapes) 1 3, 4

Lettuce head 5 4 Peppers chili 2 4 Rye 0.1 3, 4

Completed: M. Ne gussie; 11/08/2013

1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = posth arvest treatment, such as treatment of stored grains. PoP = processed posthar vest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

3 Based on data for carbendazim other than thiophanate-methyl.Page 62 of 62 4 Based on data for thiophanate-methy l (c) Tolerances with regional registrations . A tolerance with a regional registration is established for residues of thiophanate-methyl, dimet hyl ((1,2-phenylene) bi s(iminocarbonothioyl)) bis(carbamate), including its metabolites and degradates, in or on the commodity in the following table. Compliance with the tolerance le vel specified in this paragraph is to be determined by measuring only the sum of thi ophanate-methyl, dimethyl ((1,2-phenylene) bis (iminocarbonothioyl)) bis(carbamate), and its me tabolite, methyl 2-benzimidazoyl carbamate (MBC), calculated as the stoichiometric equi valent of thiophanate-methyl, in or on the commodity.

Commodity Parts per million

Canola, seed 0.1