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 Pesticide Re-Evaluation Division (7508P) 

 Office of Pesticide Programs 

Attached is the Health Effects Division’s (HED) human health risk assessment scoping 

document for thiophanate-methyl and its metabolite, carbendazim, to support registration review. 
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Executive Summary 

The Health Effects Division (HED) Thiophanate-Methyl/Carbendazim and the Antimicrobial 

Division (AD) Carbendazim Risk Assessment Teams have evaluated the database and the most 

recent human health risk assessments for the systemic benzimidazole fungicides, thiophanatemethyl (TM) and carbendazim (MBC). MBC is a pesticide active ingredient but is also a 

metabolite, environmental degradate and the pesticidally 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 for both active ingredients. The primary sources of information 

were recent human health risk assessments 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 characterization for TM and MBC (D340134, 2007), and 

HED’s revised residential exposure assessment for MBC in paint (D364554, 2009). Residue 

chemistry, dietary exposure and non-dietary exposure assessments, and toxicology evaluations 

were also considered. 

The use patterns for these compounds are extensive, 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, vegetables and field 

crops, commercial treatment of a variety of seeds including potato seed pieces and peanuts, 

greenhouses and nurseries (including bulb dip treatment). It is also registered for use on turf, 

which includes sod farms, golf courses, athletic and recreational fields, ornamental grasses for 

landscapes and interiorscapes. End-use products are formulated as liquids, granules (G), water 

dispersible granules (WDG), wettable powders (WP), water soluble bags (WSB) and dusts (for 

seed treatment). Products may be applied as a broadcast foliar or soil directed spray by ground, 

aerial, or hand held equipment, granular spreader, and commercial and on-farm seed treaters. 

The personal protective equipment (PPE) for applicators 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 complete for assessment of human health risk; 

however, additional toxicology data are required. Based on the potential for applicator 

inhalation exposure during spray application uses, a rat subchronic inhalation study is required. 

A developmental thyroid study is also required to assess potential 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 the rabbit, decreased food consumption was observed 

with dermal exposure. 
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Rat and rabbit developmental studies and a rat two-generation 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 animals: effects were 

reported in both generations but at a lower incidence in the F1 offspring. TM did not show 

evidence of neurotoxicity, and a developmental 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 aneugenicity, with a cancer potency factor (Q1*) 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 Protection Act (FQPA) Safety Factor was reduced to a 

3X due to a data gap for a developmental thyroid 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 susceptibity 

following in utero exposure to rat and rabbits and pre/post natal exposure to rats; 3) there was no 

concern for potential developmental neurotoxicity, and a developmental neurotoxicity study is 

not required; and 4) the point of departure used risk assessment would adequately address any 

potential for the concern for 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 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 effects that might occur during late gestational 

and early postnatal development and therefore will not have an impact on the point of departure 

or the endpoint of concern used for acute dietary risk assessment. 

HED has not revised the endpoints, doses, and safety factors for 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 findings from the new studies, HED recommends reevaluation of: 

(1) endpoints selected for risk assessment and (2) reconsideration of the FQPA safety factor. 

The residue chemistry database supporting the registered uses of TM is complete, and no new 

residue chemistry data are required. A revised dietary risk assessment will be conducted to 

include updated percent crop treated estimates, monitoring data if available, changes in 

toxicological endpoints, and revised estimated drinking water concentrations. The most recent 

drinking water assessments used modeling to estimate surface water and groundwater residues. 

The dietary exposure database is adequate to support the registration of TM. If the outstanding 

toxicity studies identify a more sensitive point of departure than any used in the most recent risk 

assessment, or if the points of departure are revised 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 the fungicide, benomyl. The structure of benomyl is similar to 

that of carbendazim. At one time, there were U.S. tolerances for benomyl, but these tolerances 
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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 tolerance 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 risks of concern. 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, and 

updated cancer and non-cancer exposure and risk assessments will be needed. Furthermore, a rat 

subchronic inhalation exposure study is required. Since inhalation risks were previously 

assessed using an endpoint and dose from an oral study, revised residential handler exposure 

assessments (non-cancer) will be required under registration review to support use on residential 

turf, incorporating any new inhalation data as well as the 2012 SOPs. 

An aggregate exposure assessment was performed for the 2005 TM RED document. This 

assessment 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-term and cancer risks for TM alone were not of 

concern. [HED notes that the proposed TM uses were not granted because they would have led 

to additional dietary exposure to MBC, for which 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 registration review that includes current use patterns 

and incorporates any changes in endpoint selection, safety factors, and updated dietary and 

residential exposure estimates. 

Occupational handler and post-application exposures were assessed in 2009 for proposed uses of 

TM on a variety of agricultural crops and non-crop land areas. The 2009 occupational 

assessment resulted in handler and post-application 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 additional data are not required. 

Carbendazim: MBC (methyl 1H-benzimidazol-2-ylcarbamate) is a systemic fungicide of the 

benzimadazole chemical class. Its pesticidal 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 formulated 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 coatings, sealants, stains, and textiles. Conventional use is for 
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seasonal suppression of fungus for ornamental trees, and the active is formulated as ready-to-use 

capsules applied via tree injection. The products registered for tree injection are intended for use 

by professional applicators only, including arborists. 

The toxicology database for MBC is incomplete at this time. Under the revised 40 CFR Part 158 

Guidelines (toxicology data requirements), an immunotoxicity study is required. An extended 

one-generation reproductive toxicity study is currently 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 susceptibility in the offspring, the occurrence of 

malformations in fetuses following in utero exposures, and the need for additional data to better 

characterize potential neurodevelopmental effects 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 evaluate immunotoxicity parameters; this study could 

therefore also address the immunotoxicity study requirement. 

