Page 2 of 13 

triazolopyrimidine sulfonamide herbicide registered for use on soybean only. Other members of 

this class include flumetsulam, penoxulam and florasulam. The permanent tolerance request for 

cloransulam-methyl in/on soybean was completed on August 28, 1997. Exposures can be 

expected to occur via the dietary (food and drinking water), and occupational (handler and postapplication) routes for cloransulam-methyl. 

The toxicology database for cloransulam-methyl has been determined to be nearly complete. The 

technical and formulated products are classified in toxicity category III based on acute dermal 

toxicity, and eye irritation studies. Cloransulam-methyl is classified as “not likely” to be a 

human carcinogen based on the carcinogenicity studies in rats and mice. In accordance with the 

revised 40 CFR Part 158 data requirements, a subchronic neurotoxicity and an immunotoxicity 

study will be required under a data call-in (DCI) in the near future. Following the data 

evaluation, HED will determine if these studies will impact the toxicity endpoints for 

cloransulam-methyl. 

Tolerances are established for residues of cloransulam-methyl, N-(2-carboxymethyl-6-

chlorophenyl)-5-ethoxy-7-fluoro-(1,2,4)-triazolo[1,5c]-pyrimidine-2-sulfonamide, plus its acid, 

cloransulam, calculated as parent ester in/on soybean seed (0.02 ppm), soybean forage (0.1 ppm) 

and soybean hay (0.2 ppm) [40 CFR § 180.514]. No field studies were conducted with rotational 

crops. The label restrictions on plantback intervals (small grains, 3 months; corn, sorghum, 

cotton, peanuts, alfalfa, and rice, 9 months; sugar beets, sunflowers, and tobacco; 30 months and 

a successful field bioassay) are based on confined rotational crop studies due to the potential of 

phytotoxicity to susceptible plants. 

The Environmental Fate and Effects Division (EFED) has determined that a new drinking water 

assessment should be conducted which considers the potential for cloransulam-methyl formation 

during water treatment. Upon receipt of the revised drinking water assessment, new dietary 

exposure and risk assessments will be required which incorporate current consumption 

information, updated residue values, and percent crop treated information while directly 

incorporating drinking water values into the assessment. 

There are no residential uses of cloransulam-methyl; therefore a residential risk assessment is not 

required. An updated occupational handler exposure assessment is necessary. The mixer/loader 

and applicator scenarios must be assessed in accordance with current guidelines and standard 

operating procedures for all scenarios, formulations, and use sites that are currently registered. 

An occupational post-application exposure and risk assessment will need to be performed for 

cloransulam-methyl to support the registration review due to revisions to the current policies and 

procedures for conducting these assessments. Once the hazard endpoints are updated, new 

occupational handler and post-application risk assessments will be needed for registration 

review. 

The aggregate risk assessment evaluates the combined risk from dietary exposure (food and 

drinking water) and any non-occupational (residential) uses. Since there are no residential uses, 

the cloransulam-methyl aggregate risk assessment will include only dietary exposure (food and 

drinking water). The acute dietary risk assessment was not required since no acute oral toxicity 

endpoints were identified from the toxicological database. A new chronic dietary risk 

assessment is required to support the registration review of cloransulam-methyl. 
Page 3 of 13 

Prior to a final registration review decision for cloransulam-methyl, the Agency will determine if 

there is any new information, such as new hazard or exposure data or changes to the use pattern, 

which would affect the cumulative risk assessment. Should the Agency determine that new 

information on cloransulam-methyl is available that could potentially impact the cumulative risk 

assessment and result in a risk of concern, the Agency will revisit the cumulative risk 

assessment. 

