Page 2 of 13

applications to manage annual and perennial broadlea f weeds and grasses in non

- agricultural sites (i.e., forestry, rights of way, non

- crop industrial sites, and unimproved turf).

The toxicology database for this non

- food use chemical is adequate and sufficient data are available to assess potential risk from occupational exposure; there are no residential uses at this
time. HED’s Hazard and Science Policy Council (HASPOC) based on a weight of evidence approach and considering all of the available hazard and exposure information, granted waivers
to the ne wly codified acute and subchronic neurotoxicity studies as well as a subchronic inhalation toxicity study (TXR No. 0056431). The only outstanding data is an immunotoxicity study. The primary toxic effect of this sulfonyl urea pesticide is hemolytic anemi a, which represents the most sensitive toxic endpoint for risk assessment. In general, the toxicity data available indicate a low level of toxicity. Sulfometuron methyl is not acutely toxic via the oral, dermal, or inhalation routes of exposure. It shows minimal eye and skin irritation . Sulfometuron methyl is not a dermal sensitizer.

The exposure database for sulfometuron methyl has been reviewed and determined to be complete. Since sulfometuron methyl is a non

- food/non

- feed chemical, any potential d ietary exposure is attributed only to drinking water sources. The most recent acute and chronic dietary assessments (drinking water only) conducted to support of the 2008 Reregistration Eligibility Decision (RED) are well below the level of concern. Resi dential exposure/risk was not assessed since label instructions do not allow application to residential or recreational settings. The most recent occupational risk estimates are below the level of concern. Sulfometuron methyl has not been identified as a member of a common mechanism group for cumulative risk assessment.

Introduction

Sulfometuron methyl [ methyl 2

- (4,6

- dimethylpyrimidin

- 2

- ylcarbamoylsulfamoyl)benzoate ], is a sulfonylurea herbicide that prov ides broad spectrum pre

- and post

- emergence control of annual and perennial grasses and broad

- leaf weeds in forestry and non

- crop situations, including vegetative management of rights

- of

- way and railroads. Similar to other sulfonylurea herbicides,
sulfome turon methyl’s mode of action involves inhibiting the activity of the enzyme actolactase synthase (ALS), which inhibits the production of amino acids required for cell growth in plants. All sulfometuron methyl containing products are formulated as a wate r dispersible granule (WDG). Applications of sulfometuron methyl can be made aerially using fixed wing airplane and helicopter

, and by ground using groundboom, rights

- of

- way, and hand

- held equipment. Sulfometuron methyl can also be used to impregnate or coat dry bulk fertilizer for application to
forested areas. Sulfometuron methyl containing products are not labeled for use by professionals in the residential marketplace (i.e., indoor or outdoor residential use sites). There are currently 16 registered products c ontaining sulfometuron methyl with use rates ranging from 0.023 to 0.38
lb ai/A. The current registrants for sulfometuron methyl are the following: Alligare LLC; Celsius Property B.V.; E.I. DuPont de Nemours & Co. Inc. ; Loveland Products Inc. ; Makhteshim Aga n of North America Inc. ; and NuFarm Americas Inc.

Since s ulfometuron

- methyl has no current registrations which may lead to exposures from the consumption of Raw Agricultural Commodities (RACs) and/or processed foods, there are noPage 3 of 13

tolerances established for this chemical and the requirements of the Food Quality Protection Act (FQPA) do not apply.

The HED Registration Review Team has reviewed the most recent risk assessments and data requirements since the RED to determine if additional stu dies and/or risk assessments are needed to support the registration review of sulfometuron methyl. In addition, the Team has conducted a screening

- level literature search for any information that would aid in assessing the human health
risks to sulfometur on methyl.

Hazard Identification/Toxicology

The toxicology database for this non

- food use chemical is adequate and sufficient data are available to assess potential risk from occupational exposure; there are no residential uses at this
time. HED’s Hazard and Science Policy Council (HASPOC) based on a weight of evidence approach and considering all of the available hazard and exposure information, granted waivers to the newly codified acute and subchronic neurotoxicity studies as well as a subchronic inhalation toxicity study (TXR No. 0056431). The only outstanding study is an immunotoxicity study.

Sulfometuron methyl is not acutely toxic via the dermal (Toxicity Category III)

, oral or inhalation (Toxicity Category IV) routes of exposure. Sulfometur on methyl show s minimal eye
and skin irritation . It is not a dermal sensitizer.