The available toxicological data indicate the liver and testes are the major target organs for 

MBC-induced toxicity; the latter was observed 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 weight 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 exposure concentrations tested in a rat 5-day inhalation study on 

MBC. 

Increased quantitative and qualitative susceptibility was observed in developmental toxicity 

studies with MBC in the rat and rabbit. Although developmental effects on the rat nervous 

system were reported, neurotoxicity is not observed in adult animals. 

MBC was most recently classified as a Group C, or “possible 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 (Q1*) value. 

HED has previously recommended retaining the 10X FQPA factor 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 recent updated exposure assessment for MBC (D364554, 

2009) are considered appropriate based on the currently available data. 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 therefore no residue chemistry data requirements. 

However, a dietary risk assessment is required because residues in drinking water are possible as 

a result of degradation of TM in the environment, 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 identify risks of concern. However, during 

registration review, a new dietary risk assessment will be conducted incorporating the most 
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current pesticide residue monitoring data, drinking water and dietary models, along with any 

changes in endpoints, doses for risk assessment and safety factors. 

Residential handler and post-application 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 paints and a revised dermal dose 

of 20 mg/kg/day. All paint handler scenarios resulted in MOEs (ranging from 34 to 87) below 

the LOC of 1000. A paint bioavailability study with MBC was submitted to refine the exposure 

estimates for residential painters, and the results of the study will be incorporated into a revised 

handler assessment for painters during registration review. Post-application 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 assessed quantitatively in past risk assessments; 

however exposure is anticipated to be negligible. The tree injection product is formulated as 

ready-to-use, packaged in capsules which are inserted into a feeder tube which is dispensed into 

the tree. Therefore, the handler has no direct contact with MBC. No additional review of this 

scenario is needed during registration review. Post-application inhalation and 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 the turf application rate in conjunction with 

the RED, and on the results of the chemical-specific turf transferable residue (TTR) study; 

during registration review, HED does not anticipate assessing post-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 Procedures (SOPs) for Residential Pesticide 

Exposure Assessment. Therefore, during registration review, AD will conduct a new residential 

handler exposure assessment that will incorporate 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 conducting an exposure assessment for residential 

dermal and incidental oral post-application exposure for plastic toys and textiles. 

For occupational and residential exposure, paint product use information is required (i.e., pouring 

liquid/solid material preservative formulation) to refine the daily amount handled; in addition, a 

description of the pouring operations should be submitted. Furthermore, for purposes of refining 

residential post-application exposure, chemical-specific indoor surface residue dissipation data 

and a description of human activity practices will be required 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 conduct 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 toxicology and residential exposure data, dose/endpoint 

selection and safety factors, as well as updated dietary exposure estimates. 
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Introduction 

This document summarizes HED’s and AD’s evaluation of the data available for assessing 

human health risk from exposure to TM and MBC, as well as any data needed to support 

registration review. HED reviewed 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 benzimidazole 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 treated 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 considered the most recent human health risk 

assessments, HED and OPPIN/PRISM databases, open literature (via Google Scholar) and the 

latest Agency science policies and risk assessment methodologies. HED and AD have evaluated 

this information for TM and MBC in association with the updates to their toxicity, exposure, and 

usage databases to determine if sufficient data are available and if further updates are needed to 

support registration review. 

There are food and residential uses for TM. Products registered for use include dust (D), 

granular (G), wettable powder (WP), water-dispersible granular (WDG), flowable concentrate 

(FIC) and emulsifiable concentrate (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 residues in food commodities due to applications of 

TM. It is currently registered for antimicrobial use patterns that may 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 include non-food adhesives, caulks, 

concrete, grouts, inks, paints, paper, plastic, roof coatings, sealants, stains and textiles. 

THIOPHANATE-METHYL 

Hazard Identification/Toxicology 

A summary of the available toxicity 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. The 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 inhalation exposure from numerous uses and portal 

of entry effects observed in a non-guideline inhalation study. A developmental thyroid study is 

also required to evaluate potential thyroid toxicity during early development based on thyroid 

effects in adult animals and residual uncertainties for the relative sensitivity of the young. 
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However, an immunotoxicity study is not required 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 compound was identified with a single high dose or 

repeated low doses, primarily in the feces. Radioactivity was widely distributed but there was 

not significant accumulation, with the highest levels 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 rat toxicity studies. 

The liver is the major target organ for multiple species following oral exposure to TM. 

Hepatocellular hypertrophy and increased liver weight were observed in all species tested, along 

with effects on clinical chemistry parameters such as cholesterol, serum albumin, alkaline 

phosphatase and circulating thyroid 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 circulating thyroid hormones. 

In addition to liver and thyroid effects, TM also caused mild red blood cell effects at the higher 

dose levels in rats, dogs and mice following subchronic or chronic exposure. In rats, TM caused 

toxicity to the kidney as indicated by increased urinary protein (in males), lipofuscin 

pigmentation, and increased severity of nephropathy following chronic administration. An 

increase in systemic calcification was observed in males and to a lesser extent in females and 

was probably secondary to hyperparathyroidism. 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 other, testicular hyperplasia). Male rats appeared to be more 

sensitive than females overall based on greater severity of effects and 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 available on its potential to inhibit cholinesterase 

(ChE). As a class of compounds, thiocarbamates 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 toxicity/ 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 months. RBC and brain ChE activities were not 

evaluated, and ChE was not measured in the subchronic or chronic dog studies. 
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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 developmental 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 were observed at the LOAEL and 

decreased body weights at the HDT. In addition to testing a formulation 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 limited evaluation of thyroid effects 

was performed on parental (P0) and first generation (F1) animals at 8 weeks of age in the twogeneration reproductive toxicity study, along with assessment of several structural and functional 

developmental tests during lactation. Offspring had thyroid effects at comparable to parental 

animals but at lower incidence. There were no treatment-related effects on the developmental 

tests. The data did not indicate increased developmental susceptibility; however, an examination 

of offspring thyroid function during late gestation/lactation and/or early post-weaning times was 

not performed. 