Introduction 

Cloransulam-methyl is a triazolopyrimidine sulfonamide herbicide (another member of this class 

is flumetsulam) registered for use on soybean only. DowElanco has petitioned the Agency to 

register FirstRateTM for the control of broad leaf weeds in soybean. The product is an 84% 

active wettable granular material packaged in water-soluble packets. The maximum seasonal 

rates are 0.04 lb ai/A (0.64 oz ai/A) for preplant and pre-emergent use and 0.016 lb ai/A (0.26 oz 

ai/A) for post-emergent use. The tolerance petition recommended a 14-day PHI for forage and 

hay and a 65-day PHI for seed. One application per season is allowed. Applications are 

facilitated by the use of water-soluble packets; one packet treats 1.6-4.0 acres. Non-ionic 

surfactants, crop oil, or urea ammonium nitrate may be added as adjuvants. Aerial application is 

prohibited. 

HED has evaluated the most recent human health exposure and risk assessments for 

cloransulam-methyl to determine if sufficient data are available and if updates are needed to 

support registration review. During registration review, HED will considered the most recent 

exposure and risk assessments for this chemical, updates to its toxicity, exposure and usage 

databases, and the latest Agency science policy and risk assessment methodologies. 

Chemical Identity 

Tolerances are established for residues of cloransulam-methyl, N-(2-carboxymethyl-6-

chlorophenyl)-5-ethoxy-7-fluoro-(1,2,4)-triazolo[1,5c]-pyrimidine-2-sulfonamide, plus its acid, 

cloransulam, calculated as parent ester in/on soybean seed (0.02 ppm), soybean forage (0.1 ppm) 

and soybean hay (0.2 ppm) [40 CFR § 180.514]. The chemical structure and nomenclature of 

cloransulam-methyl, and the physicochemical properties of technical grade cloransulam-methyl 

are presented in Tables 1 and 2. 

Hazard Identification/Toxicology 

The available toxicological database for cloransulam-methyl is adequate to support the 

registration review process. The acute toxicity studies indicate that cloransulam–methyl, 

technical, is moderately toxic (Toxicity Category III) via the dermal and inhalation routes than 

the oral route of exposure. Cloransulam–methyl cause slight irritation to the eye (Toxicity 

Category III), but it is not a skin irritant and is not a skin sensitizer. The formulated end use 

product is classified as toxicity category III based on the acute dermal toxicity and eye irritation 

studies. There were two 21-day dermal toxicity studies in rabbits conducted for cloransulammethyl. No dermal toxicity was observed at 1000 mg/kg/day (limit dose) in either study. 
Page 4 of 13 

The most consistent toxicological effect was in the liver as indicated by increased levels of 

alkaline phosphatase and increased liver weights. These effects were noted in the subchronic 

oral studies in mice, as well as in the chronic dog, mouse carcinogenicity, and combined rat 

chronic toxicity/carcinogencity studies. In addition a decrease in red cell count, hemoglobin 

concentration and hematocrit were observed in both 21-day dermal studies in rabbits. 

Since inhalation exposure is anticipated based on the use profile, the toxicological database will 

need to be re-evaluated to determine the point of departure (POD) and uncertainty factor(s) for 

this and other exposure scenarios during registration review. 

There was no evidence of increased susceptibility following in utero exposures to rats and 

rabbits following pre and post natal exposures in the developmental studies. However, in the 

reproductive study a decrease in live pups and increase pup deaths were observed in both the P1 

and P2 generations. Due to the various science policy and risk assessment methodology, 

changes may have been implemented since the completion of the risk assessment for 

cloransulam- methyl, the Agency will examine the toxicological database as a whole and 

evaluate the potential susceptibility noted in the reproductive study and reevaluate all points of 

departure and uncertainty factors during registration review. 

Cloransulam-methyl was shown to be negative in the mouse micronucleus assay, in two 

cytogenetic assays, and in a cultured Chinese hamster ovary cell study. Also, in the combined 

chronic and carcinogenicity rat study there was no evidence of carcinogenicity for cloransulammethyl. The total tumor incidence (adenoma + carcinoma) was not increased by dosing with 

cloransulam-methyl in the mouse carcinogenicity study. Cloransulam-methyl is classified as 

“not likely” to be a carcinogen based on the lack of carcinogenicity in rat and mice studies. 

