## THE OFFICE OF PESTICIDE PROGRAM = S

GUIDANCE DOCUMENT

ON

METHODOLOGY

for DETERMINING the DATA NEEDED and the

TYPES of ASSESSMENTS

NECESSARY to MAKE FFDCA SECTION 408

SAFETY DETERMINATIONS for

LOWER TOXICITY PESTICIDE CHEMICALS

OFFICE OF PESTICIDE PROGRAMS

U.S. ENVIRONMENTAL PROTECTION AGENCY

June 7, 2002METHODOLOGY for DETERMINING the DATA NEEDED and

the TYPES of ASSESSMENTS NECESSARY

to MAKE FFDCA SECTION 408 SAFETY DETERMINATIONS

for LOWER TOXICITY PESTICIDE CHEMICALS

TABLE of CONTENTS

I. INTRODUCTION ..................................................................................................................1

II. BRIEF OVERVIEW of NEWLY DEVELOPED METHODOLOGY ..............................3

III. BACKGROUND ..................................................................................................................5

IV. HISTORY of the INERT REGULATORY PROGRAM ..................................................8

V. IMPACT of FQPA on the INERT REGULATORY PROGRAM ...................................11

VI. CONSIDERATIONS in DESIGN of a NEW APPROACH ............................................13

VII. ADDITIONAL CONSIDERATION: ALTERNATIVE APPRO ACHES FOR DETERMINING DATA REQUIREMENTS USED by VARIOUS REGULATORY

PROGRAMS .....................................................................................................................15

VIII. DEVELOPING a METHODOLOGY THAT SCREENS for LOWER TOXICITY

.................................................................................................................... .....................20

IX. USE of EXISTING CHEMICAL INFORMATION/ DATA ..........................................22

X. ROLE of EXPOSURE ASSESSMENT in this SCREENING/TIERED

METHODOLOGY ..............................................................................................................26

XI. COORDINATION with OTHER DATA GENERATION PROGRAMS at EPA .........29

XII. PRELIMINARY TIER DETERMINATION .................................................................32

XIII. EXAMPLES of TIER 1a and 1b ASSIGNMENTS for INERT INGREDIENTS ......34

XIV. DESCRIPTION of TIER 2 ASSIGNMENTS ...............................................................39

XV. EXAMPLES of TIER 3 ASSIGNMENTS ......................................................................40

XVI. WEIGHT-of-the-EVIDENCE EVALUATION for CONDUCTIN G RISK

ASSESSMENTS for TIER 1b and TIER 2 CHEMICALS .........................................42XVII. EVALUATION of the FQPA 10X SAFETY FACTOR WHEN CONDUCTING

RISK ASSESSMENTS for LOWER TOXICITY CHEMICALS .............................45

XVIII. ROLE of the INERT INGREDIENT FOCUS GROUP ............................................46

XIX. OPPORTUNITIES for REGISTRANTS and PETITIONERS ...................................50METHODOLOGY for DETERMINING the DATA NEEDED and

the TYPES of ASSESSMENTS NECESSARY

to MAKE FFDCA SECTION 408 SAFETY DETERMINATIONS

for LOWER TOXICITY PESTICIDE CHEMICALS

I. INTRODUCTION

The paper describes the newly-developed methodology that is now being used on a chemical-by-chemical basis to evaluate low toxicity chemical substances for use in pesticide products. Section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA) requires EPA to determine that there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue before granting a tolerance or exemption from the requirement of a tolerance for that pesticide chemical. Both inert and active ingredients of pesticide products, and their metabolites and degradates are considered A pesticide chemicals @

The Office of Pesticide Programs (OPP) is the Office within the Environmental Protection Agency (EPA or the Agency) responsible for evaluating pesticide products under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and FFDCA. OPP = s responsibilities (all of which could be affected by the use of this new methodology) include:

$ Registration of new active ingredients

$ Reregistration of older active ingredients

$ Reassessment of both tolerances and tolerance exemptions

$ Approval of new inert ingredients

$ List reclassification of inert ingredients.

Development of this methodology began as a result of OPP = s need to (1) develop a new methodology for assessing inert ingredients (sometimes referred to as other ingredients) to comply with the requirements of the Food Quality Protection Act (FQPA) of 1996 which amended both FFDCA and FIFRA and (2) improve the efficiency and effectiveness of the inert review process. The methodology described herein is an evolution, advancement, and refinement of the approach described in the 1987 and 1989 inert ingredient policy statements (April 22, 1987; 52 FR 13305 and November 22, 1989; 54 FR 48314). It should be noted that the term inert ingredients or inerts is used throughout this paper; however, as will be explained this methodology is appropriate for most low toxicity chemicals whether used as inert or active ingredients.

EPA believes that FFDCA section 408 safety determinations can be made for many low or low/moderate toxicity inert ingredients ba sed on significantly fewer data than would be needed for inert ingredients of higher potential toxicity. This paper explains the process EPA is now using for making chemical-by-chemical decisions for these lower toxicity chemical substances concerning how much and what kinds of data are necessary to support a petition for, or reassessment of, an exemption from the requirement of a tolerance. In many instances, a chemical can be used as an inert ingredient in some pesticideproducts and as an active ingredient in other pesticide products. Since FFDCA section 408

makes no distinction between active and in ert ingredients of a pesticide product, EPA

m a y use this tiered data screening m e thodology when evaluating any pesticide chem ical of apparent low or low/m oderate toxicity, regardle ss of whether it m i ght be characterized as an active or inert ingredient.

At this tim e, EPA has com p leted review of two tolerance exem ption petitions and over

200 tolerance reassessm ents for low or low/m oderate toxicity chem icals using essentially the process described in this paper. More reviews are underway. Based on these experiences, OPP

intends to continue its chem ical-by-chem ical reviews of pesticide chem icals according to the process described herein for the foreseeable future. However, EPA rem a ins interested in further

im provem e nts in the ef f i ciency and reliability of its process, and theref ore welcom es com m e nts
from interested persons.

This paper is intended to provide guidance to EPA personnel and decision-m a kers, and to pesticide registrants. The policies and process described herein are not binding on either EPA or pesticide registrants, and EPA m a y m odify or disregard the process described herein where

circum stances warrant and without prior notice. Li kewise, pesticide registrants m a y assert that this process is not appropriate generally or not applicable to a specific pesticide chem ical or

situation.

Page -3-II. BRIEF OVERVIEW of NEWLY DEVELOPED METHODOLOGY

The m e thodology currently being used by OPP for evaluating low or low/m oderate toxicity chem ical substances is a screening process that incorporates elem ents of a tiered data approach. In establishing this process, the Office of Pesticide Programs sought a

framework that would allow decisions to be based on sound science and achieve the risk characterization principles of transparency, clar ity, consistency, and reasonableness. There is

also a need for these decisions to be m a de in an efficient and cost-effective m a nner.

After evaluating several alternatives, OPP believes that a screening methodology is the most appropriate way to handle the variety of hazard and exposure issues posed by inert ingredients. This screening methodology will allow OPP to make decisions in a
streamlined manner for low or low/moderate toxicity chemical substances. By being able to quickly review and approve the use of these chemical substances, more low or low/moderate toxicity chemical substances wi ll be available for use in pesticide products. OPP will also be able to focus its resources on those chemical substances of potentially higher toxicity requiring in-depth evaluation.

OPP has incorporated elements of a tiered data approach into this methodology. This tiered data approach differs from the tiered approach of 40 CFR 158.101, where a basic set of data is required for every che mical substance and additional data may be required based on the results of the review of the initially required data. Instead, OPP would use existing information on the hazard potential (both human health and ecological) of a chemical substance as the basis for deciding if additional data are needed to support the use of the chemical. The hazard potential - the toxicity - is the driving force in determining tier placement. Chemical substances that are of low or low/moderate toxicity may be appropriately placed in a lower tier, with fewer data needed to make the safety finding. Chemic als of higher toxicity that can not be appropriately addressed in the lower tiers would be evaluated in a manner substantially similar to that of an active ingredient.

In its evaluations, OPP also considered that som e chem icals m a y be used as an inert ingredient in som e form ulations and as an activ e ingredient in other form ulations. EPA believes

this m e thodology m a y also be appropriate for evaluating som e low toxicity chem icals regardless of whether they are categorized as active or inert ingredients.

The m e thodology described in this paper, as currently in use by OPP, has three tiers, with the first tier being subdivided into Tiers1a and 1b. The process begins with a prelim inary Tier

determ ination that is based on widely available inf o rm ation on chem ical f a m ilies and categories. Later as the Agency begins to review chem ical-specific or surrogate inform ation in the open literature, the prelim inary Tier determ ination m a y be revised.

Page -4- Tier 1 chem icals would be those of low or low/m oderate toxicity for which there isreadily available scientifically-valid inform ation/data to m a ke a confirm a tory judgem e nt concerning these chem ical substances = low or low/m oderate toxicity. It is anticipated that the rationale and justification used to m a ke this confirm a tory judgem e nt concerning the low or

low/m oderate toxicity for these chem icals would consist of com m only or readily available knowledge on the lack of toxicity. This could include inform ation such as a review of existing data, or a SAR (structure-activity-relationship) assessm ent. Tier 1a risk assessm ents will be qualitative. Tier 1b risk assessm ents will usually be qualitative, although for som e lower toxicity

chem ical substances a quantitative risk assessm ent m a y be perf orm e d.

Tier 2 chem icals would be those for which OPP does not have and cannot locate

sufficient inform ation to assess the chem ical substance = s toxicity. Given the lack of readily

available inform ation to classify it as a Tier 1, the chem ical substance would be placed in Tier 2, and OPP would likely require the subm ission of a lim ited data set to characterize the hazard of

the chem ical substance. This data set would have sim ilarities to the internationally recognized Organization for Econom ic Cooperation and Devel opm ent (OECD) Screening Inform ation Data Set (SIDS). The data subm itted could be either existing studies that were not readily available to OPP or newly perf orm e d studies. Once the subm itted data have been reviewed and evaluated,

the Tier 2 determ ination could be revised to either Tier 1 or Tier 3. For m o st Tier 2 chem ical substances, the quantitative risk assessm ent would integrate the results of the subm itted studies,

a SAR assessm ent, and any relevant existing data (if available). However, it is also possible that

som e Tier 2 chem icals could have qualitative assessm ents based upon the review and evaluation

of

the subm itted data.