TM did not show evidence of neurotoxicity. Transient tremors following capsule dosing were 

observed in the first weeks of the chronic dog study, 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 subchronic neurotoxicity study, and did not show a 

dose-response. These findings were therefore not 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 Protection Act (FQPA) Safety Factor was reduced to a 

3X due to a data gap for a developmental thyroid 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 and pre/post natal exposure to rats; 

3) there was no concern for potential developmental neurotoxicity, and a developmental 

neurotoxicity study is not required; and 4) the point of departure used risk assessment would 

adequately address any potential for the concern for 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 would not be expected to result from a single dose and the 

additional data would not affect the 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 postnatal development and therefore will not have 

an impact on the point of departure or the endpoint 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 increased 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-glucuronosyltransferase (UDPGT) activity, the data to 

support a threshold antithyroid mode of action for thyroid tumors was considered inconclusive. 

The available genotoxicity data indicate aneugenic 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, Q1*, 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 appropriate single-dose endpoint was not identified 

for the general population. Non-dietary residential endpoints are required because there are turf 

uses of TM that may result in short- and intermediate-term handler or post-application dermal 

and inhalation exposure, as well as incidental oral exposure. HED will reevaluate endpoints and 

uncertainty factors (UFs) for risk assessment during registration review, taking into consideration 

the results of any new studies and current science policies at the time of the review. 

Conclusions for Hazard Identification/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 subchronic toxicity study in the rat (870.3465) is 

required to support registration review, based on the potential for significant inhalation exposure 

for occupational uses of TM and evidence for potential portal of entry effects. In addition, a 

developmental thyroid study is required to evaluate potential secondary effects of thyroid 

hormone alteration during late pre-natal and early post-natal development. An immunotoxicity 

study is not required, based on lack of evidence of potential immunotoxicity at relevant dose 

levels. 

During registration review, HED recommends reevaluation of the following points, which should 

take into consideration the results 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) reconsideration of safety/uncertainty factors, including the FQPA safety 

factor. 

Dietary Exposure 

The residue chemistry database is adequate to support current registration 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 and 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-MBC, and 5-OH-MBC-S. The degradates of 

concern in drinking water are TM and MBC only. 

In 2009, HED performed a human health risk assessment for proposed uses of TM on numerous 

commodities (D330467). Although there were no aggregate risk estimates of concern for TM 

alone, there were residential exposure 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 probabilistic dietary exposure 

analysis was performed for the population subgroup females 13-49 only, and was based on field 

trial and residue monitoring data [Pesticide Data Program (PDP) monitoring 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 analysis 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 field trials and PDP, percent crop treated and 

projected percent crop treated estimates, and modeled drinking water estimates. The resulting 

chronic dietary risk estimate for Children 1-2 years old, the most highly exposed population 

subgroup, was not of concern at 3.6% chronic Population 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 (EFED) 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 Concern 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 result, it’s likely that 

HED and EFED will determine that an updated drinking 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 registrations and tolerances. 

No new residue chemistry data are required. However, a new dietary risk assessment will be 

conducted during registration review to include updated percent crop treated estimates, residue 
Page 13 of 62

monitoring data if available, changes in toxicological endpoints, updated 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 residential use are formulated as 

liquids, granules (G), water dispersible granules (WDG), wettable powders (WP) and water 

soluble bags (WSP) and may be applied by a variety of hand held equipment and granular 

spreaders. 

The primary source of information used to evaluate residential handler exposure was the HED 

Human Health Risk Assessment for the 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 short-term residential non-cancer and cancer 

handler dermal and inhalation exposure resulting from use of hand held equipment (i.e., hoseend, back-pack, and manually pressurized handwand sprayers) for liquid formulations on 

ornamental plants (i.e. including backyard orchards) and push-type spreader for granular 

formulations on lawns. Furthermore, in order 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 ornamentals. 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 considered unlikely to be sold to the general public 

and was not evaluated. Since there are concerns that such label language is not legally 

enforceable (unless the active ingredient is considered to be a restricted use pesticide), HED 

typically assesses potential exposure to residential users in the event that 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 registration review. Shortterm risk estimates for residential handlers did not exceed HED’s level of concern (LOC = 

margins of exposure (MOEs) > 300) for any scenario. 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. Furthermore, in accordance with the Part 158 Data 

Requirements for conventional pesticide active ingredients a 28-day inhalation exposure study is 

now required. Since inhalation risks were assessed using the endpoint and dose from an oral 

study, a revised residential handler exposure assessment (non-cancer and cancer) will be required 

under registration review for all formulations of products used on residential 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 evaluate residential dermal post-application exposure 

and risk resulting from the use of TM on turf 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 residential turf exposure assessment (Revised TM 

Occupational and Residential Exposure Assessment and Recommendations for the Reregistration 

Eligibility Decision Document (RED), D279269, 2009) to reflect a reanalysis of the dermal and 

oral post-application exposure and risk resulting from use on turf. In accordance with the 

updated Part 158 data requirements (2007), a turf transferable residue (TTR) study for 

occupational (e.g., sod farms, golf courses, parks and recreational areas) or residential turf uses 

was submitted for TM (Dissipation of transferable turf residues of 3336WP 50 percent TM, 

MRID 45000701). HED averaged the daily predicted 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-application exposure and risk. All adult and children 

residential lawn and golf dermal scenarios resulted in risk estimates 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 risk 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 days 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 residential 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 Procedures (SOPs) for Residential Pesticide 

Exposure Assessment. Therefore, a revised residential post-application exposure and risk 

assessment (non-cancer and cancer) for turf will be required during registration review for all 

formulations of products used on commercial and residential treated turf. 