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

to establish a dose-response relationship between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors. Cloransulammethyl is not among the group of 58 pesticide active ingredients on the initial list to be screened 

under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. 

Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active 

ingredients. For further information on the status of the EDSP, the policies and procedures, the 
Page 5 of 13 

list of chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/. 

In accordance with the revised 40 CFR Part 158 data requirements, a subchronic neurotoxicity 

and an immunotoxicity study is required for all food and non- food use chemicals. Although the 

available studies showed no neurotoxicity, these studies do not use optimal methods to evaluate 

the nervous tissue structure and function. Consequently, the neurotoxicity study is required to 

detect and more fully characterize the potential neurotoxic effects of cloransulam- methyl. In 

addition, the available studies for cloransulam- methyl did not show any evidence of treatment – 

related effects on the immune system. The overall weight of evidence suggests that this 

chemical does not directly target the immune system. The Agency does not believe that 

conducting a functional immunotoxicity study will result in a lower POD than that currently use 

for the overall risk assessment, and therefore, a database uncertainty factor (UFDB) is not needed 

to account for the lack of this study. 

Conclusions 

As specified in the new 40 CFR Part 158 data requirements, an immunotoxicity study on 

cloransulam- methyl will be required. The Agency also requires a subchronic neurotoxicity 

study. Once all data have been received and reviewed, the Agency will determine if there is any 

new information, such as the points of departure and safety factors used for risk assessment 

purposes for cloransulam- methyl which would affect the cumulative risk assessment. 

Residue Chemistry 

The HED Metabolism Assessment Committee Review (MARC) determined that the residue of 

concern is cloransulam-methyl, parent, plus its acid, cloransulam calculated as parent ester 

(MARC, 08/14/97). Adequate analytical methods (GC/mass selective detection) exist for data 

collection and tolerance enforcement. The limit of quantitation (LOQ) for the method has been 

set as 0.01 ppm and the limit of detection (LOD) for the method has been set as 0.005 ppm. 

Adequate storage stability data leads us to conclude that residues of cloransulam-methyl are 

stable under frozen conditions for up to 6 months in/on soybean forage and hay, and up to 12 

months in/on soybean seed. 

Based on the magnitude of the residues in plants, residues of cloransulam-methyl are not 

expected to exceed 0.02 ppm in/on soybean seed, 0.1 ppm in/on soybean forage and 0.2 ppm 

in/on soybean hay. Based on the results of animal metabolism studies, considering the 

exaggerated rate of dosing and the low levels of residues detected, it is unlikely that significant 

residues would occur in secondary livestock commodities from this use. No field studies were 

conducted with rotational crops. 

Conclusions 

The existing residue chemistry database for cloransulam-methyl is adequate for risk assessment 

purposes. The qualitative nature of the residues of cloransulam-methyl in plants and animals has 

been adequately identified, characterized and is understood. Also, there are adequate field trial 

data, and analytical methods. No new residue chemistry data requirements have been identified 

for cloransulam-methyl to support registration review. 
Page 6 of 13 

Dietary Exposure and Risks 

An unrefined dietary risk assessment was completed for the petition of permanent tolerances of

cloransulam-methyl in/on soybean (B. Tarplee, W. Dykstra, and M. Lamont, D286828, 8/28/97). 

HED concludes that there is a reasonable certainty that no harm will result to the general 

population, and infants and children from chronic aggregate exposure to cloransulam-methyl 

residues. 

Acute 

An acute dietary (food and drinking water) risk assessment was not required since an acute oral 

endpoint was not identified from the toxicological database. 

Chronic 

An unrefined, chronic dietary exposure assessment using tolerance level residues and assuming 

100% crop treated. This assessment concludes that the chronic dietary exposure estimates did 

not exceed HED's level of concern (100% cPAD) for any population subgroup. 