The primar y toxic effect of this sulfonyl urea pesticide is hemolytic anemia (the most sensitive toxic endpoint) reported in the chronic oral toxicity study in dogs. This o bservation is consistent with reports in the open literature where hemolytic anemia has been identified as a side effect of sulfonyl urea compounds (e.g., chlorpropamide, LY186641) used therapeutically as anti

- diabetic
or anti

- tumor agents 1

. In addition t o hemolytic anemia, decreases in body weight were also seen in the chronic oral toxicity study beginning on the fourth week of exposure and persisting throughout the duration of the study.

Other studies available in the database include a de rmal toxicity study as well as pre

- natal developmental toxicity studies (in rats and rabbits). In the previous ris k assessment, it was
concluded that the 21

- day dermal rabbit study ( MRID No. 00126714, classified as acceptable

non

- guideline) was determined to be insufficient to assess dermal exposures due to a number of deficiencies in the study. However, the HED Sulfometuron Methyl Registration Review Team
has re

- evaluated this study and noted that the deficiencies were not significant, and therefore can
be considered for dermal risk assessment.

1 1 J.A. Kopicky and C.H. Packman (1986) The mechanisms of sulfonyul

- urea induced immune hemolysis: Case report and review of the literature. Amer. J. Hematol.. 23(3) : 283

- 288 Ehlhardt, W.J., et al. (1997) Disposition and metabolism of the sulfonyl urea oncolytic agent LY295501 in mouse, rat, and monkey. Drug Met. Disp. (25):6 : 701

- 712 Lee, C.W. et al. (2002). A novel stereo

- selective sulfonylurea, 1

- [1

- (4

- aminobenzoyl)

- 2,3

- dihydro

- 1H

- indol

- 6

- sulfonyl]

- 4

- phenylimidazolidin

- 2

- one, has antitumor efficacy in in vitro and in vivo tumor models. Biochem.
Pharmacol. 64(3): 473

- 480Page 4 of 13

In the rabbit pre

- natal developmental toxicity study, a slight increase in the incidence of abortions was observed from doses close to or at the limit dose (750 and 1000 mg/kg/day) while
no evidenc e of toxicity via the dermal route was reported after 21 days of exposure at a dose 2

- fold higher ( 2000 mg/kg/day ) . Given the limited use pattern and low likelihood for chronic durations of exposure for this compound, no rodent chronic toxicity or carcino ge nicity studies are required. Sulfometuron methyl was negative in the mutagenicity/ genetic toxicity studies.

In the 2008 RED, a NOAEL of 27.5 mg/kg/day established in the chronic toxicity study in rats was used as the Point of Departure (POD) for asse ssing acute and chronic dietary as well as
dermal and inhalation risks from short

- and intermediate term exposures

.

Conclusion s. The POD, endpoints and FQPA Safety Factor used in the RED will be re

- evaluated along with the results of the immunotoxicity study during the conduct of the risk assessment for registration review

.

Dietary Exposure

Since sulfometuron methyl is a non

- food use chemical, there are no residue chemistry data requirements, and the dietary assessment includes only drinking water.

Drinking water exposures can potentially occur through run

- off resulting from the outdoor applications of sulfometuron

- methyl made for controlling weeds. The chemical is mobile and persistent in the environment dissipating through aerobic and anaerobic de gradation/metabolism in soil and water with hydrolysis potentially dominant under acidic conditions. Its persistence
indicates that if sulfometuron methyl reaches surface water bodies it may remain for durations up to several months; however, it has a fai rly low use rate with treatments only being carried out every one to two years which limits exposure, especially over the chronic duration.

Tier I Estimated Drinking Water Concentrations (EWDCs) were modeled using the FIRST ( FQPA Index Reservoir Screeni ng Tool; v.1.1.0; dated 1 /1/200 7 ) model for estimating surface
water concentrations and SCI

- GROW (Screening Concentration In GROund Water v2.3) model for groundwater (D334287, M. Barrett, 10/31/2007). Residues from a number of potential water degradates w ere modeled including: sulfometuron free acid; sulfometuron pyrimidine amine; sulfometuron sulfonamide; and saccharin. These residues were combined with the residues of the parent compound for a total residue. This approach is conservative and, therefore , unlikely to
under

- estimate the concentration of sulfometuron methyl in drinking water. The highest acute ground and surface water EDWCs were found to be 1.1 and 32.4 ppb, respectively. The highest chronic ground and surface water EDWCs were found to be 1.1 and 21.8 ppb, respectively. The larger values of 32.4 ppb (acute) and 21.8 ppb (chronic) were used to perform the screening level drinking water dietary assessments.