Spray Drift and Volatilization 

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may 

occur as a result of applications of TM. The Agency is in the process of evaluating these types 

of exposures and may, as appropriate, develop policies and procedures to identify the need for 

and, subsequently, the way to incorporate these post-application exposures into the Agency's risk 

assessments. The need for spray drift and volatilization 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. Therefore, the residential exposure 

database is adequate to support the registration review process for TM. 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. 
Page 15 of 62

Therefore, revised residential handler and post-application exposure and risk assessments (noncancer and cancer) will be required during registration review for all formulations of products 

used on commercially treated and residential turf. This assessment should incorporate, as 

necessary, the additional TM inhalation toxicology study, updated human exposure factors 

assumptions (e.g., body weight) and the 2012 SOPs for Residential Pesticide Exposure 

Assessments. 

Aggregate Risk Assessment 

In accordance with the FQPA requirements for food use chemicals, when there are potential 

residential exposures to a pesticide, 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 quantitative estimates of hazard (e.g., 

a no-observed-adverse-effect-level, NOAEL or PAD), or the risks themselves can be aggregated. 

When aggregating exposure and risk from various 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). The 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 source of exposure to TM that is expected to 

result in acute exposure. Therefore, the acute aggregate exposure and risk estimates are 

equivalent to the acute dietary exposure and risk estimate discussed above and were not of 

concern. The exposures resulting from short- and 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 estimates were conducted. Non-cancer chronic 

aggregate risk is equivalent to non-cancer dietary exposure from food and drinking water, which 

was not of concern for TM as discussed above. 

A cancer aggregate risk assessment was performed for the general U.S. population. Aggregate 

cancer risk is comprised of the risk from dietary sources (food and drinking water) and the risk 

from residential handler and post-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 may change the endpoints selected for risk 

assessment, and could impact the selection of safety 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, greenhouses 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 landscapes and interiorscapes. 

TM end-use products for occupational use are formulated as liquids, granules (G), water 

dispersible granules (WDG), wettable powders (WP), water soluble packets (WSP), and dust for 

seed treatment. Products may be applied as a broadcast foliar or soil directed spray by ground, 

aerial, by hand held equipment, and granular spreaders or commercial or on-farm seed treaters. 

The PPE for applicators and other handlers consists 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 apron when mixing and loading. 

The primary source of information used to evaluate occupational handler exposure, including 

commercial and on-farm seed treatment, was from the most recent occupational exposure 

assessment written for this chemical (D335120, 2009). However, this document did not include 

a revised commercial handler assessment for turf 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 surrogate 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 acres treated per day and body weight. For seed 

treatment uses, handler assessments were based 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 identified for non-cancer handlers mixing/loading wettable powder, dry 

flowable and liquid formulations for aerial, chemigation, ground boom and airblast applications 

for a variety of proposed uses, which weren’t registered 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 Pesticide Handler Unit Exposure Surrogate Reference 

Tablei

”; in addition, standard body weights for determining risk estimates have been updated. 

Furthermore, HED is in the process of revising seed treatment Policies 14 and 15 with updated 

inputs and assumptions from additional seed treatment studies and survey information. 

Therefore, an updated non-cancer and cancer occupational handler exposure assessment will be 

required for registered agricultural, seed treatment, and commercial turf (i.e. golf course 

maintenance) uses during registration review. 

 

 

i

 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf
Page 17 of 62

TM Occupational Post-application Exposure 

As indicated previously, a quantitative dermal post-application exposure assessment was most 

recently performed in 2009. The estimations of post-application exposures were based on the 

chemical specific dislodgeable foliar residue (DFR) 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 additional data are needed at this time. 

Non-cancer dermal post-application exposure estimates were assessed based on predicted DFR 

data on day 0 (day of application), and risks of concern were identified for certain activities in a 

number of crops. Cancer dermal post-application exposure was assessed based on average DFR 

data in the range of day 1 to day 14, since TM labels 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, since it was not a new use under consideration. 

A quantitative post-application inhalation exposure assessment was not performed for TM based 

on the Agency's current practices. However, there are potential sources of inhalation exposure to 

workers performing post-application activities in previously treated 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 issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, 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-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. 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 the Agricultural Re-entry Task Force (ARTF) 

databases, with data from new exposure monitoring studies. Therefore, updated non-cancer and 

cancer occupational post-application exposure assessments will be required for registered 

agricultural and commercial turf uses during registration review. 

Conclusions for Occupational Exposure

The occupational exposure database for TM is complete and no additional data are needed at this 

time. However, 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 Pesticide Handler Unit Exposure Surrogate Reference Tableii

, 

and updated body weight assumptions are typically used for determining risk estimates. 

Furthermore, HED is in the process of revising seed treatment Policies 14 and 15 with updated 

inputs and assumptions from additional seed treatment studies and survey information. 

