Page 2 of 12 changes in toxicology endpoint and the update d assessment results were included in the Reregistration Eligibility Decision document (RED) which was issued in August 1996.

The 1996 RED addressed exposures and risks as sociated with occupational exposures to amitrole. A dietary (food) exposure assessment wa s not conducted and is not required at this

time since there are no food uses for amitrole and dietary (food) exposure is not expected based on registered uses. A drinking water assessment has not been performed. EFED will prepare a drinking water assessment under Registration Revi ew. The need for a dietary (drinking water) exposure assessment will be evaluated based on the results of the EFED assessment.

A residential exposure assessment was not condu cted and is not required at this time,

since there are no residentia l uses and no anticipated re sidential exposures.

Occupational handler assessments using current standard operating procedures and assumptions are needed for currently regist ered products of amitrole. Ther e is the possibility for postapplication workers to experience exposures to pesticide compounds. In this case, there is no dermal endpoint identified for risk assessmen t. HED believes post-application inhalation exposures are negligible. The worker activitie s for non-agricultural rights-of-way, industrial and construction sites, fencerows, and other uncultiv ated areas are exempt under Worker Protection Standard (WPS), therefore no reentr y interval is required. An a ggregate risk assessment is not required because there are no food and no reside ntial uses. There ar e several outstanding toxicology data requirements. If toxicology endpoints or points of departure are revised based on any new data, those will be considered in th e new amitrole human health risk assessment. Data requirements include the followi ng studies: 870.1300 Acute Inhalation, 870.3465 90-Day Inhalation, 870.6200a Acute Neurotoxicit y, 870.6200b 90-Day Neurotoxicity, and 870.7800 Immunotoxicity.

Introduction

HED has evaluated the existing human health risk assessments for amitrole to determine

whether sufficient data are available and whether a new human health risk assessment is needed to support Registration Review. HED has consid ered the most recent risk assessments for amitrole, updates to its toxici ty, exposure and usage databases, and current Agency science policies and risk assessment methods.

Use Profile

Amitrole is an herbicide applied outdoors for general weed control to non-agricultural rights-of-way, industrial and cons truction sites, fencerows, and other uncultivated areas. Tolerances are not currently establ ished for amitrole as there are no registered food or feed uses. Amitrole functions as a plant gr owth regulator. It inhibits ca rotenoid synthesis, chlorophyll formation, and limits the re-growth of buds. Amitrole products are formulated as a water dispersible granule and in water soluble bags (f ormulation type not specified on label). It is applied by boom sprayer. There are no reside ntial or homeowner uses and no residential exposures from any registered use is anticipated.Page 3 of 12 Chemical Identity

Amitrole Nomenclature

Chemical Structure

Common name AmitroleIUPAC name 1-H-1,2,4-triazol-3-ylamine, (formerly 1-H-3-amino1,2,4-triazole)
CAS name 1-H-1,2,4-triazol-3-amine

CAS # 61-82-5

Hazard Identification/Toxicology

Acute oral, dermal and inhalation studies indicate that amitrole exhibits low acute toxicity via the oral and dermal routes (Toxicity Category III/IV). The requirement for an acute inhalation study was previously waived based on th e availability of a 2-y ear rat inhalation study. However, the 2-year rat inhalation study was categor ized as ‘unacceptable’ and is not useful for regulatory purposes. This study al so suggested that the acute i nhalation toxicity was at least Toxicity Category III. At this time the acute inhalation study is being required for amitrole in

order to determine the acute LC 50 and to identify the toxicity hazard following acute inhalation

exposures.

Amitrole is a Toxicity Category III primary ey e irritant in rabbits. It is a Toxicity Category IV primary dermal irritant in rabbits; amitrole is not a skin sensitizer in guinea pigs. The primary target organ is the thyroid. Data from short term studi es and chronic studies indicate that effects will appear in the thyroid at lower dose levels than any other target organ. Eleven short term (oral rat) studies were conducte d with amitrole in order to study the effects of amitrole on the thyroid. Although none of the studie s can individually be categorized as being acceptable as a subchronic feeding study, the availa ble data provide an overall weight of the evidence of toxicological eff ects that can be used for making regulatory decisions.