Acute and chronic dietary risk assessments were completed using the Dietary Exposur e Evaluation Model (DEEM

- FCIDTM, v

. 2.03 ) softwa re ( D346139, W. Britton, 12/20/2007). Since FQPA requirements are not applicable, screening level risk estimates are expressed as Reference Doses (RfDs) rather than Population Adjusted Doses (PADs). For the acute dietary analyses performed, the most highly exposed population subgroup was all infants < 1 year old at 2.3% ofPage 5 of 13

the aRfD with an exposure of 0.0064 mg/k g/day. The population subgroup with the highest estimated exposure for the chronic analyses perfo rmed was also all infants < 1 year old which occupied < 1% of the cRfD with an exposure of 0.0015 mg/Kg/day.

The acute and chronic screening

- level drinking water dietary assessment indicates that exposures
to sulfometuron methyl are below the lev el of concern for the US population and all population subgroups.

Conclusions

. There are no residue chemistry data requirements for sulfometuron methyl. If drinking water concentration estimates are updated in the future, a revised dietar y assessment may be required. Further, a revised dietary assessment may also be required if there are any revisions to the toxicological points of departure or uncertainty factors.

Residential Exposure

Sulfometuron methyl containing products are not labeled for use by professionals in the residential marketplace (i.e., indoor or outdoor residential use sites). Therefore, a residential exposure/risk assessment is not required.

Conclusion. No residenti al exposure data requirements for sulfometuron methyl because these types of exposures are not anticipated.

Occupational Exposure

Sulfometuron methyl is used to control annual and perennial broadleaf weeds and grasses in non

agricultural sites (i.e., forestry, rights of way, non

- crop industrial sites, and unimproved turf). Due to the manner in which it is used, occupational exposures would be anticipated for those
involv ed in the application process (e.g., mixing/loading product for aerial application). Occupational exposures to workers re

- entering sulfometuron methyl treated areas are not anticipated because the chemical is a non

- selective herbicide used in non

- agricu ltural areas , such as forestry or railroad rights

- of

- way and, therefore, contact with previously treated areas is unlikely. All sulfometuron methyl containing products are formulated as WDGs. Applications of sulfometuron methyl can be made aerially by fi xed wing airplane and helicopter, and by ground using groundboom, rights

- of

- way, and hand

- held equipment. Additionally, sulfometuron methyl can be used to impregnate or coat dry bulk fertilizer for application to forested areas. Product application rates range from 0.023 to 0.38 lb ai/A. Based upon the use pattern of sulfometuron methyl, HED anticipates both short

- (1 to 30 days) and intermediate

- term (1 to 6 months) occupational exposures. Long

- term handler exposures (greater than 6 months) are not

exp ected to occur.

Occupational handler exposures for the WDG formulations were considered in the most recent occupational risk assessments. The majority of handler exposure scenarios assessed (dermal and inhalation combined) resulted in margins of exposu re (MOEs) ≥ 100 at some level of persona l protection and, therefore, were not of concern. The exposure scenario mixing/loading of WDGs for aerial application to forestry and non

- crop areas resu lts in a combined MOE = 90 at thePage 6 of 13

maximum level of personal protection (double layer with gloves) and, therefore, is slightly below
the level of concern

.

Short

- and intermediate

- term dermal and inhalation exposures/risks were also estimated for occupational handlers for the dry bulk fertilizer impregnation use. T wo steps were assessed for the mixing of sulfometuron methyl active ingredient: 1) mixing the product with water to form a slurry and 2) mixing of the slurry in a closed rotary drum mixer with the dry bulk fertilizer (urea and blended). Aerial applicatio n of impregnated fertilizer for forestry was also assessed. None of the exposure scenarios assessed for the impregnation of mixing/loading or application of dry
bulk fertilizer , urea or blended, with sulfometuron methyl active i ngredient were of concern ( i.e., an MOE ≥ 100) at some level of personal protective equipment (PPE)

.

Conclusions. No occupational exposure data gaps were identified during the Registration Review scoping process for sulfometuron methyl. There are no significant changes identifi ed which would require an update of the occupational exposure risk assessment. A task force effort by the Agricultural Handlers Exposure Task Force (AHETF) may provide improved exposure
data relative to that in the Pesticide Handlers Exposure Database (PH ED)

, which was used previously to assess occupational risks. Any changes to the exposure data may elicit the need for an update of sulfometuron methyl occupational exposures/risks during registration review

.

Public Health and Pesticide Epidemiology Dat a

HED has reviewed the OPP Incident Data System (IDS) to determine if there were significant
incidents related to sulfometuron methyl and human health (Recore, 2012). Based on the low frequency and severity of incident cases reported for sulfometuron methyl

, 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.