 

ii Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf
Page 18 of 62

Therefore, updated non-cancer and cancer occupational handler exposure assessments will be 

required for agricultural, seed treatment, and commercial turf uses 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 occupational 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 addressing volatilization 

exposure, as well as the potential 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 are established as follows: “Tolerances are 

established for residues of TM, dimethyl((1,2-phenylene) bis (iminocarbono-thioyl)) bis 

(carbamate), including its metabolites and degradates, 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 (iminocarbono-thioyl)) bis 

(carbamate), and its metabolite, methyl 2-benzimidazoyl 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 are expressed in terms of the sum of benomyl, 

MBC, and TM, expressed as MBC, and are, therefore, 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 established 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. Although 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 the tolerances and tolerance definitions, and 

harmonize them with the Codex and Canadian MRLs and MRL definitions, when possible. The 

international residue limit status sheet can be found in Attachment 5. 

Data Requirements 

The following toxicology studies are required for TM: 

870.3465 Subchronic inhalation study in the rat. This study is required to assess occupational 

and residential handler inhalation exposure, based on high application rates and potential 

inhalation exposure during spray application uses, and evidence of portal of entry 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 perturbation of thyroid levels. 
Page 19 of 62

No new residue chemistry, residential or occupational 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 for 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 reproductive 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 during review of this study protocol that a cohort 

for immunotoxicity should be included which may 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. Distribution 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 oxidation 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 (Category III - IV) by all routes. It is minimally 

irritating to the eye (III), slightly irritating to the skin (IV), and is not a dermal 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 characterized, 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 cholesterol levels in plasma. Unlike TM, thyroid 

effects have not been reported. 

Testicular degeneration was observed 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 adverse 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 the rat following a 28-day dermal treatment at 

720 mg/kg/day, with a NOAEL of 20 mg/kg/day. Because of the large dose spacing, a 

benchmark dose, lower confidence limit 10% (BMDL10) 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, which 
Page 20 of 62

metabolizes in vivo to MBC; this factor was used to assess 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 and weight gain in males. No effects were 

reported in the rat following five days of exposure to MBC via nose-only inhalation exposure. 

Increased susceptibility of offspring is observed in developmental toxicity studies. In the rat, 

fetuses showed skeletal variations associated with delayed growth. At doses below maternally 

toxic levels, fetuses showed decreased body weight and an increase in skeletal variations 

(bipartite ossification, dumbbelled vertebral centra). Because some of the malformations 

reported at the high dose were seen at the developmental LOAEL and not in control or low dose 

animals, it was considered a possible threshold level for developmental malformations. At 

maternally toxic levels, dams showed decreased body weight gain and increased liver weight. 

Fetal effects included decreases in live fetuses, increased early and late resorptions and decreased 

fetal weight, along with an increase in fetuses/litters with malformations that included 

exencephaly and domed head, small or no eyes, clubbed paws, and various skeletal effects. It is 

also noted that benomyl, for which MBC is a major metabolite, also produced central nervous 

system (CNS) abnormalities in rat developmental studies. In the rabbit, increased resorptions, 

decreased implantations and reduced live litter sizes were observed at doses below maternally 

toxic levels. At maternally toxic levels, decreased maternal food consumption and weight loss 

during treatment were observed. Fetal effects included fused ribs and malformed cervical 

vertebrae, which may have been secondary to maternal 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 presence of hepatocellular adenoma and/or carcinoma 

in female CD-1 mice and aneugenic potential observed in genotoxicity studies. A cancer 

potency factor (Q1*) 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 recommends 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 additional 10x uncertainty factor (UF) for all endpoints due 

to the lack of data on developmental neurotoxicity 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 registration review, based on the findings 

and acceptability of this study. 
Page 21 of 62

Conclusions for Hazard Identification/Toxicology 

Based on the recently revised pesticide data requirements (40 CFR Part 158), an immunotoxicity 

study (870.7800) is required. An extended one generation reproductive toxicity study, which 

includes additional measures of neurobehavioral parameters, is being conducted and may address 

uncertainties regarding reproductive toxicity and developmental neurotoxicity. Additionally, the 

Agency requested that the study include a cohort evaluating immunotoxicity of MBC, which 

could be used to satisfy the immunotoxicity study requirement. 

During registration review, HED recommends reevaluation of the following points, taking into 

consideration the results of the additional studies received for MBC and ensuring consistency 

with science policies in effect at the time of review: (1) endpoints for risk assessment and (2) 

selection of the FQPA safety factor for relevant populations (i.e., infants and children). 

Dietary Exposure

MBC is not registered for use on food in the US; therefore, no tolerances are established for its 

residues. However, dietary exposure to carbendazim residues can result from use of TM in food 

crops or from contamination of drinking water sources from the use 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 were 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 oranges. 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 sources 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 concern. 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 whether or not it is appropriate to use water 

monitoring data for dietary exposure assessment. 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 water models will be used for this assessment. In 

addition, the most current version of the dietary model will be used, along with any potential 

changes in endpoints and doses for risk assessment 
Page 22 of 62

Residential Exposure 

MBC provides effective protection against decay fungi, and has antimicrobial (i.e., 

microbiocide) and conventional uses. The MBC antimicrobial registered uses are formulated as 

in-can ready to use and dry-film preservatives in adhesives (non-food), caulks, concrete, grouts, 

inks, paints, paper (non-food), plastic, 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 for use for tree injection are intended for use by 

professional applicators only, including arborists, so residential handler exposure is not expected 

for tree injection. MBC may be applied to ornamental trees in residential 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 sale. There is no residential post-application 

exposure expected for the tree injection use pattern. 