Drinking Water 

EFED previously provided drinking water numbers for use in dietary risk assessments in their 

memorandum dated 04/28//97 (D223558, N.Thurman) in association with the use on soybeans. 

The GENEEC screening model was used to estimate surface water concentrations of 

cloransulam-methyl. This conservative approach represents an upper bound (worst-case) 

estimate of environmental concentrations on a high exposure site, and the drinking water 

assessment needs to be revisited to support registration review of cloransulam-methyl. 

Conclusions 

It will be necessary for HED to conduct a new dietary exposure assessment for cloransulammethyl including new and updated information and policies. The revised assessment should 

include updated consumption information and utilize the newest version of DEEM-FCID. 

Further, HED policy with respect to drinking water assessment has been revised since the most 

recent human health risk assessment based on concerns that the DWLOC approach may 

underestimate risk for some subpopulations. Once the Environmental Fate and Effects Division 

(EFED) has updated the drinking water assessment, HED will need to revisit potential risks from 

drinking water by directly incorporating drinking water estimates into the chronic aggregate 

dietary risk assessment. 

Residential Exposure and Risks 

There are no residential uses or expected residential exposures of cloransulam-methyl; therefore, 

a residential risk assessment is not required. 

Aggregate Risk Assessment 

The aggregate risk assessment evaluates the combined risk from dietary exposure (food and 

drinking water) and any non-occupational (residential) uses. Since there are no residential uses, 

the cloransulam-methyl aggregate risk assessment will include only dietary exposure (food and 

drinking water). 
Page 7 of 13 

Conclusions 

A revised aggregate risk assessment will be required to support registration review of 

cloransulam-methyl. The revised assessment should include updated consumption information 

using the newest version of DEEM-FCID and an updated drinking water assessment. 

Occupational Exposure and Risks 

Occupational Handlers 

In 1997, HED determined that the MOEs as a result of the handling and application of 

cloransulam-methyl (formulated as a dry flowable product) by workers are 2,500 for 

mixers/loaders and 14,000 for ground applicators. The MOEs do not exceed HED’s level of 

concern (i.e., MOEs>100). (B. Tarplee, W. Dykstra, and M. Lamont, DP286828, 8/28/97). 

An updated occupational handler exposure assessment is necessary. The mixer/loader and 

applicator scenarios must be assessed in accordance with current guidelines and standard 

operating procedures for all scenarios, formulations, and use sites that are currently registered. 

Occupational Post-application Workers 

An occupational post-application exposure or risk estimates will need to be performed for 

cloransulam-methyl to support the registration review due to revisions to the current policies and 

procedures for conducting these assessments. 

There are many cultural practices which require hand labor that may lead to the exposure of 

fieldworkers such as harvesting, irrigation, scouting or weeding. Exposure and risk estimates will 

need to be updated with the most current transfer coefficient values that will be developed based 

on data from the Agricultural Reentry Task Force and as discussed at the 2008 meeting of the 

FIFRA Scientific Advisory Panel meeting on this issue. The existing Restricted Entry Interval 

(REI) of 12 hours will be reviewed during the registration review of cloransulam-methyl. 

Conclusions 

Revised occupational handler and post-application exposure and risk assessments will be 

required to support registration review of cloransulam-methyl. 

Public Health and Pesticide Epidemiology Data 

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 (SENSOR) database were consulted for poisoning 

incident data on the active ingredient cloransulam-methyl. For IDS, from 2000 to May 25, 2010, 

there are two low severity cases reported for cloransulam (low severity incidents include minor, 

unknown or no effects). Because they are low severity incidents, there are no unique reports that 

provide details about the incident and single chemical incidents cannot be distinguished from 

multiple chemical incidents. From 2000 to May 25, 2010, there is one high severity case reported 

for products containing the single chemical cloransulam only (high severity incidents include 

death, major, and moderate incidents). High severity incidents are captured in the main IDS 

database and each incident is reported as a unique case. In this case, which was classified as a 

moderate severity, a 48 year old male got some product on his hands while applying it and he 

washed his hands 30 minutes later. The next day he developed a rash all over his body. For 
Page 8 of 13 

NIOSH SENSOR, no cases were identified that involve the active ingredient cloransulam from 

1998-2007. 

