Page 2 of 13 triazolopyrimidine sulfonamide he rbicide registered for use on s oybean 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 diet ary (food and drinking water), a nd occupational (handler and postapplication) routes for cloransulam-methyl.

The toxicology database for cloran sulam-methyl has been determined to be nearly complete. The technical and formulated products are classified in toxicity ca tegory 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 s ubchronic neurotoxicity an d an immunotoxicity study will be required under a da ta call-in (DCI) in the near future. Following the data evaluation, HED will determine if these stud ies 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 pare nt 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 inte rvals (small grains, 3 months; corn, sorghum, cotton, peanuts, alfalfa, and rice, 9 months; suga r beets, sunflowers, and tobacco; 30 months and a successful field bioassay) are ba sed on confined rotational crop st udies due to the potential of phytotoxicity to susceptible plants.

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

assessment should be conducted which considers th e potential for cloransulam-methyl formation during water treatment. Upon receipt of the revised drinking water assessment, new dietary exposure and risk assessments will be requi red which incorporate current consumption information, updated residue values, and percen t crop treated information while directly incorporating drinking water va lues into the assessment.

There are no residential uses of cloransulam-methy l; therefore a residential risk assessment is not required. An updated occupational handler exposur e assessment is necessary. The mixer/loader and applicator scenarios must be assessed in accordance with current guidelines and standard operating procedures for all scenarios, formulatio ns, and use sites that ar e 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 revisi ons 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 co mbined risk from dietary exposure (food and drinking water) and any non-occupati onal (residential) uses. Since there are no residential uses, the cloransulam-methyl aggregate risk assessm ent will include only dietary exposure (food and drinking water). The acute dietar y risk assessment was not require d since no acute oral toxicity endpoints were identified from the toxicologi cal database. A new chronic dietary risk assessment is required to support the regi stration 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 assessm ent. 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 sulf onamide 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 weed s 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 pe tition recommended a 14-day PHI for forage and hay and a 65-day PHI for seed. One applica tion per season is allowe d. 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 h ealth exposure and risk assessments for cloransulam-methyl to determine if sufficient da ta are available and if updates are needed to support registration review. Duri ng registration review, HED will considered the most recent exposure and risk assessments for this chemi cal, updates to its toxic ity, exposure and usage databases, and the latest Agency scien ce policy and risk asse ssment 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 pare nt 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 st ructure and nomenclature of cloransulam-methyl, and the physicochemical prope rties of technical grade cloransulam-methyl are presented in Tables 1 and 2.

Hazard Identification/Toxicology

The available toxicological database for clor ansulam-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 irritatio n 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 th e acute dermal toxici ty and eye irritation studies. There were two 21-day dermal toxicity studies in ra bbits 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 increase d liver weights. These effect s were noted in the subchronic oral studies in mice, as well as in the chr onic 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 toxico logical database will need to be re-evaluated to determine the point of departure (POD) and uncertainty factor(s) for this and other exposure scenario s during registration review.

There was no evidence of increased susceptibility following in utero exposures to rats and rabbits following pre and post nata l exposures in the developmen tal studies. However, in the reproductive study a decrease in live pups and increas e 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 su sceptibility noted in the reproductive study and reevalua te all points of departure and uncertainty factor s during registration review.

Cloransulam-methyl was shown to be negativ e in the mouse micronucleus assay, in two cytogenetic assays, and in a cultured Chinese ha mster ovary cell study. Also, in the combined chronic and carcinogenicity rat st udy there was no evidence of ca rcinogenicity 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 la ck of carcinogenicity in rat and mice studies.