MBC Handler Exposure 

The primary source of information used to evaluate residential handler exposure and risk for use 

of MBC was the 2000 occupational and residential exposure assessment for MBC (D265419, 

2000) and the 2009 residential exposure assessment 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 study with MBC. Since the 2002 RED, the most 

recent residential risk assessment for MBC was conducted for the purpose of completing an 

aggregate exposure and risk assessment associated 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, low-pressure hand wand and airless sprayers. The 

short-term handler dermal exposure was recalculated 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 study had not yet been completed, HED concluded 

that an additional 10X FQPA factor should be retained as a database uncertainty factor (UFDB) 

for all residential scenarios. Therefore, the LOC for risk assessment continued to be MOEs 

<1000. All dermal handler risk scenarios resulted in MOEs well below 1000 (MOEs ranging 

from 34 to 87) and were of concern. Short-term handler inhalation exposure scenarios 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 contacted the registrant who indicated that they will 
Page 23 of 62

reduce the rate to 0.35% a.i. AD anticipates the need to reassess residential handler paint use 

scenarios during registration review to ensure application 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 product labels state that they are 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 labels is not considered enforceable, and HED 

assumes there is potential for homeowners to purchase and use these products. Currently, HED 

does not have unit exposure data to assess residential handler exposure associated with this use 

pattern. Furthermore, these products are formulated 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 considered 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 evaluate residential post-application exposure and risk 

for use of MBC was the 2000 occupational and residential exposure assessment for MBC 

(D265419, 2000) and the 2009 residential exposure assessment for use in paint (D364554, 2009). 

Paint Additive 

Post-application exposure (non-cancer and cancer) to MBC-treated paints, 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 vapors in a treated room; in addition 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 assessment of potential inhalation exposure was 

conducted by modeling the emission rate of the active ingredient from the product. The MultiChamber Concentration and Exposure Model (MCCEM) 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 adults were MOEs of 1.1 x 106

 and 4.6 

x 106

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

Based on the Agency’s current practices, a quantitative post-application 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 registration review. 
Page 24 of 62

Plastic Toys and Textiles 

Previous residential exposure assessments (D273465, 2001 and D364554, 2009) did not assess 

the new uses of plastic toys and textiles impregnated with MBC. Based on the use of MBC as a 

material preservative to treat textiles and plastics, there is potential for dermal and incidental oral 

exposure resulting from contact with treated clothing 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 the residential risks are not of concern using the 100% default 

transfer rate assumption, residential 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% transfer rate, an indoor surface 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 trees. However, the potential for post-application exposure is 

anticipated to be negligible due to the method of application, previously explained, the low 

application rate, and due to the tree tissue incorporation 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 required for MBC. During registration review, AD will 

conduct a new residential handler exposure assessment that will incorporate any new 

toxicological endpoints, and methods 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 data for applying paints and stains (see data 

requirements, below) as well as chemical specific product use information. AD also anticipates 

the need to conduct a residential dermal and incidental oral post-application exposure assessment 

for plastic toys and textiles. In order to support the uses of MBC in textiles (e.g. clothes) and 

plastics (e.g. toys), AD will require a chemical-specific 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, considering 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 with other metabolites of concern, were added 

together for total risk estimates, based on both showing liver toxicity and developmental effects, 

and on simultaneous exposure to both compounds in a given food commodity. The acute 

aggregate risk was based on evaluation of diet + drinking water only and for uses of TM and 
Page 25 of 62

MBC combined exceeded the LOC for infants less than one year of age, but not other 

subpopulations. Short-term aggregate risk estimates were not conducted for TM and MBC from 

TM uses because the risks from MBC alone exceeded 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 risks for TM and MBC will not be combined because 

although both compounds share a common target organ (liver), their overall toxicological profile 

differs. An updated aggregate risk assessment is anticipated during registration review that will 

take into account changes in endpoint selection and safety factors and scientific policies at the 

time of registration review. 

Conclusions for Aggregate Exposure

A new aggregate risk assessment is anticipated during registration review that will reflect current 

scientific and exposure assessment policies. Additional 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-term, chronic, and cancer risks for registration 

review. 

Occupational Exposure 

Handler Exposure 

Registered MBC formulations include soluble concentrates/solid, emulsifiable concentrates, 

ready-to-use solutions, wettable powders and water dispersible granules. Products may be 

applied using a paint brush/roller, low pressure sprayer 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 occupational 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/loading of wettable powders (0.5% a.i.) scenario 

resulted in an inhalation risk estimate of concern (MOE=8) at a baseline level of protection. In 

an effort to mitigate human health risks of concern posed by MBC, the RED required that label 

amendments should 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 

<100). AD identified that one label (EPA Reg # 365-80) was still at 0.5 % a.i. and contacted the 

registrant who indicated that they will reduce the rate to 0.35% a.i. AD anticipates the need to 

reassess this scenario during registration review to determine whether or not the rates are 

acceptable with updated toxicological endpoints and exposure data. 

As indicated previously in the residential section, a quantitative assessment for residential 

handler exposure resulting from the use of MBC for tree injection was not previously performed 
Page 26 of 62

(D265419, 2000). Currently, HED does not have unit exposure data to assess residential handler 

exposure associated with this use pattern. Furthermore, these products are formulated as ready to 

use and packaged in capsules which are inserted into a feed tube and dispensed into the tree. 

Therefore, the potential for occupational handler exposure to MBC from tree injection 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 occupational exposure to dried or “cured” paint containing MBC is not 

expected to be of concern. Handlers of MBC or MBC-treated materials are anticipated to have a 

greater exposure to MBC than any post-application occupationally-exposed group. Given the 

uncertainty and lack of information about post-application exposure to MBC, it is assumed that 

the handler risk estimates represent the high-end for possible post-application 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 registration 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 explained, the low application rate, 

and due to the tree tissue incorporation of the product thus preventing its release. No additional 

exposure assessments are anticipated during 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 paint 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 respirator) or engineering controls (i.e., water soluble 

packets). Based on the Agency's current practices, a quantitative post-application inhalation 

exposure assessment was not performed for MBC, and 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-generation 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 residue chemistry data requirements have been 

identified for MBC to support registration review. 