Chem ical substances which appear to have a ppreciable toxicity would be assigned to Tier

3. The m e thodology discussed in this paper is not appropriate for m a king FFDCA Section 408 safety determ inations for higher toxicity chem ical substances. OPP anticipates that it would need

to review a com p lete (food-use) 40 CFR Part 158 database to m a ke these safety determ inations.

It should be em phasized that a Tier determ ination is m e rely a tool used by OPP to assist

in m a king its decisions on how to evaluate the risk of a chem ical substance. In and of itself, the

Tier Determ ination has little regulatory m eaning. In fact, this m e thodology could be perform e d

without form al tiers; however, OPP has found it to be a useful tool in its internal discussions.

Page -5-III. BACKGROUND

Definition of Inert Ingredient

A Inert ingredients @ are all ingredients contained in a pesticide product that are not A active ingredients @ as defined in 40 CFR 153.125. These substances have a very wide range of physical/chem i cal characteristics and potential t oxicological effects ranging from practically non-toxic to effects of high toxicological concer n, such as carcinogenicity. One of the m o st significant challenges EPA faced in developing a m e thodology for a com p rehensive inert ingredient assessm ent program was determ ining the m o st appropriate procedure for evaluating such a diverse group of substances.

Statutory and Regulatory Framew ork of Pesticide Regulation

Pesticide products are regulated under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and the Federal Food, Drug, and Cosm etic Act (FFDCA). Both

statutes were am ended by the Food Quality Protection Act (FQPA) of August 3, 1996.

FIFRA authorizes EPA to register a pesticide if am ong other things, it will perform its

intended function without unreasonable adverse effects on the environm ent and its com position and labeling m eet requirem e nts under FIFRA secti on 3(c)(5) or 3(c)(7). FIFRA prohibits the sale or distribution of any unregistered pesticides in the United States unless the Agency

authorizes an em ergency exem ption from FIFR A requirem e nts under section 18 of FIFRA, or issues a regulation exem pting a pesticide from FIFRA requirem e nts under section 25(b) of FIFRA. FIFRA also authorizes States, subject to EPA review, to grant special local needs registration under FIFRA section 24(c). FIFRA sec tion 4 also requires EPA to reevaluate all pesticides first registered before Novem b er 1, 1984, through a program called reregistration.

FFDCA prohibits the introduction or delivery for introduction into interstate com m e rce of any food that is A adulterated @ (FFDCA section 301(a)). Food is deem ed adulterated if, am ong other reasons, A it bears or contains a pesticide chem ical residue that is unsafe within the m eaning of section 408(a) @ (FFDCA section 402(a)(2)(B)). Under FFDCA section 408(a)(1), A any pesticide residue in or on a food shall be deem ed unsafe for the purposes of section 402(a)(2)(B)

unless a tolerance ....is in effect.... @ and residues in/on the food are within the tolerance.

FQPA clarified EPA = s authority to establish a tolerance (or tolerance exem ption) f o r residues of a pesticide active ingredient, any inert ingredient and any m e tabolites and degradates of active or inert pesticide ingredients that are in or on a food. FQPA redefined A pesticide

chem ical @ in FFDCA section 201(q)(1) to m ean: A any substance that is a pesticide within the

m eaning of FIFRA, including all active and inert ingredients of such pesticide @ . FQPA also

added a definition of A pesticide chem ical residue @ in FFDCA section 201(q)(2). This term m eans any residue of a pesticide chem ical or any other substance that results prim arily from the

m e tabolism or degradation of a pesticide chem ical. This definition m a kes explicit the longstanding EPA interpretation that tolerances established under section 408 of the FFDCA cover

Page -6-chem ical com pounds form ed through the breakdown or m e tabolism of pesticidally active and inert ingredients of a pesticide form ulation.

FQPA significantly changed the basis for m a king a safety finding when establishing a tolerance (or tolerance exem ption). Under FFDCA section 408(b)(2)(A) and (c)(2)(A), the Agency m u st find that: A There is reasonable certainty that no harm will result f r om aggregate exposure to the pesticide chem ical residue, including all anticipated dietary exposures and all other exposures for which there is reliable inform ation. @

In addition to assessing exposure to pesticide residues in food and water, EPA m u st assess exposures to pesticide residues from non-occupational uses, such as, in and around the

hom e, garden, recreational areas, and schools. Additionally, the Agency is required to assess the risk of a pesticide chem ical exposure to infants and children using an additional 10-fold m a rgin of safety to take into account potential pre-and post-natal exposures and com p leteness of the data with respect to exposure and toxicity for infants and children, unless EPA determ ines, based on reliable data, that a dif f e rent m a rgin of saf e ty will be saf e f o r inf a nts and children. It is important to note that the new safety standard applies to all components of the pesticide residue on food

B the active ingredient and its metabolites or degradates and all inert ingredients and their metabolites and degradates.

FFDCA also requires the Agency to review over a 10-year period which ends August

2006 all A tolerances and exem ptions for pesticide chem ical residues in effect on the day before

the date of the enactm e nt of the Food Quality Protection Act of 1996. @ In m a king its

reassessm ent determ ination, the Agency applies a A reasonable certainty of no harm @ standard.

W h ile FIFRA governs the sale, distribution and use of a pesticide through a registration process and enforcem ent of the requirem e nts on the pesticide label, FFDCA provides a direct

m eans of policing pesticide residue levels in food through a tolerance or an exem ption from tolerance for the pesticide residues. Under 40 CFR 152.112(g) and 152.113(a), EPA will not register the use of a pesticide if all needed tolerances or tolerance exem ptions have not been established for each of the active and inert ingredients in the form ulation.

Authority to Regulate Inert Ingredients under FIFRA and FFDCA

EPA = s authority and obligation to regulate inert ingredients is clear. FFDCA section 408(q)(1) expressly includes A all active and inert ingredients @ within the definition of A pesticide

chem ical @ . FIFRA section 3(c)(5) requires EPA to determ ine, for each individual pesticide product, whether its com position is such as to warrant the proposed claim s m a de for it, whether it will perform its intended function without unreasonable adverse effects on the environm ent, and whether, when used in accordance with widespread and com m only recognized practice, it will not generally cause unreasonable adverse ef f ects on the environm ent. Making such f i ndings in regard to each individual pesticide product necessarily requires that EPA take into account the

characteristics of the inert ingredients of the pesticide.

Page -7-FIFRA specifically requires the subm ission of various inform ation on the inert ingredients in a pesticide form ulation. FIFRA section 2(n) requires that the total percentage of all inert ingredients be listed as part of the ingredient statem ent on the label, and FIFRA section (3)(c)(1)(D) requires the subm ission of A the com p lete f o rm ula of the pesticide @ as a condition of registration. Additionally data-call-in notices for inert ingredients are issued under FIFRA section (3)(c)(2)(B). Although regulations established in 1984 require the subm ission of a battery of acute toxicity tests on the pesticide form ulation (which would include both the active and inert ingredients), there were no specific inert ingredient data requirem e nts. 40 CFR 158.155(b) requires the identification and characterization of the inert ingredients in a pesticide

form ulation. Moreover, the general requirem e nts of the FFDCA apply equally to active and inert ingredients.

Summary of the Pesticide Program Risk Assessment and Risk Management Process

In evaluating possible im pacts of pesticide exposures on hum an health and the

environm ent, the Agency uses a process known as risk assessm ent. The National Academ y of

Sciences and EPA risk assessm ent guidelines define risk assessment as the process for analyzing scientific data to describe the form , dim e nsion, and characteristics of risk

. T hat is, a

risk assessm ent answers the question: W h at is the likelihood of harm to hum ans or the

environm ent? Risk assessm ents are perform e d in a four-step process:

$ Hazard Identification/Assessm ent: determ ining whether a particular chem ical is or is not linked to a particular effect

$ Dose-Response Assessm ent: determ ining the relationship between the m a gnitude of the exposure and the probability of the particular effect occurring at a particular exposure

$ Exposure Assessm ent: determ ining the nature and extent of the exposure

$ Risk Characterization: a description of the nature (qualitative) and the m a gnitude (quantitative) of risk, including a discussion of the strengths and weaknesses of the

assessm ent

Once the risk assessm ent is com p lete, the conclusions of the risk assessm ent are used to

m a ke an inform ed risk m a nagem e nt determ ination. In m a naging the risk, the OPP risk m a nager considers the statutory requirem e nts and the f easibility of the risk m itigation/risk reduction

m easures.

Page -8-IV. HISTORY of the INERT REGULATORY PROGRAM

Pesticide products have a wide variety of purposes and uses. They are used at a wide variety of sites: farm s and feed lots, hom es and schools. Som e pesticide products can be used to

fum i gate soil, others to kill weeds. Som e are used to prevent food spoilage or insect infestation

after harvest. Som e products are intended to be used in sm all, localized spots, while others are

m eant to be broadcast over a large area. Som e are used to kill germ s on food-contact surfaces in

hom es, restaurants and processing f acilities.

Most active ingredients cannot be used in their pure form . Generally, it is necessary to

add other substances to a pesticide formulation to ensure that the active ingredient will be delivered to the target site at a consistent concentration in a controlled manner . These substances that are added to the active ingredient are referred to as inert ingredients. Exam ples of inert ingredients uses include:

$ stickers (to increase the tim e that the active ingredient rem a ins on the plant part or other solid surface),

$ solvents,

$ surfactants (to m odify the surface characteristic s, such as reducing the surface tension of water often described as wetting agents, detergents, penetrants, and em ulsifiers),

$ carriers such as clay and diatom aceous earth on which the active ingredient is coated,

$ thickeners such as carrageenan and m odified cellulose,

$ propellants in aerosol dispensers; and

$ encapsulating agents which can fix the active ingredient in a m a trix and, thus, control its

rate of release.