Based on the low severity and low number of incident cases, there does not appear to be a risk 

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 (08/04/10, S. Recore). 

Tolerance Assessment and International Harmonization 

Tolerances are established for residues of cloransulam-methyl, N-(2-carboxymethyl-6-

chlorophenyl)-5-ethoxy-7-fluoro-(1,2,4)-triazolo[1,5c]-pyrimidine-2-sulfonamide, plus its acid, 

cloransulam, calculated as parent ester in/on soybean seed (0.02 ppm), soybean forage (0.1 ppm) 

and soybean hay (0.2 ppm) [40 CFR § 180.514]. The tolerance expression must be revised in 

accordance with the most current guidelines as follows: 

Tolerances are established for residues of the herbicide, cloransulam-methyl, N -(2-

carboxymethyl-6-chlorophenyl)-5-ethoxy-7-fluoro-(1,2,4)-triazolo[1,5c]-pyrimidine-2-

sulfonamide, and its acid, cloransulam, calculated as the stoichiometric equivalent of 

cloransulam-methyl, in or on the commodity. 

The Agency has determined that tolerances for cloransulam-methyl residues in eggs, poultry and 

ruminant tissue are not required based on the results of the ruminant/poultry metabolism studies 

(CFR §180.6(a)(3)). There are no Codex Alimentarius Commission and Mexican maximum 

residue limits (MRLs) for cloransulam-methyl. 

Environmental Justice 

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

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

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

http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. The Office of 

Pesticide Programs (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 may be exposed when harvesting crops. Should these high 

exposures indicate potential risks of concern, OPP will further refine the risk assessments to 

ensure that the risk estimates are based on the best available information. 

Cumulative Risk Assessment 

At this time, EPA does not have available data to determine whether cloransulam-methyl has a 

common mechanism of toxicity with other substances. EPA has not made a common mechanism 

of toxicity finding as to cloransulam-methyl and any other substances, and cloransulam-methyl 

does not appear to produce a toxic metabolite produced by other substances which have 

tolerances in the U.S. Therefore, EPA has not assumed that cloransulam-methyl has a common 

mechanism of toxicity with other substances. 
Page 9 of 13 

Human Studies 

Future exposure and risk assessments will rely in part on the use of the Pesticide Handlers Exposure 

Database (PHED), the Agricultural Handlers Exposure Task Force (AHETF), and the Agricultural 

Reentry Task Force (ARTF). All data from PHED have been reviewed and found to be compliant 

with requirements for the ethical conduct of such studies. Studies conducted as part of the AHETF 

prior to 2006 have gone through appropriate ethics review. Protocols and subsequent reviews for 

studies conducted after 2006 will be addressed by the Human Subjects Review Board. In addition, 

data from the ARTF would be used to calculate current worker postapplication risks. These data have 

been reviewed and found acceptable from an ethical perspective. As the studies in PHED, AHETF, 

and ARTF are considered appropriate (or ethically conducted) they will be used for 

incorporation into future risk assessments 

Data Requirements

HED does not anticipate that additional residue chemistry, toxicology or occupational/residential 

exposure data will be required for the cloransulam-methyl registration review process, with the 

exception of the following studies listed below: 

• Immunotoxicity Study (OPPTS 870.7800) 

• Neurotoxocity Study 

References 

Author Barcode Date Title 

B.Tarplee, W. 

Dykstra and M. 

Lamont 

D286828 08/28/1997 Permanent Tolerance Request for the use 

of the New Chemical: Cloransulammethyl in/on Soybean. 