Exposure 

Occupational Handler 

875.1200/875.1400 (Exposure Data): 

 Occupational handler dermal and inhalation exposure applying paints/stains, slurries (airless 

sprayer, low pressure handwand and brush/roller); 

875.1200/875.1400 (Exposure Data): 

 Occupational dermal and inhalation for pouring liquid and or solid material preservatives 

formulations (paints/stains, slurries); and 

875.1700 Product use information 

 For occupational exposure assessments product use 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 the 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 paint/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 data for plastic toys and textiles 
Page 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 exposure 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 OPP 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 Occupational 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 effects 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 health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Since 1992, OPP has compiled these reports in IDS. The IDS contains reports from 

across the U.S., and most incidents have all relevant 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 system stores incident data for death, major and 

moderate incidents, and it includes information about the location, date and nature of the 

incident. Main IDS incidents involving only one active ingredient (as opposed to 

pesticide products with multiple active ingredients) are considered to provide more 

certain information about the potential effects of exposure from the pesticide. 

Aggregate IDS contains incidents resulting in less severe human incidents (minor, 

unknown, or no effects outcomes). These are reported by registrants only as counts in 

what are aggregate summaries. 

For the Main IDS, from January 1, 2008 to September 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 classified as major severity (Table 1). The other 

incidents reported were classified as moderate severity. 
Page 29 of 62

In Aggregate IDS, from January 1, 2008 to September 11, 2013, there were 14 reported incidents 

involving TM and MBC. Overall, there are few incidents involving TM and MBC reported to 

IDS. 

Table 1. Major Severity Incident 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 states from 1998-2009, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR-Pesticides is focused on 

occupational pesticide incidents, and is of particular value in providing that information. The 

state coordinator at each of the 11 respective state Departments of Health conducts case followup activities such as obtaining medical records to verify symptoms and severity. Using 

standardized protocol and case definitions derived 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 active 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 incident cases reported for both TM and MBC in 

both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would 

warrant further investigation. The Agency will continue to monitor 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 associated with antimicrobial use of MBC in OPP’s 

Incident Data System (IDS) for the time period spanning 1997 to 2013. There were only 2 minor 

human incidents involving MBC reported in OPP’s Incident Data 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 further investigation. 

Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

human-health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal 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 diets within the U.S., and 

people who might be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the 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 and 
Page 31 of 62

MBC and share a common mechanism of toxicity with 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 exposure data or information on changes to the use 

pattern, which would affect the need for a cumulative 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 time for TM and MBC, but may be required in the 

future if a cumulative assessment group (CAG) for 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 evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s OPP concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/. 

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 pesticide to determine their dermal and inhalation 

exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the 

Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting 

these multi-pesticide generic exposure databases, 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 prevailing at the time the research was conducted. All 

applicable requirements of EPA’s Rule for the Protection of Human Subjects 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. Thiophanate-Methyl and Carbendazim: Summary of 

Hazard and Science Policy Council (HASPOC) 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. Carbendazim: 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, the Bushberry Subgroup, Citrus, Ginseng, Leafy 

Brassica Greens, Turnip Greens, Mushroom, Mustard, 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-methyl. 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, Mustard, 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-methyl. HED Response to the Registrant’s 

Rebuttal to the 2007 Updated Hazard Characterization Regarding Retention of the 10X FQPA 

Factor and Requirement of a Developmental Neurotoxicity Study. 

S. Dapson, D350585, April 28, 2009. Carbendazim, Review 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, Citrus, 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 ® M 
Page 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-Methyl. Required Data Provided to Support 

the October 2005 Reregistration Eligibility Decision. Summary of Analytical Chemistry and 

Residue Data. 

M. Collantes, D364554, May 1, 2009. Revised Residential Exposure and Risk Assessment for 

Use in Residential Paint. 

M. Collantes, D360623, March 4, 2009. Revised Residential 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. Discussion of FQPA Factor Retention and DNT 

Study Requirement in Response to the Registrant’s Rebuttal to the Agency’s 2007 Hazard 

Assessment. 

L. Hansen, D340134, September 12, 2007. Thiophanate Methyl. Updated Hazard 

Characterization: Toxicology Summary for Proposed New Uses (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 Reregistration 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-methyl. 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. REVISED Thiophanate-methyl: Occupational and 

Residential Exposure Assessment and Recommendations 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 Assessment Document for Carbendazim (MBC). 

Attachments 

Attachment 1. Chemical Identity Table for Thiophanate-methyl and Carbendazim 

Attachment 2a. Thiophanate-methyl Endpoint Selection Tables 

Attachment 2b. Carbendazim Endpoint Selection Tables 

Attachment 3a. Summary of Acute, Subchronic 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. International Residue Limit Status 
Page 35 of 62

Attachment 1. Chemical Identity Table 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(iminocarbonothioyl)]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 Reg. 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

CH3

O

HN

S

N

H

N

H

O

CH3

O

N

N

H

NH

O

O CH3

N

N

H

NH2
Page 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 and 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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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) 

UFA= 10x 

UFH=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 and 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) 

UFA= 10x 

UFH=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) 

UFA= 10 

UFH=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 Q1* = 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 point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

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 

UFA=10x 

UFH=10x 

UFDB = 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) 

UFA=10x 

UFH=10x 

UFDB = 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) 

UFA=10x 

UFH=10x 

UFDB = 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) 

UFA=10x 

UFH=10x 

UFDB = 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 Q1* = 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 point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 
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 (Residential) 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 

UFA= 10x 

UFH=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) 

UFA= 10x 

UFH=10x 

UFL = 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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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) 

UFA= 10x 

UFH=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 (Residential) 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 

UFA= 10x 

UFH=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 characterization for 

MBC. A BMDL10 has also been 

calculated) 

Dermal LongTerm (>6 

months) 

Oral 

NOAEL=2.5 

mg/kg/day. 