Amitrole had been classified as a Group B2 -probable human carcinogen by the Office of Pesticide Programs Carcinogenicity Peer Re view Committee (document dated August 30, 1991). This B2 Carcinogen classification was based on t hyroid tumors in both se xes of multiple strains of rats, pituitary tumors in rats, and liver tumors in two strains of mice. The Agency calculated a Q1* from the thyroid tumor effects. In 2006, the HED Cancer Assessment Review Committee (CARC) re-evaluated the carcinoge nic potential of amitrole. The CARC classified amitrole as

“ Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone

Homeostasis ”. This decision was based on the following:

i) Treatment-related thyroid follicular cell tumors we re seen in male and female rats (multiple strains) based on evidence provided collectiv ely from several studies (Keller 1959; Johnson 1981; Steinhoff 1979; and Tsuda 1976);Page 4 of 12 ii) No treatment-related tumors were seen in male or female mice (Steinhoff and Boehme 1979); iii) Amitrole is considered to be nonmutagenic and does not mediate thyroid carcinogenesis through a mutagenic mode of action; iv) The overall weight-of-the-evidence was considered sufficient to indicate that amitrole induced thyroid follicular tumors through an antithyroidal mode of action; v) Rats are substantially more sensitive than human s to the development of thyroid follicular cell tumors in response to thyroid hormone imbalance.

Therefore, the previous quantif ication of carcinogeni c potential as B2 is not applicable (document dated 5/11/2006; TXR 0054224).

Based on the overall weight of the eviden ce found in the genotoxicity database (published by Hill et al. 1989 and IARC 2001), amitrole is not considered to be a mutagen or to cause thyroid follicular cell carcinogenesis through a mutagenic mode of action.

For developmental toxicity, four studies are av ailable to the Agency. They consist of an oral developmental toxicity study in the rat, two oral developmental toxicity studies in the rabbit and a dermal developmental toxicity study in the rabbit. All studies are acceptable for regulatory purposes. A 2- generation reproducti on study conducted in the rat is available to the Agency. The study is acceptable for regulatory purposes.

Toxicity points of departure (PoDs) were se lected for use in risk assessment for short term and intermediate term inhalation exposur es for the 1996 assessment. For short term inhalation occupational exposure (1 to 7 days), the maternal and developmental NOAEL of 4.0 mg/kg/day from the oral developmental toxicity study in the rabbit was selected as the PoD for

risk assessment. The maternal LOAEL is 40.0 mg/kg/day based on decreases in body weight gain during the dosing period and an increase in abortions. The developmental LOAEL is 40.0 mg/kg/day based on increases in the number of litters with a variety of malformations and variations and decreases in fetal body weight and percent live fetuses/litter.

For intermediate term inhalation occupational exposure (1 week to several months), the NOAEL of 0.90 mg/kg/day from the 2-generatio n reproduction study was selected. The LOAEL was based on clinical signs, death, decreas es in mean body weight, body weight gain, food consumption, food efficiency and selected absolute and relative organ wei ghts, an increase in thyroid weight and activity, follicular cell hypertrophy and hyperplasia and nodular hyperplasia and/or adenoma, hepato cellular hypertrophy and other microscopi c changes in the adrenals, liver, pituitary, mammary gland and kidney, a high inci dence of pseudopregnancy, decreases in mating and 18 fertility indices, implantat ion sites/litter and mean pup ma le/female ratio and a slightly higher gestation interval.

A sub-chronic inhalation study was not performed for amitrole. The previous

intermediate inhalation assessment used a PoD fr om an oral study. A route-specific study is preferred to route extr apolation. The 90/28-day inhalation study is now required for amitrole.

Toxicity endpoints for short term and intermediate term occupational dermal exposures

were not selected for the 1996 assessment. For s hort and intermediate term dermal exposures, a maternal and developmental NOAEL of 1,500 mg/ kg/day was identified from the dermalPage 5 of 12 developmental toxicity study. Since the dose select ed was so high, a quantit ative risk assessment was not required for dermal exposure.

The requirement for the 90-day dermal study was previously waived. The Less-thanLifetime Committee of the Agency's Office of Pe sticide Programs determined (document dated July 20, 1995) that results from a dermal absorp tion study and from the oral and dermal rabbit developmental studies indicate that dermal absorpti on is very low (only up to 1-2%). Therefore, it was considered unlikely that a 90-day derm al study conducted with amitrole would provide any additional useful data. Based on current policy, the 90-day dermal study waiver is still applicable. A 90-day feeding study will not be required in place of the 90-day dermal study

because sufficient data are available to indicat e that a 90-day oral study will not provide any

additional useful data for the purposes of risk assessment.

Acute and chronic dietary exposure endpoints were not selected because there are no registered food or feed uses for amitrole.

Screening batteries for acute and subchroni c (90 day) neurotoxic ity have not been submitted for amitrole and are now required under 40 CFR Part 158 guidelines (870.6200). The battery is designed to evaluate the potential adverse effects of a pest icide on the nervous system.