Tolerance Assessment and International Harmonization

Sulfometuron methyl is a non

- food use chemical ; therefore, there are no tolerances and
international harmonization is not an issue

.

Environmental Justice

Potential areas o f environmental justice concerns, to the extent possible, were considered in this assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.
Extensive data on food and drinking water consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide riskPage 7 of 13

assessments for all registered food uses of a pesticide. These data a re analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditio ns or circumstances warrant. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Human Studies

Past sulfometuron methyl risk assessments relied in part on data in generic databases 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

p esticides, are included in generic pesticide exposure databases such as the Pesticide Handler Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF), and the Outdoor Residential Exposure Task Force (ORETF). Also, there will be a reliance on the work of the Agricultural Handlers Exposure Task Force (AHETF) for revisions to the occupational handler risk assessments possibly needed in the future. These studies have been determined to require a
review of their ethical conduct and have received t he appropriate review.

Endocrine Disruption

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. T ier 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 po tential 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 endocr ine related effects caused by the substance, and 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 con tains 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.

Sulfometuron methyl 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 mu st screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

ins for all pesticide active ingredients.Page 8 of 13

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Data Requirements

No dietary or occupational exposure data are needed at this time. The acute and subchron ic neurotoxicity studies, as well as the 28

- day inhalation toxicity study, were waived by the Hazard and Science Policy Council ( HASPOC ) on August 2, 2012 and are, therefore, no longer required. The following toxicity studies are required:

870.7800 Immun otoxicity Study

The rationale for requiring this studies are attached to this document.

References

Author DP

Barcode/
Record No. Date Title

Britton, W. D385620 8/11/2008 Sulfometuron Methyl: Phase 3 Amendment of “Sulfometuron Methyl: HED Chapter of the Reregistration Eligibility Decision Document (RED).”

Britton, W. D346173 8/11/2008 Sulfometuron Methyl: Addendum to “Sulfometuron Methyl: Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision (Non

- Food).”

Britton, W. D345025 12/20/2007 Sulfometuron Methyl: Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision (Non

Food).

Britton, W. D 346139 12/20/2007 Sulfometuron Methyl: Acute and Chronic Screening

- Level Drinking Water Only Dietary Risk Assessment for the Non

Food/Non

- Feed Use Reregistration Eligibility Decision (RED).

Barrett, M. D334287 10/31/2007 Tier 1 Sulfometuron Methyl Drinking Water Assessment for Reregistration Eligibility Decision Document Recore, S. D402495 8/1/2012 Sulfometuron Methyl: Review of Human Incidents

Bradbury, S. Case No.

3136 9/2008 Reregistration Eligibility Decision (RED) Sulfometuron MethylPage 9 of 13

Attachments

Table A. Chemical Identity

Chemical Structure

Empirical Formula C 15 H 16 N 4 O 5 S

Common Name Sulfometuron Methyl

IUPAC name methyl 2

- (4,6

- dimethylpyrimidin

- 2

- ylcarbamoylsulfamoyl)benzoate

CAS Name methyl 2

- [[[[(4,6

- dimethyl

- 2

- pyrimidinyl)amino]carbonyl]amino]sulfonyl]benzoate CAS Registry Number 74222

- 97

- 2
Chemical Class Pyrimidinylsulfonylurea Herbicides

Table A

. 2. Physiochemical Properties

Parameter Value Reference Molecular Weight 364.4

The Pesticide Manual: A World Compendium, 9 th ed., 1991, C.R. Worthington, ed. The British Crop Protection Council, Surrey, UK pg. 774 Melting point 203

- 205°C Physical state Colorless Solid Vapor pressure (25°C) 6.0 x 10 - 5 mm Hg Water solubility (25°C) 70 ppm Log Kow (25°C) 1.2

Appendix B: Sulfometuron Methyl Toxicology

Table B.1. Acute Toxicity Profile

- Test Substance 1

Guideline No. Study Type MRID
No. (s) Results Toxicity Category

870.1100 Acute oral rat 43089201 LD 50 >5g/kg IV

870.1200 Acute dermal rabbit 43089202 LD 50 > 2g/kg III

870.1300 Acute inhalation rat 43089203 LC 50 >5.0 mg/L IV

870.2400 Acute eye irritation rabbit 00071412 Minimal irritant III

870.2500 Acute dermal irritation rabbit 41672808 Not a dermal
irritant 2 IV

870.2600 Skin sensitization rabbit 43089204 Not a dermal
sensitizer N/A

1 All studies were conducted on technical grade Sulfometuron methyl, of at least 98.8%, purity.Page 10 of 13

2 Minimal skin irritation was noted in the acute dermal toxicity study (MRID No. 43089202) and an older
dermal irritation study of a 75% formulation (MRID No. 00071411)Page 11 of 13