Although the term A inert @ may connote physical, chemical or biological inactivity,

use of the word A inert @ to describe a component in a pesticide product means only that the substance is not intended to exert a pesticid al effect (i.e., to prevent, destroy, repel or mitigate any pest or to function as a plan t regulator, desiccant, or defoliant) in that product. The A inert @ ingredient may have biological activity of its own, it may be toxic to humans, and it may be chem ically active. However, while inert ingredients m a y be

im portant in delivering the pesticide product in a controlled m a nner, they are not the ingredient

in the form ulation that is intended to prevent, destroy, repel, or m itigate the target pest.

Prior to the creation of EPA, the Food and Drug Adm i nistration (FDA) had the responsibility for establishing pesticide residue tolerances under section 408 of FFDCA. The Departm e nt of Agriculture (USDA) registered pesticides under FIFRA. USDA determ ined in

1961 that all ingredients in a pesticide (then referred to as an A econom ic poison @ ) are A pesticide

chem icals @ under FFDCA and therefore residues of inert ingredients of pesticide formulations on raw agricultural commodities would be subject to section 408 of FFDCA. On April 11, 1962, FDA promulgated tolerance exemptions for substances known to be

used in pesticide f o rm ulations applied to growing crops or raw agricultural com m odities. Later,

Page -9-in 1969, a process was established whereby persons wishing to use additional inert ingredients in food-use pesticides could subm it a petition to FDA requesting approval of the use

. To support the requested use, petitioners were required to submit two subchronic toxicity studies, and, for postharvest use, two chronic toxicity studies. Petitioners could ask FDA to waive some or all of these data requirements if they could demonstrate that the inert ingredient was useful in the form ulation and had been previously determ ined to be generally recognized as safe (GRAS) for that purpose.

Many of the inert ingredients approved for food-use during the 1970s and early 1980s were approved using a data review process that was less rigorous than that used today, but was

consistent with the standards of the tim e. In those cases where data were provided, the substances being considered for use as inert ingredients were often FDA-approved food additives for which toxicological data had already been developed.

In response to concerns that the then existing process for reviewing inert ingredients did not adequately account for potential effects on human health or on the environment, OPP reevaluated its procedures for approving inert ingredients in pesticide products. On April 22, 1987, O P P p u b l i s h e d i n t h e F e d e r a l R e g i s t e r (52 FR 13305) a policy

statem ent on inert ingredients that established f our categories of toxicological concern for the inert ingredients in use at the tim e:

$ List 1 inert ingredients were A inerts of toxicological concern. @ List 1 inert ingredients were classified on the basis of peer review ed studies which dem onstrated carcinogenicity, adverse reproductive effects, neurotoxicity or other chronic effects, developm ental toxicity (birth defects), ecological effects and the potential for bioaccum u lation.

$ List 2 inert ingredients were A potentially toxic inerts/high priority f o r testing. @ Many of these inert ingredients are structurally sim ilar to chem icals known to be toxic; som e have data suggesting a concern.

$ List 3 inert ingredients were A unknown toxicity. @ An inert ingredient was placed on List 3 if there was no basis for listing it on any of the other three lists.

$ List 4 inert ingredients were A inerts of m i nim a l concern. @

On Novem b er 22, 1989, (54 FR 48314) List 4 wa s further subdivided into List 4A and

List 4B:

$ List 4A inert ingredients are m i nim a l risk inert ingredients.

$ List 4B inert ingredients are A inerts f o r which EPA has suf f i cient inf o rm ation to reasonably conclude that the current use pattern in pesticide products will not adversely affect public health or the environm ent. @

The 1987 policy also specified a m i nim u m or base set of data that would be needed to assess all new inert ingredients. These data were a subset of the data requirem e nts for pesticide active ingredients and included:

Page -10-$ general inform ation (use patterns, types of form ulated products, and purpose of the inert ingredient in the form ulation),

$ eight product chem istry studies,

$ toxicity studies

$ two 90-day (subchronic) (rat and non-rodent) feeding studies (food uses)

$ derm al subchronic (non-food uses)

$ rat developm ental toxicity study

$ m u tagenicity studies

$ for outdoor uses only, four ecotoxicity studies

$ acute f i sh toxicity

$ acute invertebrate toxicity

$ acute bird toxicity

$ 8-day bird toxicity

$ for outdoor uses only, five environm ental fate studies

$ hydrolysis

$ aerobic soil m e tabolism

$ photodegradation in water

$ photodegradation in soil

$ soil adsorption/desorption (Koc or Kd)

If, during the Agency = s review and evaluation, concerns were identified, then additional data could be requested.

The resulting review process typically resulted in a qualitative assessm ent in which the toxicity inform ation was com p ared with the expected dietary exposure (usually a worst-case

estim ate) to determ ine if there were any risk concerns. If a substance had FDA approval (s) for various food additive uses, EPA generally considered that the uses regulated by FDA would result in greater dietary exposures than would typically occur as a result of its use as an inert ingredient in pesticide form ulations. Accordingly, EPA would generally determine that no additional data were needed to support the inert ingredient use of the substance.

Page -11-V. IMPACT of FQPA on the INERT REGULATORY PROGRAM

FQPA included specific am endm ents to FFDCA section 201(q)(1)) that defined an inert ingredient as a pesticide chem ical. Thus, the FQPA standard of A reasonable certainty of no

harm @ applies to both active and inert ingredients when establishing a tolerance or tolerance

exem ption.

EPA = s regulations at 40 CFR part 180 do not specify exactly what data m u st be subm itted with a petition to establish a tolerance or an exem ption f r om the requirem e nt of a tolerance. Section 180.7(b) identifies in general term s the types of inform ation needed for approval of a

tolerance or tolerance exem ption. W ithin this regulatory fram ework, EPA m a kes decisions

about what data are needed on a chem ical-by-chem ical basis, and acquires them through either FFDCA or FIFRA. For pesticide chem icals currently subject to a tolerance or exem ption, or contained in a registered pesticide product, EPA m a y require data pursuant to either FFDCA section 408(f)(1)(C) or FIFRA section 3(c)(2)(B).

In an application for registration under FIFRA of a pesticide product, EPA routinely requires subm ission of a com p rehensive array of test data on the pesticide active ingredient (see 40 CFR part 158), which provide the basis for EP A to m a ke the section 408 safety finding in regard to that active ingredient.

In the 1987 policy statem ent on inert ingredients discussed above, EPA identified a base set of data that it generally found sufficient to evaluate the risks of new inert ingredients, or new uses of existing inert ingredients. This policy statem ent stated that in its chem ical-specific

deliberations EPA could conclude that som e or all of these studies are unnecessary, or m i ght

deem additional data necessary to fully assess the risks. Since the enactm e nt of the FQPA,

which am ended both FFDCA and FIFRA, OPP has been advising persons seeking a tolerance

exem ption for an inert ingredient that the base set of data described in the 1987 policy statem ent is no longer appropriate since it did not include information on exposure beyond that in a pesticide product and limited data with respect to developmental and reproductive toxicity.

The only information in the1987 data set pertaining to exposure is the provision calling for a description of the expected use pattern for the proposed inert ingredient. The 1987 data set did not consider that most substances used as inert ingredients in pesticide products could be chemicals that are commonly used in other industries. The Agency considers information on exposures to the chemical substance from all other sources in order to assess the safety from A all other exposures for which there is reliable

inf o rm ation, @ as required by FFDCA section 408.

Additionally, the Agency is required to assess the risk from pesticide residues in food to infants and children taking into account potential pre-and post-natal exposures, and com p leteness of the data with respect to exposure and toxicity for infants and children. The 1987 inerts policy

Page -12-requested the subm ission of only a single developm ental toxicity study, and no reproductive toxicity study. A single developm ental toxicity study is generally considered insufficient

inform ation, especially when coupled with the lack of exposure inform ation, to assess the special

sensitivities of inf a nts and children.

The 1987 base set of data is no longer appropriate; however, the 1987 inert ingredient policy also A categorized inert ingredients according to toxicity @ by creating Lists 1, 2, 3, and 4. As previously explained List 4 was subdivided in 1989 to List 4A and 4B. These Lists rem a in in existence, continue to be used by the Agency, and will be updated.

Page -13-VI. CONSIDERATIONS in DESIGN of a NEW APPROACH

One of the most significant challenges in implementing an effective and efficient regulatory program for inert ingredients is creating a review process that is protective of human health and the environment, but which also recognizes that a large percentage of inert ingredients are not, in fact, likely to be of significant toxicological concern. It would be a poor use of societal resources to routinely require the submission and governmental review of an estimated 12 milli on dollars worth of data (the estimated current cost of the 40 CFR Part 158 (food-use) data set for every inert ingredient when the Agency = s expectation is that on the order of 50% of inert ingredients would be of low or low/moderate risk. At the same time, EPA must be able to identify potentially problematic inert ingredients and then have the resources to take appropriate action to

reduce these risks.

In searching for options for m odifying the current inerts review process to ensure

com p liance with FQPA, EPA considered whether it was appropriate to sim p ly require a

com p lete Part 158 data set to support the use of an inert ingredient in a pesticide. EPA exam ined the proposition that if a Part 158 data set was necessary to support decision-m a king on an active pesticide ingredient, then the sam e data set should also be necessary for the other ingredients in a pesticide form ulation.

Inert ingredients are not intended to poison or repel pest organism s; therefore, with som e exceptions, inert ingredients generally do not possess the sam e kind of biological activity as substances used as active ingredients in pesticides. Biologically active chem icals are those that are capable of altering an organism = s biological processes. Many chem icals have such activity. Inert ingredients are not generally used for their biological activity per se, but are used in pesticide form ulations prim arily for their physical/chem i cal characteristics

. Active ingredients, on the other hand, are intentionally used because of their ability to alter the biological processes

in a m a nner that can significantly im pact the target organism . The 40 CFR Part 158 data set was designed to define the characteristics of a substance that was already known or suspected of being biologically active, and thus suspected of being potentially hazardous to hum an health.