(dermal 

absorption rate 

= 3.5% 

relative to oral 

absorption) 

UFA= 10x 

UFH=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) 

UFA= 10x 

UFH=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/m3

)

UFA= 10x 

UFH=10x 

FQPA SF= 10x, 

Residential 

LOC for MOE 

= 1000 

90-day rat inhalation study with benomyl 

LOAEL = 4.8 mg/kg/day (50 mg/ m3) 

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 for 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 potential. A 10X FQPA factor was not retained for chronic exposure because the 

windows of developmental sensitivity are not expected to be of chronic duration. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 
Page 41 of 62

date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

 
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/m3

) 

LOC for MOE = 100 for 

occupational workers 

90 day rat inhalation study with benomyl 

LOAEL= 4.8 mg/kg/day (50 mg/m3

) 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 Exposure 

 
Page 43 of 62

Attachment 3a. Summary of Acute, Subchronic and Chronic Toxicity Profile, 

Toxicological Doses for Thiophanate-Methyl for 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 LD50 >5000 mg/kg, both sexes IV 

870.1200 Acute Dermal, Rabbit 41644302 LD50 >2000 mg/kg, both sexes III 

870.1300 Acute Inhalation, Rat 41482804 LC50 = 1.7 mg/L, males 

1.9 mg/L, females 

II 

870.2400 Primary Eye Irritation, Rabbit 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 Toxicity 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 Toxicity 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 weight 
Page 45 of 62

Table 3a.2. Subchronic, Chronic and Other Toxicity 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/reproductive NOAEL ≥32 

mg/kg/day 

Parental systemic/reproductive 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 870.4300 
Page 46 of 62

Table 3a.2. Subchronic, Chronic and Other Toxicity 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 phosphatase 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 circulating 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 Toxicity 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 termination), 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 Toxicity 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 Toxicity 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 Toxicity 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 14Cthiophanate-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. Tmax 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 CO2 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 feces 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 thyroid and liver mechanistic studies, supplement to chronic feeding/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 serum 

cholesterol 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-450 

and 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 10-4M, Guaiacol 

method 

Positive control: 10-4 to 

10-6 PTU 

The ED50 (effective dose to achieve 50% 

inhibition of thyroid peroxidase) for TM was 6 

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

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

The ED50 for PTU was 2 x 10-5M and no 

inhibition was reported at 4 x 10-7M. 
Page 52 of 62

Table A.2.3: Special thyroid and liver mechanistic studies, supplement to chronic feeding/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, Subchronic and Chronic Toxicity Profile, 

Toxicological Doses for Carbendazim for Use in Human Health Risk Assessments 

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

Guideline 

No. 

Study Type % a.i. MRID Results Toxicity 

Category 

870.1100 Acute Oral, Rat 98 

00154508 

LD50 >10,000 mg/kg IV 

870.1200 Acute Dermal, Rabbits 75 

00154514, 

00154515 

LD50 >2,000 mg/kg III 

870.1300 Acute Inhalation, Rat 75 

00154512, 

00154513 

LC50 >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 Toxicity 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 Toxicity 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 BMDL10 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 Toxicity 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, therefore 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 guideline. 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 in 

seminiferous 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 Toxicity 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 systemic) = 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 systemic) = 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 Toxicity 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 males and females. No 

evidence of carcinogenicity. 

Note: Dietary levels in 2,500 ppm were 

increased to 7,500 ppm at 18 weeks and to 

10,000 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 Toxicity 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, M45 
Page 59 of 62

Table 3a.2. Subchronic, Chronic and Other Toxicity 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 degree 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 International Residue Limit Status 

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

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico1 Codex2,3,4 

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-methyl 

methyl benzimidazol2-ylcarbamate 

(carbendazim) and 

1,2-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 Mexico1 Codex2,3,4

Almond 0.1 

Almond, hulls 0.5 

Apple 2.0 5 3 pome fruits3,4

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 beet4

Cherry, sweet 20.0 5 cherries 10 cherries4

Cherry, tart 20.0 5 cherries 

Grain, aspirated 

fractions 12 

Grape 5.0 5 33, 4

Onion, bulb 0.5 

Onion, green 3.0 

Peach 3.0 10 

Peanut 0.1 0.14 

Peanut, hay 5.0 3 peanut fodder4

Pear 3.0 5 3 pome fruits3,4
Page 61 of 62

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico1 Codex2,3,4 

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 

summer4

Wheat, forage 1.1 

Wheat, grain 0.1 0.053, 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 54

Peppers chili 24

Rye 0.13, 4 

 

Completed: M. Negussie; 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 = postharvest treatment, such as treatment of stored 

grains. PoP = processed postharvest 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-methyl 

(c) Tolerances with regional registrations. A tolerance with a regional registration is established 

for residues of thiophanate-methyl, dimethyl ((1,2-phenylene) bis(iminocarbonothioyl)) 

bis(carbamate), including its metabolites and degradates, in or on the commodity in the 

following table. Compliance with the tolerance level specified in this paragraph is to be 

determined by measuring only the 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, in or on the 

commodity. 

Commodity Parts per million 

Canola, seed 0.1