B. Tarplee D227957/227958 08/23/1997 Amended Registration for Cloransulammethyl on Soybeans 

N. Thurman D223558/223560 04/28/1997 NC Food/Feed Use; Environmental Fate 

Data; Cloransulam-methyl 

T. McMahon D225109 04/22/1997 XDE-565 Technical (Cloransulam 

methyl, FirstRate® herbicide) and NAF75 89% a.i. Herbicide: Review of 

Toxicology Data submitted by the 

Registrant in support of Registration. 

H. Spencer TXR#012332 10/30/1997 RfD/Peer Review Report of XDE-565: 

N-[2-carboxymethyl-6-chlorophenyl]-5-

ethoxy-7-fluro(1,2,4) triazolo-[1,5c]-

pyrimidine-2-sulfonamide. 
Page 10 of 13 

Table 1: Nomenclature

Common Name/Code

Chemical name

Structure

Cloransulam‐methyl

Common Name Cloransulam‐methyl

IUPAC

N‐(2‐carboxymethyl‐6‐chlorophenyl)‐5‐ethoxy‐7‐fluoro‐(1,2,4)‐

triazolo[1,5c]‐pyrimidine‐2‐sulfonamide

PC Code 129116

Chemical Abstracts Number 147150‐35‐4

Registration Review Case Number 62719‐299

Table 2. Physicochemical Properties of Cloransulam-methyl 

Parameter Value Reference 

Melting point/range 216- 218 oC 

http://www.epa.gov/opprd001

/factsheets/cloransulam.pdf 

pH 3.0 (9.8% dispersed in water) 

Density 1.538 (20 oC) 

Water Solubility 3 ppm at pH 5; 180 ppm at pH7; 3400 ppm at 

pH 8.5 

Vapor Pressure 4x10-14 Pa (3 x 10-16 mm Hg ) @ 25 oC 

Octanol/water partition 

coefficient, Log(Kow) 

0.268 (distilled water) 

1.12 (pH 5); -0.365 (pH 7); -1.24 (pH 8.5) 

Table 3. Acute Toxicity Profile – Cloransulam-methyl Technical 

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral [Rat] 43003413 LD50 > 5000 mg/kg IV 

870.1200 Acute dermal [Rabbit] 43004314 LD50 >2000 mg/kg III 
Page 11 of 13 

870.1300 Acute inhalation [Rat] 43003415 LC50 > 3.77 mg/L III 

870.2400 Primary eye irritation 43003416 Slight irritation III 

870.2500 Primary skin irritation 43003417 Non irritation IV 

870.2600 Skin sensitization 43003418 Non - sensitizer --- 

Table 4. Toxicological Doses and Endpoint for Cloransulam –methyl Human Health Risk 

Assessment 

Exposure/ 

Scenario

Point of 

Departure 

Uncertainty/ 

FQPA Safety 

Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and Toxicological 

Effects

Acute 

Dietary 

(General US 

Pop.) 

No appropriate effect attributable to a single dose was identified. 

Chronic 

Dietary (all 

populations) 

NOAEL= 10 

mg/kg/day 

UFA= 10X 

UFH= 10X 

FQPA SF= 1X 

 

Total UF= 

100X 

cPAD= Chronic RfD

 FQPA SF 

cPAD= 0.10 mg/kg/day 

1 year chronic dog (MRID 

43668909) 

LOAEL = 50 mg/kg/day, 

based on the microscopic 

histopathologic and 

elevation of serum enzymes 

of the liver. 

Dermal 

(short term) 

NOAEL= 

500 

mg/kg/day 

30% dermal 

absorption 

factor 

UFA= 10X 

UFH= 10X 

FQPA SF= 1X 

 

Total UF= 

100X 

Occupational LOC for 

MOE = 100 

21day dermal studiesRabbits 

(MRID 43668908 and 

43668919) 

LOAEL= 1000 mg/kg/day, 

based on decrease red cell 

count, hemoglobin, and 

hematocrite; anisocytosis 

and macrocytosis of red 

cells in females. 