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar 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 ap proach 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 estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and to establish a dose-response relationship be tween 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 pesticid e active ingredients and 9 inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construe d as a list of known or likely endoc rine 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 Agen cy 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, thePage 5 of 13 list of chemicals, the test guidelines and the Ti er 1 screening battery, pl ease 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 re quired for all food and non- f ood 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 neurot oxicity study is required to detect and more fully characterize the potential ne urotoxic effects of cloransulam- methyl. In addition, the available studies for cloransulam- me thyl did not show any evidence of treatment – related effects on the immune system. The ove rall weight of evidence suggests that this chemical does not directly targ et the immune system. The Agency does not believe that conducting a functional immunotoxicity study will resu lt in a lower POD than that currently use for the overall risk assessment, and theref ore, a database uncer tainty factor (UF DB ) 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 review ed, 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 woul d 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 it s acid, cloransulam calculated as parent ester (MARC, 08/14/97). Adequate analytical methods (GC/mass selective detec tion) exist for data

collection and tolerance enforcem ent. 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 conc lude that residues of cloransulam-methyl are stable under frozen conditions for up to 6 mont hs in/on soybean forage and hay, and up to 12 months in/on soybean seed.

Based on the magnitude of the residues in pl ants, residues of cloran sulam-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 th e low levels of residues detecte d, 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 da tabase 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 ar e adequate field trial data, and analytical methods. No new residue ch emistry data requirements have been identified for cloransulam-methyl to s upport registration review.Page 6 of 13 Dietary Exposure and Risks

An unrefined dietary risk assessment was comple ted 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 chroni c aggregate exposure to cloransulam-methyl

residues.

Acute An acute dietary (food and drinki ng water) risk assessment was not required since an acute oral endpoint was not identified from the toxicological database.

Chronic An unrefined, chronic dietary exposure assessmen t using tolerance level residues and assuming 100% crop treated. This assessment concludes th at 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 appr oach 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 ne w dietary exposure assessment for cloransulammethyl including new and updated information and policies. The revised assessment should include updated consumption information and ut ilize the newest version of DEEM-FCID. Further, HED policy with respect to drinking wa ter 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 asse ssment is not required.

Aggregate Risk Assessment

The aggregate risk assessment evaluates the co mbined risk from dietary exposure (food and drinking water) and any non-occupati onal (residential) uses. Since there are no residential uses, the cloransulam-methyl aggregate risk assessm ent 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 assess ment is necessary. The mixer/loader and applicator scenarios must be assessed in accordance with current guidelines and standard operating procedures for all scenar ios, formulations, and use sites that are currently registered.

Occupational Post-application Workers An occupational post-application exposure or ri sk estimates will need to be performed for cloransulam-methyl to support the registration review due to revisi ons to the current policies and procedures for conducting these assessments.

There are many cultural practices which require ha nd labor that may lead to the exposure of fieldworkers such as harvesting, irrigation, scout ing or weeding. Exposure and risk estimates will need to be updated with the most current transfer coefficient valu es that will be developed based on data from the Agricultural Reentry Task For ce 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 re gistration review of cloransulam-methyl.

Conclusions Revised occupational handler and post-applica tion exposure and risk assessments will be required to support registration re view 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 Sa fety and Health (CDC/N IOSH) Sentinel Event Notification System for Occupa tional Risk (SENSOR) database were consulted for poisoning incident data on the active ingredient cloran sulam-methyl. For IDS, from 2000 to May 25, 2010, there are two low severity cases reported for cl oransulam (low severity incidents include minor, unknown or no effects). Because they are low severi ty incidents, there are no unique reports that provide details about the incide nt and single chemical incident s cannot be distinguished from multiple chemical incidents. From 2000 to May 2 5, 2010, there is one high severity case reported for products containing the single chemical cloransulam only (hi gh severity incidents include death, major, and moderate incidents). High seve rity 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. ForPage 8 of 13 NIOSH SENSOR, no cases were iden tified that involve the active ingredient cloransulam from

1998-2007.