An immunotoxicity study is required as a pa rt of new data requirements in the 40 CFR Part 158 for conventional pesticide registration. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s poten tial immunotoxicity. While da ta from hematology, lymphoid organ weights, and histopathology in routine chronic or subchroni c toxicity studies may offer useful information on potential immunotoxic effects, these endpoi nts alone are insufficient to predict immunotoxicity (s ee Appendix A).

Dietary Exposures

A dietary exposure assessment was not pr eviously conducted because amitrole has no registered food uses. A dietary assessment for food exposures is not required. EFED will be performing a drinking water assessm ent under Registration Review. The need for a dietary assessment (for drinking water exposures only) w ill be evaluated based on the results of the new estimated drinking water concentrations.

Residential Exposure

Based on the currently register ed uses there are no resident ial exposures for amitrole. Therefore, a residential exposure assessment is not required.

Aggregate Exposure

The aggregate risk assessment evaluates the combined risk from dietary exposure (food and water) and any non-occupational (residential) uses. Since there are no registered food and residential uses of amitrole, an aggr egate assessment is not required.Page 6 of 12 Occupational Exposure

Amitrole (3-amino-1,2,4-triazole), is a non-selective herbicide used to control vegetation on a variety of non-crop sites (e.g.,r ights-of-way spray). Amitrole is currently formulated as a water dispersible granule (86.2 pe rcent active ingredient, Reg. # 33688-10) and as an unspecified

formulation in a water solubl e bag (88.2 percent ac tive ingredient, Reg. # 33688-6). A liquid concentrate (21.6 percent ai) wa s voluntarily canceled by the regi strant during development of

the 1996 RED.

Applications are made by fixed-boom sprayers attached to tractors/ trucks or railroad wagons. At this time no products containing amitr ole are intended primarily for homeowner use. All products containing amitrole ar e intended for occupational use.

Handler

The following scenarios were assessed in 1996 for short and intermed iate-term inhalation occupational handler exposure:

(1) Mixing/loading the liquid formula tion for ground equipment application (2) Mixing/loading the wettabl e powder formulation (in water soluble bags) for ground equipment, and (3) Applying the products as a spray with a groundboom sprayer as surrogate for the fixed-boom applications.

The handler assessments included inhala tion exposures estimates only. A dermal exposure assessment was not conducted as part of the 1996 RED. The dermal NOAEL selected from the dermal developmental toxicity st udy in the rabbit was high (1,500 mg/kg/day). Therefore, since the dose selected for risk as sessment was high, a quantitative dermal exposure risk assessment was not required.

The 1996 assessment indicated that the MOEs fo r short- and intermediate-term inhalation exposures at baseline protecti on (i.e. no respirator) were not of concern for the Agency.

Cancer risk estimates were also determined for handlers. At the time of the 1996 RED, amitrole was classified as a probable human car cinogen. Since that time, amitrole has been reclassified as “not likely to be carcinogenic to humans at do ses that do not alter rat thyroid

hormone homeostasis”. Therefor e, a cancer assessment is no longer required. Since the dermal data (PHED v.1.1) used for the cancer assessment were rated as ‘low confidence’, the RED required a confirmatory dermal exposure study fo r handlers (Guideline 231; current Guideline 875.1100, Dermal Exposure) to provide data on mi xers and loaders during the use of watersoluble packages and "no glug" containers. An OECD-based study was subsequently submitted and reviewed in June 2005 (MRID 46343704; D318601) . That review concluded that the study

was “not well suited for use in risk assessmen t”. A confirmatory dermal exposure study for handlers is no longer required because a cancer dermal assessment is not currently needed. Furthermore, if it is determined that dermal e xposure scenarios for non-canc er effects need to bePage 7 of 12 assessed under Registration Review the updated dermal exposure assumptions and data from the revised PHED or AHETF databases may be considered.

Under Registration Review, a handler asse ssment should be performed for mixing, loading, and applying water dispersible granules. The exposure scenario for this use was not previously assessed for amitrole. In addi tion, because of updates to standard operating procedures and exposure assumptions, occupation al assessments should be revisited for all currently registered amitrole form ulations. If toxicology endpo ints or points of departure are revised based on any new data, those w ill be considered in the new assessment.

Post-application

In general, amitrole is used in areas, such as rights-of-way, industrial areas, and other non-crop areas, where frequent or routine entry by persons who contact treated surfaces is unlikely. For the 1996 risk assessment, EPA determined that su ch post-application exposures do not appear to pose an unreasonable risk to persons entering tr eated areas, as long as entry is not permitted immediately after application. T ypically there is the possibility for post-application workers to experience post-application exposures to pesticide compounds. In this case, there is no dermal endpoint identified for risk assessment. HED be lieves post-application in halation exposures are negligible. The worker activities for non-agricultural rights-of-w ay, industrial and construction sites, fencerows, and other uncultivated areas are exempt under Worker Protection Standard (WPS), therefore no reentry interval is required. For the ab ove reasons, a post-application risk assessment is not necessary.