Generally when considering the term pesticide, one thinks primarily of conventional pesticides that are intended to kill rodents, insects or weeds. It is

reasonable to be concerned that a substanc e that can kill a complex biological system such as a rodent, insect or plant can also be potentially hazardous to hum an health . For example, it is no surprise that organophosphate pesticides (such as chlorpyrifos and diazinon)

and carbam a te insecticides (such as carbaryl) can interfere with the hum an nervous system . The 40 CFR Part 158 data requirem e nts and the current paradigm for assessing A conventional pesticides @ was created for conventional active ingredients. Registrants of active ingredients have the option of requesting waivers of data requirem e nts that they believe to be inappropriate.

Sim ilarly, the existing Part 158 data requirem e nts are not always necessary to assess the risk of the lower toxicity inert ingredients.

Page -14-EPA also considered whether a com p lete Part 158 data set would be sufficient to support the safety findings required by FFDCA for inert i ngredients. In evaluating this proposition, EPA

found that, when outlining the data requirem e nts f o r pesticide active ingredients, the general

assum p tion had been m a de that the only significant source of exposure to the pesticide would be through the use of the substance as an active ingredient in pesticides. At the tim e that Part 158

was prom ulgated in 1984, EPA was not explicitly required to consider non-pesticidal exposure

sources in its risk assessm ents. Therefore, while the pesticidal exposures are well understood, EPA = s data requirements in Part 158 do not routinely solicit or require information on the other non-pesticidal sources of exposure to those substances.

Finally, EPA considered the appropriateness of routinely requiring submission of

a Part 158 data set rather than the use of ex isting data, to support an assessment of a substance proposed for use as an inert ingredient in pesticides. Given that many inert ingredients have a long history of use in non-pesticidal products, there are existing bodies of available information which may be able to provide a sufficient basis for supporting a safety finding for a low or low/ moderate toxicity chemical. What would be the added value of new data, when existing information may be able to provide sufficient information to support a safety findi ng? Even if the existing information could not provide sufficient information, it may be possible that the existing information

when combined with a limited number of a dditional studies could provide the quality and quantity of data appropriate to support a safety finding.

In establishing a policy of relying on th e existing, available information for a low or low/moderate toxicity chemical, the Agency considered not only the cost of routinely generating and reviewing an extensive data se t, but also the impact of this decision on the use of laboratory animals. While taking into consideration principles of sound science including the need to conduct scientif ically sound pesticide chemical hazard/risk assessments, as well as the legal requiremen ts of FIFRA and FFDCA to protect humans (including sensitive subpopulations) and the environment from unreasonable adverse effects of pesticides, the Agency remains committed to avoiding unneeded or duplicative animal testing.

Given the toxicity characteristics and readily available toxicity inf o rm ation on som e inert ingredients, as well as the reality that the public could receive more value if the resources involved in the testing were applied to substances that posed greater potential risks to human health or the environment, EPA believes that it does not necessarily need a 40 CFR Part 158 data set for all pesticide inert ingredients in order to m a ke the safety findings prescribed

in FIFRA and FFDCA.

Page -15-VII. ADDITIONAL CONSIDERATION: ALTERNATIVE APPRO ACHES FOR DETERMINING DATA REQUIREMENTS USED by VARIOUS REGULATORY

PROGRAMS

As part of the developm ent of this approach, OPP also examined various regulatory systems elsewhere. OPP was particularly interested in understanding how other regulatory bodies dealt with similar circumst ances; that is, how other regulatory bodies balanced the need for effective regulation with efficiency. OPP paid particular attention to tiered assessment methods, tiered data requirements, or other approaches used to determine data requirements.

Food and Drug Adm i nistration (FDA)

Som e of the sam e substances used as inert ingredients in pesticide products are also considered by FDA under its adm i nistration of FFDCA. These substances m a y have uses as food additives (both direct and indirect), cosm e tics, dietary supplem ents, hum an drugs, and color additives, as well as anim al drugs and anim al f eed item s

B all of which are (to varying degrees) regulated by FDA.

Direct Food Additives : These are substances deliberately added to food to achieve a specific technical effect, such as em ulsification.

Since 1982, FDA has used the concept of tiered testing requirem e nts to obtain

inform ation about the safety of direct food additives and color additives. The concept is based on

the assum p tion that the degree of effort expended to reduce uncertainty about the safety of a

direct food additive or color additive should relate in som e logical way to the likelihood that use of the substance poses a health risk to the public.

The criteria used by FDA in its safety assessm ent of direct food additives and color additives are provided in an FDA Center fo r Food Safety and Applied Nutrition (CFSAN)

docum ent entitled A Toxicological Principles for the Safety Assessm ent of Direct Food Additives

Used in Food. @ This docum ent (often referred to as the A Redbook @ ) sets out guidelines based on
a system of tiered inform ation recom m e ndations for additives in food and describes how FDA

determ ines which toxicity tests are recom m e nded to assess the safety of direct food additives. The Redbook delineates the toxicology inform ation deem ed appropriate for assessing the safety of direct food additives and color additives. The FDA approach incorporates inform ation about expected hum an exposure and chem ical structure/activity relationships into initial A Concern

Levels @ for food and color additives used in food. The extent and type of toxicity testing

recom m e nded for direct food additives or color additives used in food will depend on the initial Concern Level to which that additive has been assigned and available inform ation about the

m e tabolism

, chem ical com position, and toxicity of the additive. Recom m e ndations for m i nim u m testing are associated with each Concern Level, and these recom m e ndations reflect FDA = s conclusion that extensive toxicity testing should be reserved for additives with high

Page -16-exposures and potentially reactive structures and for additives that induce adverse toxic effects at low doses or after short exposures

Indirect food additives: These are substances that m a y com e into contact with food as part of packaging or processing equipm ent, but are not intended to be added directly to food. They are also known as food contact substances.

Historically, FDA has based its recom m e ndations for toxicity data to support the safe use

of indirect food additives on the estim ated intake of these additives. As a general rule, higher

estim ated intakes of substances in the diet pose both an increased risk of toxicity and a wider range of potential toxic effects. Uses of a food contact substance that increase the cum u lative

estim ated dietary intake (CEDI) to greater than 1 part per m illion (ppm ) or, in the case of biocides, to greater than 200 parts per billion (ppb) are the levels at which FDA has historically requested m o re com p rehensive toxicity testing in order to address a substance = s potential to

induce diverse toxic effects. To address the risk of these effects, FDA has asked for longer term toxicity studies and toxicity studies that m easure a wider variety of toxic endpoints. FDA believes that uses of food contact substances that have the potential for inducing diverse toxic effects of consequence to hum an health generally require longer term and m o re specialized toxicity testing to support their safe use.

Cosm etic Regulation : FDA is only able to regulate cosm etics after products are released

to the m a rketplace. Cosm etic ingredients, with the exception of color additives, are not reviewed or approved by FDA before they are sold to the public. FDA cannot require com p anies to do safety testing of their cosm etic products before m a rketing. If, however, the safety of a cosm etic product has not been substantiated, the product' s label m u st read: "W ARNING: The safety of this product has not been determ ined." FDA does not have the authority to require

m a nufacturers to register their cosm etic establishm ents, file data on ingredients, or report

cosm etic-related injuries.

Dietary Supplem ent Regulation : FDA regulates dietary supplem ents under a different set of regulations than those covering "conventi onal" foods and drug products. The dietary supplem ent m a nufacturer is responsible for ensuring that a dietary supplem ent is safe before it is

m a rketed. FDA is responsible for taking action against any unsafe dietary supplem ent product

after it reaches the m a rket. Generally, m a nufacturers do not need to register with FDA or get FDA approval before producing or selling dietary supplem ents. Manufacturers m u st m a ke sure that product label inform ation is truthful and not m i sleading.

Hum a n Drug Regulation : FDA evaluates drugs (including prescription drugs, over-thecounter drugs and generic drugs) under FFDCA to determ ine if the drug is safe and effective for its intended use, and that the established benefits of the drug outweigh its known risks.

Page -17-Since 1938, every new drug has been the subject of an approved New Drug Application (NDA) before U.S. com m e rcialization. The data gathered during the anim al studies and hum an clinical trials of the Investigational New Drug phase becom e part of the application.

The inactive com ponents of a drug, referred to by FDA as excipients, are also reviewed as part of the NDA review. If the excipient has been previously approved for use in another drug (FDA m a intains a list of A approved @ excipients), FDA will first determ ine if the use in the NDA results in any significant increase in exposure (particularly duration of exposure) to the excipient. If there is a significant increase in exposure, or if the excipient has not previously been approved, FDA will evaluate its safety in light of the proposed drug use. These safety evaluations are done on a case-by-case basis, with no specified toxicological testing requirem e nts. FDA generally considers a weight of the evidence type approach when

determ ining the need for additional toxicological testing of drug excipients.

Office of Pollution Prevention and Toxics : Prem anufacturing Notice (PMN) Program

Under the Toxic Substances Control Act (TSCA) in order to require that testing be perform e d on a chem ical, the Agency m u st either find that, am ong other things, the chem ical

A ...m ay present an unreasonable risk to hum an health or the environm ent... @ or A ...is or will be produced in substantial quantities, and such substance either enters or m a y reasonably be anticipated to enter the environm ent in substantial quantities or there is or m a y be signif i cant or
substantial hum an exposure to the substance... @ The latter finding has been term ed an > exposurebased finding = and allows EPA the option to require testing if certain production volum e and exposure triggers are m e t.