Based on the low severity and low number of incide nt cases, there does no t 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 con cern 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 pare nt 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 expr ession 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-fl uoro-(1,2,4)-triazolo[1,5c]-pyrimidine-2- sulfonamide, and its acid, cloransulam, calcula ted 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 resu lts of the ruminant/poultry metabolism studies (CFR §180.6(a)(3)). There ar e no Codex Alimentarius Commission and Mexican maximum residue limits (MRLs) for cloransulam-methyl.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.epa.gov/compliance/resour ces/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 ri sk assessments, including, but not limited to, people who obtain drinking water fro m sources near agricultural ar eas, the variability of diets within the U.S., and people who may be expos ed when harvesting crops. Should these high exposures indicate potential risks of concern, OPP will further refi ne the risk assessments to

ensure that the risk estimates are ba sed 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 w ith other substances. EPA has not made a common mechanism of toxicity finding as to cloran sulam-methyl and any other subs tances, 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 et hically 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 cloransula m-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 Amende d Registration for Cloransulammethyl on Soybeans

N. Thurman D223558/223560 04/28/1997 NC F ood/Feed Use; Environmental Fate Data; Cloransulam-methyl T. McMahon D225109 04/22/1997 XDE-565 Technical (Cloransulammethyl, 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: Nomencl ature

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(K

ow ) 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 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal [Rabbit] 43004314 LD 50 >2000 mg/kg IIIPage 11 of 13 870.1300 Acute inhalation [Rat] 43003415 LC 50 > 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 (intermediateand longterm) NOAEL= 10 mg/kg/day

30% dermal absorption

factor UF A = 10X

UF H = 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 liverPage 12 of 13 Table 5 OPPTS Test Guideline Number: 870.7800 Study Title: Immunotoxici ty 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 pesticid e (food and non-food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functi onal immunotoxicity testing and is designed to evaluate the potenti al of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immu ne 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 Respir atory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, stud ies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’ s potential imm unotoxicity. While data from hematology, lymphoid organ wei ghts, and histopatholo gy in routine chronic or subchronic toxicity studies may offer usef ul information on potenti al immunotoxic effects, these endpoints alone are insuffici ent to predict immunotoxicity.

Practical Utility of the Data

How will the data be used? Immunotoxicity studies provide cri tical scientific information ne eded 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 characte rize a pesticide’s potential imm unotoxicity 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 a ll exposure scenarios and are considered a primary data source for reli able reference dose calc ulation. For example,

animal studies have demonstrated that immunotox icity in rodents is one of the more sensitive manifestations of TCDD ( 2,3,7,8-tetrachlorodibenzo-p-di oxin) among developmental, reproductive, and endocrinologic toxicities. A dditionally, 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 Ag ency's future decision-making? If the immunotoxicity study shows th at the test material poses eith er 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 th e magnitude of potential risk derived from the

new data. If the Agency does not have th is data, a 10X database uncertain ty 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 fo r 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 pesticid e (food and non-food uses).

The Neurotoxicity Screening Battery (OPPTS 8 70.6200) is designed to ev aluate the potential

adverse effects on the nervous system from exposure to pestic ide 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 poten tial toxicity to the nervous tissue structure and function. To detect and characterize these po tential 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 a nd/or behavioral effects, the level of motor activity, and the histopathology of the nervou s system. The acute ne urotoxicity study is required to detect possible effects resulting from a si ngle exposure. The subchronic neurotoxicity study is intended to detect possibl e effects resulting from repeated or long-term

exposures.

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotox icity studies provide critical scientific information needed to characterize potential hazard to the human population on the ne rvous system from pesticide exposure. These studies can provide data on a wi de range of functional tests for evaluating neurotoxicity including sensor y effects, neuromuscular effects, learning and memory and histopathology of the nervous system For ex ample, animal studies with organophosphorous chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase inhibition) of concern in rodent s and non-rodents. These animal studies can be used to select endpoints and doses for use in ri sk assessment of all exposure scenarios a nd are considered a primary data source for reliable reference dos e calculation. The Agency has established an oral reference dose (RfD) for assessing diet ary risks for a number of chemicals (e.g., organophosphates and carbamates) where neurotoxi city was the most sensitive endpoint of

concern.

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

If the acute or subchronic neur otoxicity 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 magnit ude of potential risk derived from the new data.

If the Agency does not have this data, a 10X da tabase uncertainty factor may be applied when conducting a risk assessment using the currently available studies.