Previously, the Agency was concerned about the post-application e xposures to workers following applications of amitrole on commercial or research nurseries. EPA established an interim 24-hour restricted-entry interval within the scope of the Worker Protection Standard (WPS) and required confirmatory data ( 132-1(a) Foliar Residue Dissipation; 133-3 Postapplication Dermal Passive Dosimetry E xposure; and 133-4 Postapplication Inhalation Passive Dosimetry Exposure). There are no nursery use sites listed on the current labels and the confirmatory data are no longer required.

Incident Report

A summary report for incidents of amitrol e has been provided in the memorandum “Amitrole Review of Human Incidents” (D386310, K. Oo, 3/1/11). The evaluation of the OPP Incident Data System (IDS) indicated no incident s identified in the United States from 2002 thru 2010 for the single chemical amitrole. In Aggreg ate IDS, from 2002 to February 2011, there are five cases reported for amitrole. Because it falls within the categories re ported as counts (which includes minor, unknown or no effects) , there is no unique report that provides details about the incident and single chemical incidents are not distinguished from multiple chemical incidents; however, a high frequency of inci dents indicates there is a high potential fo r exposure and vice versa. For amitrole, there appears to be a low pot ential for exposure. Amitrole is not included in the Agricultural Health Study (AHS ), and therefore, does not provide information for this report. There does not appear to be a c oncern at this time that would wa rrant further investigation. ThePage 8 of 12 Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Cumulative

Amitrole is a triazole-derived herbicide. There is a triazole-metabolite aggregate

assessment for the triazole class of chemicals. Amitrole has not been included in this assessment because it is not expected to form the free triazo le, triazole-alanine or triazole acetic acid metabolites. Furthermore, the toxicity profile of amitrole is distinct from the triazole metabolites, producing primarily thyroid hyperp lasia with a NOAEL of 0.35 mg/kg/day in chronic studies. Conversely, the triazole metabolites produc e neurotoxicity, developmental toxicity, blood cell toxicity a nd skeletal deformations. .

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to amitrole and any other substances. For th e purposes of this registration review assessment of data needs, EPA has not assumed nor determ ined that amitrole has a common mechanism of toxicity with other s ubstances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity a nd to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedur es for cumulating effects from substances

found to have a common mechanism on EPA’s website at: http://www.epa.gov/pesticides/cumulative/ . If, in the future, the Agency determines that new

information on amitrole is available that could potentially impact a cumulative risk assessment and result in a risk of concern, the Agency will re visit the need for a cumulative risk assessment.

Human Studies

The Amitrole RED relied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies were used in developing the PHED Surrogate Exposure Guid e which was used to estimate exposure to

workers. The studies have been determined to require a review of thei r ethical conduct and have received the appropriate review.

The 1996 amitrole risk assessment did not rely directly on any huma n toxicology studies for endpoint selection, PoDs, or determining the uncertainty factors. The 1996 RED did summarize the results of a 1974 IARC monograph in which a person ingested amitrole and a 1982 dermal study in which workers were exposed to amitrole. If after cons idering these, or any other human study, we decide to rely on one or more for risk assessment, we will ensure that all regulatory requirements are me t, including EPA ethics and Human Studies Review Board (HSRB) reviews of the data.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA review s numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,

subchronic and chronic toxici ty, including assessments of carcinogenicity, neurotoxicity,Page 9 of 12 developmental, reproductive, and general or syst emic toxicity. These studies include endpoints which may be susceptible to endocrine influenc e, including effects on endocrine target organ histopathology, organ weights, es trus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard asse ssments, EPA evaluates

acute tests and chronic studies that assess growth, developmen tal and reproductive effects in different taxonomic groups. As part of its reregistration decision

, EPA reviewed these data and selected the most sensitive endpoi nts for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), amitrole is subject to the endocrine screening part of the Endocrine Disruptor Screenin g Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredie nts) may have an effect in hu mans or wildlife similar to an effect produced by a “naturally occurring estr ogen, 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 w ith 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 sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Ti er 2 tests are necessary based on the available data. Tier 2 testing is designe d to identify any adverse endocr ine-related effects caused by the substance, and establish a dose-re sponse relationship between the dos e and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. 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. Amitrole is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issu e future EDSP orders/data callins, requiring the submission of EDSP screening assays for amitrole. For further information on the status of the EDSP, the policie s and procedures, the lis t of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Conclusions/Future Actions Needed

The actions needed in the future Registra tion Review for amitrole are listed below.