Section 5 of TSCA does not require any toxicity testing for a new chem ical prior to

subm ission of a Prem anufacture Notification (P MN), although if toxicity data are in the

> possession and control = of the subm itter, these data m u st be presented at the tim e of the PMN

subm ission. Since, in general, little or no data are received with a PMN, hazard assessm ents for the subject chem ical depends heavily on m odels, structure-activity relationships (SAR) based on analogous chem icals, or data on the subject chem ical retrieved from public databases or

reference m a terial. Using the available inform ation, both hum an health and ecotoxicity concerns are identified. Levels of concern are generally described by term s such as high, m oderate, or

low. After the hazard assessm ent has been perform e d, then an exposure assessm ent, based upon

the scenarios m o st appropriate to the chem ical, is com p leted.

Alm o st 90 percent of the PMNs subm itted to the program com p lete the review process without being restricted or regulated in any way. If the Agency determ ines that a new chem ical

substance m a y pose a risk to health or the environm ent, and lacks sufficient toxicological

inform ation; then, section 5(e) of TSCA allows EPA to issue an order requiring the PMN

subm itter to m a nufacture or im port the new substance under specified conditions (risk-based consent order). The order m a y require developm ent of additional test data as a pre-condition of

its term ination. In the absence of a risk finding and sufficient toxicological data, and faced with the potential for substantial hum an or environm ental exposure, section 5(e) of TSCA allows EPA

Page -18-to issue an order to collect data that will better characterize the substance = s toxicity and risk (exposure-based consent order). In cases where the Agency determ ines that a new substance will present an unreasonable risk, section 5(f ) of TSCA allows EPA to prohibit the m a nuf acture, processing, or distribution in com m e rce of the substance.

Office of Pesticide Program s (OPP): Conventional Pesticide Active Ingredients

Historically, OPP = s focus has been prim arily on conventional pesticide active ingredients which are generally synthetic/m anuf actured chem icals that directly kill or inactivate the pest. As discussed above, the Agency has presumed, when assessing the risk posed by an active ingredient in pesticides, that the pesticid al uses of the substance will account for virtually all exposures. Because of this presumption, the Agency has linked data requirements to the expected exposures associ ated with the various uses of a pesticide active ingredient. Accordingly, pesticide use patterns that result in pesticide residues in or on food trigger a requirement for data that show the effects of dietary exposures to the active ingredient (and its biologically significant degradates or metabolites). Pesticide use patterns that could result in residues in drinking water trigger requirement for data that show the likelihood of such occurrence. If these data show that the pesticide is capable of migrating into drinking water, the Agency requires

additional data to further characterize this hazard. If the pesticide has uses in and around the home, then the Agency can also require additional data to further

characterize this hazard

.

Petitioners and registrants can also ask the Agency to waive data requirem e nts that they believe are not necessary. The Agency examines the information submitted to support the

waiver and determ ines whether to grant the request.

Office of Pesticide Program s (OPP): Biological Pesticides

Biological pesticides or biopesticides are alm o st exclusively derived from naturally occurring m a terials (anim a ls, plants, bacteria, and certain m i nerals). Biopesticides are generally considered to be inherently less toxic to hum ans than conventional pesticides. Biopesticides are

of

ten ef f ective in very sm all quantities and decom pose quickly. Due to the relatively specif i c nature of their pesticidal effects, biopesticides generally affect only the target pest and closely related organism s.

Biopesticides include the f o llowing three categories: microbial, plant, and

biochemical

$ Microbial pesticides , which include a m i croorganism (e.g. a bacterium

, fungus, virus, or protozoan) generally as the active ingredient.

Page -19-$ Plant-incorporated protectants which are pesticidal substances intended to be produced and used in a living plant and the genetic m a terial necessary for the production of the pesticidal substance.

$ Biochem i cal pesticides which are naturally occurring substances or synthetic com pounds essentially identical to natural substances that control pests by non-toxic m e chanism s

. This would include substances such as insect sex pherom ones that interfere with m a ting as well as various scented plant extracts that attract insect pests to traps.

Since biopesticides generally tend to pose lower risks to hum ans than conventional pesticides, the Agency generally requires m u ch less data concerning hum an dietary toxicity and exposure to register a biopesticide than to register a conventional pesticide. Not only are the data requirem e nts generally less extensive for biopesticides, but EPA can require different types of studies that target other potential types of risks. (See 40 CFR 158.65, 158.690, and 158.740)

Of f i ce of Pesticide Program s (OPP): Antim icrobial Pesticides

Antim icrobial pesticides, such as disinfectants and sanitizers, are defined in FIFRA section 2(m m )(1)(A) as pesticides that are intended to "(i) disinf ect, sanitize, reduce, or m itigate growth or developm ent of m i crobiological organism s; or (ii) protect inanim ate objects, industrial
processes or system s, surfaces, water, or other chem ical substances from contam ination, fouling, or deterioration caused by bacteria, viruses, fungi, protozoa, algae, or slim e." FIFRA section 3(h)(3)(A)(ii)(III) requires that EPA A conform the degree and type of review to the risks and benefits presented by antimicrobial pestic ides and the function of review under this Act, considering the use patterns of the product, toxicity, expected exposure and product type. @ Thus, EPA considers the need to ensure efficacy of public health pesticides when the pests are invisible disease-causing m i crobes. The data requirem e nts for each

antim icrobial use category are com m e nsurate with the potential exposure and risks associated with that use pattern, including the need to dem ons trate the effectiveness of the form ulation with respect to controlling the public health pest. In som e cases requirem e nts are tiered so that higher exposures or higher potential risks require a second level of data. The am ount and types of data required to support a use determines the level of detail and the complexity of the review

process.

Page -20-VIII. DEVELOPING a METHODOLOGY THAT SCREENS for LOWER TOXICITY

The m e thodology for determ ining the data needs, characterizing the hazard, and

determ ining the risk of inert ingredients m u st be flexible enough to apply to a broad range of possible use patterns including those of conventional pesticides, biopesticides, and antim icrobial pesticides. EPA believes that a screening process that incorporates elem ents of a tiered data approach is appropriate due to the wide differences in toxicity am ong inert ingredients.

The term s A inert ingredient @ and A active ingredient @ as used under FIFRA refer to the

function of the chem ical substance within a particular pesticide product. There is no such

functional distinction under the FFDCA. Under FFD CA, an inert ingredient is evaluated under

the sam e standard as an active ingredient, that is, A a reasonable certainty of no harm

. @ However, the statute does not stipulate that there is only one risk assessm ent approach that could be used by the Agency when m a king these assessm ents. Indeed, just as it would be inappropriate to require identical data sets for all ingredients in all pesticides (as discussed in Units VI and VII), the use of only one risk assessm ent approach would also be inappropriate. The Agency intends

to use the m e thodology described in this paper for reassessing som e of the 870 inert ingredient

tolerance exem ptions as required by FFDCA section 408(q) by the August 2006 deadline, as well as processing petitions f o r new inert ingredients f o r use in pesticide f o rm ulations f o r use on food or feed, and reviewing new inert ingr edients proposed for non-food form ulations.

FIFRA distinguishes active pesticide ingredients from other ingredients in the

form ulation. Active ingredients are always identified on the pesticide label. List 1 inert ingredients are listed as part of the form ulation. But the identities of other inert ingredients in a pesticide form ulation are not norm a lly listed on the label. Therefore, as part of its review of an application for pesticide registration, the Agency m u st determ ine whether the ingredient listing on the product label is accurate. In distinguishing whether a pesticide ingredient should be regulated as an active ingredient or as an inert ingredient, the Agency considers inform ation on the concentration, purpose, and m ode of action of the ingredient in the form ulation. This

distinction m u st be m a de on a product-by-product basis since som e substances are used as an active ingredient in one pesticide product and an inert ingredient in another pesticide product. The following are exam ples of chem icals, that have uses as both an active ingredient and an inert ingredient.

$ Ethanol is a disinfectant and m i crobiocide (an active ingredient) at high concentrations. Ethanol is also a powerful solvent; therefore, a sm all am ount of

ethanol could be used to dissolve another chem ical, which could then be added to

the form ulation. At m u ch lower concentrations, ethanol cannot function as a

disinfectant or m i crobiocide (an active ingredient), but does function as a solvent - an inert ingredient.

Page -21-$ FD&C Blue No. 1 is approved by FDA for use as a colorant in foods, drugs and

cosm etics. As an inert ingredient it is used as a dye to color the pesticide product. It is also an active ingredient, an algicide. W h en added to water in a fish pond, the dye absorbs the light needed by the algae; and causes the algae to die. This is considered a pesticidal use, for which the dye is the active ingredient.

$ Canola oil, which is also known as rapeseed oil, is a refined vegetable oil that can be used as an active ingredient to control insects in a wide variety of crops. Scientists believe that canola oil repels insects by altering the outer layer of the leaf surface or by acting as an insect irritant. Oils such as canola, however, can also be used as a surfactant (to m odify th e surface characteristics of a solution) in pesticide form ulations. W h en used in this capacity, canola oil would be an inert, rather than an active, ingredient.

FIFRA also requires the Agency to determ ine whether a pesticide product as a whole, including the active ingredients and all other ingredients poses an unreasonable risk to hum ans or the environm ent. FQPA am ended FFDCA to stipulate that, when establishing tolerances or

exem ptions from the requirem e nt of a tolerance for pesticide chem ical residues, the Agency m u st be reasonably certain of no harm from exposures to pesticide chem ical residues in or on food. A

chem ical substance = s hazard characterization is a function of toxicity, not whether the chem ical is considered to be an inert or an active ingredient.

The chem ical = s potential toxicity should drive the selection of data that will be needed to

characterize the hazard rather than the chem ical substance = s classification as an active or inert ingredient in a pesticide product. For those low toxicity food-use pesticide chem icals for which only a m i nim u m toxicology database is deem ed necessary, a A reasonable certainty of no harm @ finding could be accom p lished in the qualitative sense, particularly for those pesticide chem icals

for which an exem ption from a tolerance would be granted.