Dermal 

(intermediate 

and longterm) 

NOAEL= 10 

mg/kg/day 

30% dermal 

absorption 

factor 

UFA= 10X 

UFH= 10X 

FQPA SF= 1X 

 

Total UF= 

100X 

Occupational LOC for 

MOE = 100 

1 year chronic dog (MRID 

43668909) 

LOAEL = 50 mg/kg/day, 

based on the microscopic 

histopathologic and 

elevation of serum enzymes 

of the liver 
Page 12 of 13 

Table 5 OPPTS Test Guideline Number: 870.7800 

 Study Title: Immunotoxicity on Cloransulam-Methyl 

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity 

testing and is designed to evaluate the potential of a repeated chemical exposure to produce 

adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in 

the ability of the immune system to respond to a challenge of bacterial or viral infections such 

as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because 

the immune system is highly complex, studies not specifically conducted to assess 

immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. 

While data from hematology, lymphoid organ weights, and histopathology in routine chronic 

or subchronic toxicity studies may offer useful information on potential immunotoxic effects, 

these endpoints alone are insufficient to predict immunotoxicity. 

Practical Utility of the Data 

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize potential 

hazard to the human population on the immune system from pesticide exposure. Since 

epidemiologic data on the effects of chemical exposures on immune parameters are limited 

and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal 

studies are used as the most sensitive endpoint for risk assessment. These animal studies can 

be used to select endpoints and doses for use in risk assessment of all exposure scenarios and 

are considered a primary data source for reliable reference dose calculation. For example, 

animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive 

manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, 

reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral 

reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in 

animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a greater or a diminished 

risk than that given in the interim decision’s conclusion, the risk assessments for the test 

material may need to be revised to reflect the magnitude of potential risk derived from the 

new data. 

 If the Agency does not have this data, a 10X database uncertainty factor may be applied for 

conducting a risk assessment from the available studies. 
Page 13 of 13 

Table 6 

OPPTS Test Guideline Number: 870.6200 

Study Title: Neurotoxicity Battery for Cloransulam-Methyl (Subchronic Study) 

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential 

adverse effects on the nervous system from exposure to pesticide chemicals. The Agency 

believes that the guideline studies are inadequate in their assessment of behavioral effects and 

do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure 

and function. To detect and characterize these potential effects more fully, a battery of more 

sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate 

the incidence and severity of the functional and/or behavioral effects, the level of motor 

activity, and the histopathology of the nervous system. The acute neurotoxicity study is 

required to detect possible effects resulting from a single exposure. The subchronic 

neurotoxicity study is intended to detect possible effects resulting from repeated or long-term 

exposures. 

 

Practical Utility of the Data 

How will the data be used?

The acute and subchronic neurotoxicity studies provide critical scientific information needed 

to characterize potential hazard to the human population on the nervous system from pesticide 

exposure. These studies can provide data on a wide range of functional tests for evaluating 

neurotoxicity including sensory effects, neuromuscular effects, learning and memory and 

histopathology of the nervous system For example, animal studies with organophosphorous 

chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase 

inhibition) of concern in rodents and non-rodents. These animal studies can be used to select 

endpoints and doses for use in risk assessment of all exposure scenarios and are considered a 

primary data source for reliable reference dose calculation. The Agency has established an 

oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., 

organophosphates and carbamates) where neurotoxicity was the most sensitive endpoint of 

concern. 

How could the data impact the Agency's future decision-making? 

If the acute or subchronic neurotoxicity studies show that the pesticide poses either a greater 

or a diminished risk than that given in the interim decision’s conclusion, the risk assessment 

may need to be revised to reflect the magnitude of potential risk derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied when 

conducting a risk assessment using the currently available studies.