Hazard Identification an d Endpoint Selection There are several outstanding toxico logy data requirements. If t oxicology endpoints or points of departure are revised based on any new data, those will be considered in the new amitrole assessment. Data requirements include: 870.1300 Acute Inhalation, 870.3465 90-Day Inhalation, 870.6200a Acute Neurotoxicity, 870.6200b 90-Day Neurotoxicity (Sub chronic), and 870.7800 Immunotoxicity.

Dietary Exposure and Risk A dietary (food) exposure assessmen t is not required. The need for a dietary (drinking water) exposure assessment will be evaluated based on the results of the EFED drinking water

assessment.Page 10 of 12 Residential Exposure and Risk

A residential risk assessm ent is not required.

Aggregate Exposure and Risk An aggregate exposure assessm ent is not required.

Occupational Exposure and Risk Occupational assessments using current standa rd operating procedures and assumptions are needed for currently registered formulations of amitrole. If toxicol ogy endpoints or points of departure are revised based on any new data, those will be considered in the new assessment.

Incident Report An updated incident report is not required at this time.

Data Requirements

Toxicity:

870.1300 Acute Inhalation 870.3465 90/28-Day Inhalation 870.6200a Acute Neurotoxicity 870.6200b 90-Day Neurotoxicity 870.7800 Immunotoxicity

870.1300 Acute Inhalation: The requirement for an acute inhalation study was previously waived because a 2-year rat inhalation study was available which, while categorized as ‘unacceptable’ and not useful for regulatory purpose s, suggested that the acute inhalation toxicity was at least Toxicity Category II I. At this time the acute inha lation study is being required for

amitrole in order to determine the acute LC 50 and to identify the toxic ity hazard following acute inhalation exposures.

870.3465 90/28-Day Inhalation: A subc hronic inhalation study was not performed for amitrole. The previous intermediate inhalation assessm ent used a PoD from an oral study. A routespecific study is preferred to route extrapolation. The 90-day inhalation study is required for amitrole. The study can be reduced to a 28-day prot ocol if the data platea us during the testing, or if exposure potential is not expected to exceed 28 days.

870.6200a Acute Neurotoxicity and 870.6200b 90-Day Neurotoxicity (Sub chronic): Screening batteries for acute and subchronic (90 day) neur otoxicity have not been submitted for amitrole and are now required under 40 CFR Part 158 guide lines (870.6200). The battery is designed to evaluate the potential adverse effects of a pesticide on the nervous system.

870.7800 Immunotoxicity: An immunotoxicity st udy is required as a part of new data requirements in the 40 CFR Part 158 for convent ional pesticide regist ration. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxicPage 11 of 12 endpoints are inadequate to charact erize a pesticide’s potential im munotoxicity. While data from hematology, lymphoid organ weights, and hist opathology in routine ch ronic or subchronic toxicity studies may offer useful information on potential immunotoxic e ffects, these endpoints alone are insufficient to predict i mmunotoxicity (see Appendix A).

References

HED Chapter of the Reregistration Eligibility Document (RED) for Amitrole (T. Myers, 12/26/95, HED doc no. 011752).

Occupational and Residential Exposure Assessmen t and Recommendations for the Reregistration Eligibility Document for Amitr ole (J. Evans, 12/6/95, D219471).

Amitrole: Toxicology Endpoint Selecti on Document (rev 5/21/96, HED doc no.013093).

Reregistration Eligibility D ecision (RED) Amitrole (8/96).

Amitrole : Fifth Report of the Cancer Assessment Re view Committee (J. Kidwell, 5/11/06, TXR No. 0054224).

1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and Re gistration Actions for Triazole-derivative Fungicide Compounds (DP Number: 322215)Page 12 of 12 Appendix A

Rationale for Requiring Immunotoxicity Testing

Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data

This is a new data requirement under 40 CFR Pa rt 158 as a part of the data requirements for registration of a pestic ide (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to eval uate 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 vira l infections such as tuberc ulosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia . Because the immune system is highly complex, studies assessing functional i mmunotoxic endpoints are helpful in fully characterizing a pesticide’s pot ential immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity st udies 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 demonstrated that immunotoxicity in

rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenzop-dioxin) among developmental, reproduc tive, and endocrinol ogic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxici ty in animal studies (IRIS, 1997).

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

If the immunotoxicity study show s that the test material pos es either a greater or a diminished risk than that given in the inte rim decision’s conclusion, the risk assessments for the test material may need to be revise d 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.