OPP has always set different data require m e nts under FIFRA for broad categories of pesticides (e.g., antim icrobial public health pesticides, conventional pesticides, biopesticides). In regard to FFDCA data requirem e nts, OPP has concluded that it is appropriate to m a ke a

sim ilar distinction between chem ical residues of high toxicity and those of low or low/m oderate toxicity. OPP believes that this distinction is of far greater significance to dietary risk than the purely functional distinction between chem icals = roles as A inert @ or A active @ ingredients in any particular pesticide product, and that the data needed should reflect the expected risks. This

m e thodology was originally developed for evaluating inert ingredients. However, under the appropriate circum stances, OPP proposes to use this m e thodology to establish exem ptions from the requirem e nt of a tolerance based on the toxicity of the chem ical substance, not on its use as an inert or active ingredient.

Page -22-IX. USE of EXISTING CH EMICAL INFORMATION/ DATA

In addition to relying on existing chem ical inf o rm ation/data to m a ke the initial Tier

determ inations, OPP intends to use existing chem ical inf o rm ation/data in its ef f o rts to m a ke a

confirm a tory judgem e nt concerning a chem ical = s low or low/m oderate toxicity provided the

inform ation/data can provide sufficient, credib le inform ation to m a ke a safety finding. As previously discussed, if the confirm a tory judgem e nt concerning a chem ical substance = s low or

low/m oderate toxicity cannot be m a de, then the use of this m e thodology is not appropriate. The

determ ination as to whether or not the existing chem ical inform ation/data are acceptable for assessing the hazard of a particular chem ical substance will be m a de by OPP on a chem ical-bychem ical basis as part of the overall review and evaluation process of each chem ical.

OPP has used and will continue to use this m e thodology on a chem ical-by-chem ical basis. But, even considering the pilot projects that have been undertaken by OPP that have

included the search f o r and use of existing inf o rm ation/data, this is still the beginning stages of process developm ent, and totally com p rehensive guidance on the types and sources of

inform ation/data that could be used to m a ke the confirm a tory judgem e nt concerning the low or

low/m oderate toxicity of a chem ical is not po ssible at this tim e. However, OPP can provide

som e basic principles of data acceptability and a description of how OPP would attem p t to locate existing, scientifically-valid data.

First of all, the inform ation/data m u st be relevant. The types of inform ation/data needed are those that address endpoints that are relevant to evaluating a chem ical = s toxicity and then perform i ng a risk assessm ent. This would include ecotoxicity and hum an health effect endpoints, environm ental fate endpoints a nd physical-chem i cal property endpoints.

Second, the inform ation/data m u st be of sufficient quality and quantity. It m u st be credible, that is, scientifically valid. Generally, when evaluating active ingredients , the Agency has relied on data generated using the protocols given under the OPPTS Harm onized Test Guidelines. These guidelines contain m a ny param e ters of toxicity (e.g, studies that address

hum an health endpoints would generally need to report the num ber of organism s tested, the dose/concentration levels used, the route/type of exposure, the duration of the exposure, the species tested, description of controls and statistical analysis). Conform a nce to these param e ters result in studies which provide scientifically adequate data that can be used to determ ine a doseresponse relationship, which is critical for perform i ng a quantitative risk assessm ent.

Considering the considerable am ount of testing that has been conducted on m a ny chem icals, there could be existing inform ation/data which m a y not have been generated in accordance with OPPTS test guidelines. However, m a ny of these studies have been vetted in peer review or have undergone a form al review process. These vetted, peer-reviewed studies can significantly inform the risk assessm ent process for low or low/m oderate toxicity chem icals.

Page -23-Thus, in its review and evaluation process, OPP would f o cus on the credibility and scientif ic validity of the inform ation/data, not on whether the existing inform ation/data is a guideline study.

The data that would be m o st useful to OPP would be articles from peer-reviewed, internationally recognized journals. Generally, these articles would discuss studies that were conducted no longer than 10 years ago. (Note the 10-year tim e-fram e is offered as a guideline: an older study could still provide valuable inform ation.) It should be ascertained that the study would provide an appropriate am ount of info rm ation on how the study was conducted, and what data were obtained, as well as the conclusions th at were drawn. The Agency requires sufficient,

credible inform ation with which to m a ke its decision, not an overwhelm ing am ount of

inform ation.

There are num erous sources for locating existing studies and data. OPP is currently using a process of the following type when conducting searches to identify and locate existing

chem ical inform ation/data.

OPP begins its search for chem ical inform ation/data with electronically searchable databases that can be accessed via governm e nt operated (.gov), publicly available websites. These databases contain inventories of scientifically peer-reviewed data on a large num ber of

chem icals. The National Library of Medicine m a intains such a database that can be accessed at:

www.toxnet.nlm .nih.gov. This website contains links to HSDB (Hazardous Substances Data Bank), IRIS (Integrated Risk Inform ation Syst em ), CCRIS (Chem i cal Carcinogenesis Research

Inform ation System ), and GENE-TOX. All of these contain validated peer-reviewed data. Other databases also located at the National Library of Medicine can be found at

www.nlm .nih.gov/. Careful consideration needs to given to the search term s used with a site such as NLM Gateway, otherwise hits on hundreds of journal articles are possible.

The National Toxicology Program (NTP) conducts chem ical bioassays on a num ber of

substances. Sum m a ry reports of the bioassays reviewed by NTP can be found at: ntpserver.niehs.nih.gov. The Agency for Toxic Substances and Disease Registry (ATSDR) produces "toxicological profiles" for certain hazardous substances which can be found at www.atsdr.cdc.gov/toxprofiles/. There is various information from OSHA/NIOSH (Occupational Safety and Health Administration/Na tional Institute for Occupational Safety and Health), such as that on a Chem ical Sam p ling Inform ation Card or an International Safety Card.

These can be found at www.cdc.gov/niosh/ipcsneng/neng0000.html and www.cdc.gov/niosh/npg/npg.html

. The Firstgov website, www.firstgov.gov/, can also be used.

The International Agency for Research on Cancer (IARC) is part of the W o rld Health Organization. The IARC evaluates chem ical bioassays and the IARC website, www.iarc.fr/,

contains sum m a ry reports of those bioassays reviewed by IARC.

Page -24-Another source of inform ation would be EPA = s High Production Volum e (HPV) Challenge Program which is part of the Agency = s Office of Pollution Prevention and Toxics (OPPT) Chem ical Right-to-Know Initiative. (www.epa.gov/chem rtk/volchall.htm ) This voluntary program was developed to collect and m a ke publicly available a baseline set of health

and environm ental data (hazard inform ation) on the industrial chem icals that are the m o st widely used in the United States, i.e., those produced or im ported into the U.S. in am ounts greater than 1

m illion pounds per year. This baseline or screening data set is consistent with the international Organization for Econom ic Cooperation and Deve lopm ent (OECD) HPV SIDS Program , and represents an internationally agreed upon set of tests that can screen chem icals for potential hazards. Sponsors of HPV chem icals under the HPV Challenge Program have agreed to gather and assess the adequacy of existing inform ation/studies and, if adequate inform ation does not exist, to develop the needed data. The sponsors prepare robust sum m a ries of the data (both existing and newly developed data), which are then posted on the Agency = s Chem RTK W e b Site.

Depending on the level of detail in the data sum m a ries, the voluntarily subm itted

inform ation could be useful to OPP = s decision-m a king process. It is possible that som e robust

sum m a ries could be used as is, or, in other cases, that the original study could be subm itted to OPP for review and evaluation. The HPV Program has issued a guidance docum ent

A Determ ining the Adequacy of Existing Data @ ( www.epa.gov/chem rtk/datadfin.htm ). This guidance docum ent should be helpful to those wishing to subm it data to OPP.

EPA = s Voluntary Children = s Chem ical Evaluation Program (VCCEP) is also part of the Agency = s Chem ical Right-to-Know Initiative and will focus on industrial chem icals to which children are likely to be exposed. The goal of this voluntary program is to gather and/or develop

both chem ical hazard and exposure inform ation that can then be carefully evaluated to ensure that children are adequately protected from potential risks associated with exposure to industrial

and com m e rcial chem icals. No subm issions have yet been received; however, these subm issions could also eventually provide inform ation that could be useful to OPP = s decision-m a king

process.

EPA = s TSCA Section 4 Testing Program addresses industrial chem icals and has required by rule the developm ent of a range of health and environm ental effects data on several hundred

industrial chem icals. Full study reports are subm itted to the Agency. Sum m a ries of the testing results are posted on the Agency = s website at www.epa.gov/opptintr/chem t est/4top.htm

.

Generally, OPP would not attem p t to search further than the above sources. However,

there are other sources of inform ation that could be used by a proponent of a tolerance

exem ption to locate and identify existing inform ation/data which could then be provided to OPP.

For exam ple, there could be a scientific assessm ent that was perform e d by an expert panel.

These could include assessm ents perform e d by various trade associations and docum ented in the

form of a m onograph, or a self-affirm ed GRAS (generally recognized as safe) determ ination.

There are also evaluations that were perform e d by FDA to evaluate a dye or to affirm a

Page -25-GRAS substance. Many of these assessm ents are based on peer-reviewed data. However, FDA = s GRAS determ ination relates to the use of a particular chem ical substance in food, and can specify lim itations on the food-use pattern. Additionally, FDA does not consider the possible presence of the chem ical in drinking water, or in other products that can be used in and around

the hom e, as EPA is required to do under FFDCA section 408. Under FIFRA, the Agency m u st also consider ecological effects of the chem ical when sprayed on a agricultural field. Thus, the

FDA GRAS determ ination can provide valuable inform ation, which can then be supplem ented by other existing, scientifically-valid inform ation/data.

Most form ulators of pesticide products purchase the chem ical substances that are then incorporated into pesticide products. Therefore, another possible source of data is the

m a nufacturer/supplier who could subm it these data to OPP.