Table B .2

. Subchronic, Chronic and Other Toxicity Profile

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

870.3200 21

- Day dermal

toxicity (rabbit) 00126714 (1983)

Acceptable/non

- guideline M/F: 0, 125, 500, 2000 mg/kg/day NOAEL = 2000 mg/kg/day
LOAEL = Not observed

870.3700a Prenatal

developmental (rabbit) 00078798 (1981)

Acceptable/non

- guideline F:0, 30, 100, 300 mg/kg/day Maternal NOAEL =300 mg/kg/day (HDT)
LOAEL = 750 mg/kg/day based on abortion observed in the range

- finding study. Developmental NOAEL =300 mg/kg/day
LOAEL not observed

Prenatal developmental (rabbit)

– Range

finding study 00078797 (1981)

F: 100, 300, 750, 1000 mg/kg/day Maternal LOAEL = 750 mg/kg/day based on
abortion

870.3700b Prenatal

developmental in (rat) 00078796 (1981)

Unacceptable/guideline Run I F: 0, 5,000, 20,000, 40,000 and 60,000 ppm Run II & III F: 0, 50, 1000 and 5,000 ppm (433 mg/kg/day) Materna l NOAEL> 433 mg/kg/day LOAEL
not observed Developmenta l NOAEL>433 mg/kg/day
LOAEL not observed

870.4100b Chronic toxicity

(dog) 00129051 (1983)

Acceptable/guideline M: 0, 5.2, 27.5, 152.6 mg/kg/day F: 0, 5.3, 28.3, and 148.5 mg/kg/day NOAEL = 27.5mg/kg/day LOAEL = 148.5 mg/kg/day, based on hemolytic anemia in both sexes, decrea sed body

- weight gain in males, and increased alkaline phosphatase in males and females. Effects on body weight were observed beginning on the fourth week of exposure (and persisting throughout the study).

Gene
Mutation Salmonella/

Microsome assay 00078792 (1979)

Acceptable/guideline in strains TA 1535, TA 1537, TA 98 and TA 100 in the presence or absence
of activation. No mutagenic activity for all strains of bacteria
tested.

Gene
mutation Chinese Hamster

Ovary 00078793 (1981)

Acceptable/guideline

CHO cell line was used to
detect mutations for
HGPRT No mutagenic activity with or without
activation.

Chromo

some aberration Chinese Hamster

Ovary in vitro cytogenetic assay 00146846 (1981)

Acceptable/guideline
CHO in vitro assay with
and without activation No increase in chromosome damage and
aberrations.Page 12 of 13

Table B .2

. Subchronic, Chronic and Other Toxicity Profile

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

Un

scheduled
DNA synthesis Unscheduled DNA

synthesis in rat hepatocytes in vitro 00146847 (1983)

Acceptable/guideline No induction of UDS was observed.

Table B. 3 Summary of Toxicological Doses and Endpoints for Sulfometuron M ethyl for Use in Dietary and Occupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty

Factors RfD, Level of

Concern for Risk
Assessment Study and Toxicological Effects

Acute Dietary (all population subgroups) NOAEL= 27.5

mg/kg/day UF A = 10 x

UF H =10 x Acute RfD =

0.275 mg/kg/day

Chronic 1

- year dog study

LOAEL = 148.5 mg/kg/day based on decreases in body weight in males (beginning on the fourth week of exposure and persisted throughout), hemolytic anemia and a slight increase in alkaline phosphatase in males and females. Chronic Dietary (All Populations ) Chronic RfD = 0.275 mg/kg/day

Dermal Short

- (1

- 30 days) and
Intermediate

- Term (1

- 6 months) (no residential uses) NOAEL= 27.5

mg/kg/day UF A = 10x

UF H = 10x LOC for

MOE = 100 Inhalation Short

- (1

- 30 days) and
Intermediate

- Term (1

- 6 months) (no residential uses) Cancer (oral, dermal, inhalation) No data available for assessment.

Rationale for Requiring an Immunotoxicity Study

Guideline Number: 870.7800 Study Title : Immunotoxicity 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 desig ned 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 assessing functional immunotoxic endpoints arePage 13 of 13

helpful in fully characterizing a pesticide’s potential immunotoxici ty. These data will be used in combination with data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects.

Practical Utility of the Data
How will the data be used?

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 demons trated 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 dimin ished 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 these data, a 10X databas e uncertainty factor may be applied for conducting a risk assessment from the available studies.