In conclusion, it should be rem e m b ered that those persons wishing to establish or

m a intain a tolerance or tolerance exem ption have the responsibility of providing sufficient and adequate inform ation, appropriate to conducting a hazard and risk assessm ent, to the Office of Pesticide Program s. In the absence of sufficient inform ation to support an FFDCA section 408 safety determ ination, EPA m a y deny or revoke a tolerance or exem ption from the requirem e nt of

a tolerance.

Page -26-X. ROLE of EXPOSURE ASSESSMENT in this SCREENING/TIERED

METHODOLOGY

This paper, up to this Unit, has focused on the role of the toxicity, the hazard assessm ent,
of the chem ical substance. Toxicity is the driving force in determ ining tier placem ent. However, risk, the basis for the FQPA safety finding, is a function of both hazard and exposure. The

exposure assessm ent can potentially im pact the type of risk assessm ent to be perform e d. It is also possible that chem ical substances of lo w toxicity could need subm ission of additional toxicity and/or exposure data if the exposure assessm ent indicated the potential for extrem ely high exposure.

In the typical hum an health risk assessm ent perform e d by the Office of Pesticide Program s for a conventional active ingredient the m e thodology for perform i ng the exposure

assessm ent relies on an extensive data set and m odeling. Exposure assessm ents for dietary, drinking water, residential, and occupational exposures can be perform e d in a tiered fashion to refine the exposure estim ates. Perform a nce of probabilistic (Monte Carlo) sim u lations for dietary exposure are routinely perform e d. The different kinds of exposures for each active ingredient are well-docum ented. Each new use of the active ingredient is docum ented in a new

risk assessm ent to m a ke sure that the Agency = s level of concern is not exceeded and that the FQPA safety finding can continue to be m a de. The result of the quantified risk assessm ent is that tolerances with specific num erical lim itations are established under FFDCA.

This screening/tiered m e thodology is different, because tolerance exem ptions are

dif f e rent f r om num erical tolerances. For the low or low/m oderate toxicity substances that will be considered, the intent is to determ ine whether tolerance exem ptions are appropriate.

Establishm ent of a tolerance exem ption can be unlim ited (no restrictions), or can have som e specific types of lim itations such as indicating that the chem ical substance would only be used as

a surfactant or a lim itation on the percent of the chem ical substance in the form ulation. Once a

tolerance exem ption has been established, there is no lim itation on the am ount of residues of the

chem ical substance that could be present in food or feed, and the chem ical substance has the potential to be used in any pesticide product, applied to any crop, at any percent in the

form ulated pesticide product (subject only to the lim itations as discussed above, if present). Thus, as pesticide products exit and enter the m a rket place, the use patterns for any particular

chem ical substance with a tolerance exem ption can change.

Given this potential for shifting use patterns, it is necessary to exam ine a wide range of use patterns. The need to assum e wide-ranging, constantly-changing exposure scenarios (instead of having specific, well-defined exposures) for tolerance exem ptions necessitates a unique approach for both dietary (food and drinking water) exposures and residential exposures. Rather than conducting a separate exposure assessm ent for every conceivable scenario, representative exposure estim ates will be used to account for a wide range of potential uses.

Page -27-Under this m e thodology exposure assessm ents will be conducted in either a qualitative or quantitative m a nner. A qualitative exposure assessm ent would yield a qualitative risk

assessm ent, that would discuss both the potential pesticidal exposures and the non-pesticidal exposures, as can best be determ ined.

Risk assessm ents for m o st Tier 1 chem ical substances would be perform e d in a qualitative m a nner. The risk assessm ent would f o cus on the low toxicity of the chem ical

substance which would be com b ined in a qualitative m a nner with the understanding of the

exposure assessm ent. The com b ination of low toxi city even after considering the possibility of extensive exposures resulting from a wide-ranging exposure pattern would generally result in a

low risk concern for the chem ical substance. However, if concerns were identified during the perf orm a nce of the qualitative risk assessm ent, there would be the option of switching to a quantitative risk assessm ent.

Under this screening/tiered m e thodology, quantitative risk assessm ents would focus on bounding the wide-ranging exposure pattern. The bounding level approach is based on all the practices currently used by OPP = s exposure assessors. However, instead of using inputs defined by the known/existing use practices, the inputs for this screening/tiered m e thodology will be

based on conservative estim ates of the potential high-end exposures that could occur. Bounding level exposure estim ates would be generated for dietary (food and drinking water) and residential (derm a l and inhalation) exposures.

OPP has already developed one bounding level exposure estim ate for dietary exposure resulting from pre-harvest uses of a chem ical substance. The m odeling assum e d that the

A chem ical @ would be used on all crops, that 100% of all crops would be treated with the

A chem ical @ , that residue levels could be as high as the highest established tolerance levels for

each com m odity, and that secondary residues in m eat, m ilk, poultry and eggs could occur. These inputs were then com b ined with the consum ption inform ation used in all OPP dietary m odeling. Dietary exposure estim ates were then generated for acute and chronic scenarios for various population subgroups. At this tim e, additional bounding level exposure estim ates are being developed for other routes of exposure.

The resulting exposure estim ates would be com p ared to the hazard data to determ ine whether any risk concerns exist. This qualitative com p arison would not involve m a them atical operations to add up the exposures. It would not be scientifically valid to try to quantify risk based on these bounding level exposure assessm ents because their conservative assum p tions would overstate the risk. If, based on the qualitative com p arison, there are no risk concerns, then

no further assessm ent would be conducted, and the tolerance exem ption would be established.

However, it is always possible during the perf orm a nce of either a qualitative or quantitative risk assessm ent that risk concerns could be identif ied. Once these concerns have been identified, then under this m e thodology there are various actions that could be taken. As previously stated, the determ ination could be m a de to shif t f r om a qualitative to a quantitative

risk assessm ent, or there could be a request for inform ation to better characterize either the

Page -28-hazard or the exposure. Under FFDCA, to establish either a tolerance or tolerance exem ption, the Agency m u st find that A there is a reasonable certainty of no harm @ . In the absence of

sufficient inform ation to support an FFDCA section 408 safety determ ination, EPA m a y deny or

revoke a tolerance or exem ption from the requirem e nt of a tolerance.

Under this m e thodology, consideration will also be given to ecotoxicity and worker exposures. These exposures are not expressly considered when establishing tolerance

exem ptions under FFDCA section 408, but are evaluated as part of the pesticide product registration process under FIFRA. Any substance- specific concerns for potential adverse effects to nontarget organism s or to those persons who m a y be involved in the application of pesticides will be flagged for further consideration as part of the product registration requests as well as being considered during List reclassification determ inations.

As OPP reassesses the 870 inert ingredient tolerance exem ptions List reclassifications are also being perform e d (see Unit IV for List descriptions). All tolerance exem ptions that have been reassessed are by definition List 4. However, OPP m u st distinguish between a List 4A and List 4B inert ingredient. The determination that a chemical is List 4A
would be based on a recognition of the overall saf e ty of the chem ical (such as very low toxicity or practically non-toxi c) considering the widely available inform ation

on the chem ical = s known properties, and a history of safe use under reasonable circum stances. List 4A substances are recognized as safe for use in all pesticide products subject only to good agricultural practices or good m a nufacturing prac tices. Classification as a List 4A inert ingredient is a high standard to m eet. As an exam ple, substances of high acute toxicity are usually not considered for classification to List 4A. The critical distinction between List 4A

m i nim a l risk substances and other substances, is that the Agency does not define how, where,

when or in what m a nner the substance can be used. Any reasonably foreseeable use of these substances is not expected to present a risk to hum ans. Accordingly, there should not be any

unreasonable adverse effects from the inclusion of a List 4A substance in a pesticide product to the person applying a pesticide product in and around their hom e, to a child in a day-care center, or when ingesting a food com m odity that has been treated. In m a king a List 4A reclassification OPP will consider not only the exposures that are assessed under a FFDCA section 408 decision, but also potential ecotoxicity and worker exposure concerns.

For all Tier 1 and Tier 2 chem ical substances, a quantitative worker exposure assessm ent, as perform e d in the active ingredient higher toxicity paradigm , would not be perform e d. However, as part of the FIFRA registration pr ocess the Agency requires the subm ission of six acute end-product toxicity tests. These tests are the basis for labeling language for the first aid

statem ent, determ ine the types of protective equipm ent such as gloves and respirators, and affect the decision on whether or not the product can be used in and around the hom e. This approach to worker protection is only possible due to the lower toxicity of the chem ical substances that are considered under this screening/tiered m e thodology.

Page -29-XI. COORDINATION with OTHER DATA GENERATION PROGRAMS at EPA

It is entirely possible that a chem ical substance could be regulated by the Office of Pesticide Program s (OPP) as a pesticide chem ical, as either an inert or an active ingredient, and

that sam e chem ical could also be regulated by the Office of Pollution, Prevention and Toxics (OPPT) under the New Chem icals Program (NCP) or as an existing chem ical subject to TSCA Section 4 test rules. Or, the chem ical substance could be the focus of data collection/developm ent efforts such as the High Production Volum e (HPV) Challenge Program or the Voluntary Children = s Chem ical Evaluation Program (VCCEP). These are very different Program s.

$ OPP is a regulatory program that opera tes under FFDCA and FIFRA. W ithout EPA = s prior approval, a pesticide product cannot be offered for sale or distribution in the United States. Registrants of pesticide products m u st subm it the necessary data to m a intain their registration to OPP for review and evaluation. There can be statutory deadlines.

$ The NCP (TSCA section 5 prem anufacture notification program ) regulates the

m a nufacture of new industrial chem icals. There are no pre-set data requirem e nts; therefore, the program relies heavily on the use of SAR (structure-activity-relationship)

to assess hum an and environm ental toxicity. The NCP has successfully used SAR to assess over 35,000 chem ical substances since its inception.

$ EPA = s TSCA Section 4 Testing Program addresses industrial chem icals and has required by rule the developm ent of a range of health and environm ental effects data on several

hundred industrial chem icals. Full study reports are subm itted to the Agency.

Sum m a ries of the testing results are posted on the Agency = s website.

$ HPV is a voluntary program that was desi gned with significant stakeholder input. Sponsors of HPV chem icals under the HPV Challenge Program have agreed to gather and assess the adequacy of existing inform ation/studies and, if adequate inform ation does not exist, to develop the needed data. Robust sum m a ries and test plans are prepared by the sponsors and are posted on the Agency = s website. The adequacy of the data is

determ ined based on robust sum m a ries of key studies for the various endpoints.

$ VCCEP is also a voluntary program whose goal is to gather and/or develop both

chem ical hazard and exposure inform ation that can then be carefully evaluated to ensure that children are adequately protected from potential risks. VCCEP was designed with significant stakeholder participation.

There are also program m a tic sim ilarities. The com m on them e am ong these Program s is the critical need to collect/develop data. Each of the Program s has a tiered approach to characterizing its data needs. There is a f unctional sim ilarity between OPP = s Tier 2 and HPV = s and VCCEP = s Tier 1. (See Appendix) OPP = s Tier 3 is a very extensive data set that can have

sim ilarities to a TSCA section 4 test rule. OPP and OPPT will coordinate, as best possible, to

Page -30-assure that the three program s operate efficiently and productively while supporting each other = s efforts. However, it is entirely possible that the sam e or sim ilar data could be evaluated in a

som e what different m a nner under these different Program s.

Coordination could involve the following types of scenarios:

Currently VCCEP has a pilot program to assess 23 chem icals. There is overlap with

chem icals that are used in pesticide products. However, in m o st cases, the overlapping VCCEPsponsored chem icals are those inert ingredients of potentially higher toxicity and therefore would not be assessed using OPP = s screening/tiered m e thodology described herein. Pesticide

form ulators are encouraged to work with the m a nufacturer/supplier of the VCCEP chem icals that are incorporated in their form ulation to provi de input for preparation of the VCCEP exposure profiles. Since som e of the VCCEP chem icals are List 2 inert ingredients, OPP does intend to issue Data Call-In (DCI) Notices to pesticide registrants who incorporate these List 2 inert ingredients into their products. As a result of their VCCEP sponsorship, the

m a nufacturers/suppliers would have already identified and/or generated som e of the data required under the DCI. These data could be reviewed and evaluated, and then be used in a risk

assessm ent to support OPP = s regulatory decision.

Another area of overlap, that has already occurred is with the HPV Program ; som e chem icals sponsored under HPV are also used as either inert or active ingredients in pesticide products. In one case the HPV robust sum m a ries had been recently posted on the internet. A

com p arison of the robust sum m a ries with the data subm itted to OPP indicated for the m o st part
that it was the sam e data, and there was general agreem ent on the selection of doses and endpoints in the various studies. In another case, OPP was able to review the robust sum m a ries

subm itted to OPPT before posting. There was a difference in the data subm itted to OPP and the

robust sum m a ries subm itted to OPPT. OPP = s data were conducted on the chem ical of interest

and its calcium and sodium salts. The robust sum m a ries were conducted on the chem ical of interest and two derivatives. Also present was a rationale including m e tabolic argum ents as to the appropriateness of the use of the derivatives. OPP is m oving forward on its regulatory

decision based on the data subm itted to OPP, with consideration of the inf o rm ation subm itted to

OPPT. OPP = s regulatory decision is based on the inform ation available at the tim e the decision

is m a de. However, a ny submission of data as part of the HPV Challenge Program may, at any time in the future, be used by OPP to revise or update any decision as deemed necessary and appropriate. OPP and OPPT intend to coordinate, as appropriate, to keep each

other inf o rm ed of any new data subm itted and in particular the status of any assessm ents of overlapping chem icals in their respective Program s.

OPP and OPPT staff will also coordinate on developm ent of m e thodologies for assessing exposure and on com m on docum entation. Currently subm issions of data to OPP are the studies. OPPT receives full studies under its regulatory Program s. However, robust sum m a ries are

Page -31-subm itted to som e OPPT Program s. Those persons subm itting data to OPP f o r chem icals that are also sponsored under HPV or VCCEP are encouraged to also subm it robust sum m a ries of the

data to OPPT.

For chem icals of lower toxicity that can be appropriately addressed under this screening/tiered m e thodology, OPP anticipates in m a ny cases, that the data subm itted voluntarily to the HPV or VCCEP Program s could significantly inform its decisions. However, if a

chem ical is also used as a pesticide inert ingredient, and m o re specifically is on List 1 or List 2, the Agency would like to clearly articulate that the data set that OPP would seek through a FIFRA DCI, would require registrants to generate an extensive data set specifically designed and proven over tim e to provide the appropriate data for assessing hum an health risk as required by the FQPA am endm ents to FIFRA and FFDCA. Although data satisfying the FIFRA DCI would generally m eet the criteria of the HPV Challenge Program and the VCEEP Program , obtaining the baseline data set asked for under the HPV Challenge Program or the VCCEP Program would not be expected to fully satisfy a FIFRA DCI issued for a List 1 or List 2 pesticide inert ingredient.

Page -32-XII. PRELIMINARY TIER DETERMINATION

The m e thodology currently being used by OPP is a screening process that incorporates

elem ents of a tiered data approach. EPA tiers many of its data requirements. Under most tiered systems, the decision to continue to te st the substance is based on the results of a previous tier of studies. However, given that this methodology is also a screening process, the tiered approach works in a somewhat different manner by immediately placing the chemical substance in the most appropriate tier.

It should be noted that the Agency = s tier determ ination begins in a prelim inary m a nner, focusing on the toxicity, the hazard characterization, of the chem ical substance and an understanding of the types of assessm ents (qualitative or quantitative) possible for each tier. As the existing, scientifically-valid inform ation/data on a particular chem ical substance is reviewed and evaluated, the Agency m a y revise its tier determ ination.

OPP = s preliminary tier determination is based on the available inform ation on the

chem ical substances = potential toxicity. This can include not only the existing, scientificallyvalid inform ation/data but also a judgem e nt m a de by OPP based on structural sim ilarities and

chem ical fam ilies and categories, such as, alcohols or fatty acids.

The Tiers are briefly described below:

Tier 1a: Chem ical substances that can be assessed under this tier would be those substances with a long history of safe usage. They are consider ed to be of low toxicity, and therefore even considering a wide-ranging exposure pattern would also be of low risk concern. It is anticipated that the rationale and justif ication conf irm i ng the low toxicity f o r these chem icals could be

extrem ely lim ited and would consist of com m only or readily available knowledge on the lack of toxicity; therefore, Tier 1a chem ical subs tances would not require subm ission of any toxicological data.

Tier 1b: Chem ical substances that can be assessed under this tier would include chem icals for

which som e inform ation/data would be necessary to m a ke the confirm a tory judgem e nt concerning the substances = low or low/m oderate toxicity. Confirm a tion of the low or

low/m oderate toxicity of substances in Tier 1b would be based upon inform ation such as a review of existing, scientifically valid inform a tion/data (see Unit IX) and/or a SAR (structureactivity-relationship) assessm ent. The qualitative exposure and risk assessm ent for these

chem icals would be m o re than that needed for a Tier 1a rationale and justification. However, it is also possible that a quantitative risk assessm ent sim ilar to that perf orm e d f o r Tier 2 m a y be perform e d.

Tier 2: Generally, Tier 2 chem ical substances woul d be those for which OPP does not have and could not locate sufficient existing, scientifically-valid inform ation/data to assess a chem ical

substance = s toxicity. If the toxicity of the chem ical cannot be determ ined, a Tier 1 determ ination

Page -33-is not possible. For these Tier 2 chem ical s ubstances, OPP would request the subm ission of a

lim ited data set to characterize the hazard of the substance. The data would consist of a unique

data set - the Tier 2 data set - which would have sim ilarities to the internationally recognized OECD screening inform ation data set (SIDS). (see the Appendix) The Tier 2 hazard assessm ent would integrate the results of the subm itted studies, a SAR assessm ent, and any existing, scientifically valid data (if available). Generally, Tier 2 exposure and risk assessm ents will be quantitative.

Tier 3 : OPP would request for Tier 3 chem ical substances the subm ission of a com p lete (fooduse) 40 CFR Part 158 database, that is, a data set com p arable to the data required to evaluate a conventional active ingredient intended for food use. Under Tier 3, List 1 and som e List 2 inert ingredients would be evaluated in a sim ilar m a nner to that of an active ingredient. These are

chem icals that EPA suspects m a y involve significan t toxicity and/or exposure concerns, such as endocrine disruption, carcinogenicity, neurotoxic ity, developm ental and reproductive effects, ecotoxicity, persistence/bioaccum u lation and/or significant derm al penetration.

In sum m a ry, the prelim inary tier determ ination would be based on the available

inform ation. During a chem ical = s review and evaluation, and as additional inform ation is received, the Agency can revise the tier determ ination either up or down. Thus, it is possible that a prelim inary Tier 1b determ ination could go to Tier 2, or the reverse.

The am ount and quality of the data required to establish or reassess a tolerance

exem ption increases as the level of toxicity increases. The intent of this screening process is not only to assure that each chem ical is adequately assessed, but also to focus the Agency = s resources on those chem icals of potentially higher toxicity and therefore potentially higher risk.

Under this m e thodology OPP anticipates needing the com p lete 40 CFR Part 158 data set only

for those chem ical substances of significant toxico logical concern such as List 1 or som e List 2 inert ingredients. However, this screening/tiered m e thodology will provide sufficient

inform ation to allow the Agency to distinguish the lower toxicity chem icals from the higher toxicity chem icals as well as provide sufficient inform ation for the characterization and

assessm ent of lower toxicity chem icals.

Page -34-XIII. EXAMPLES of TIER 1a and 1b ASSIGNMENTS for INERT INGREDIENTS

Tiers 1a and 1b would m a ke use of existing inform ation to m a ke a confirm a tory judgem e nt concerning a chem ical substance = s low or low/m oderate toxicity, and therefore even considering a wide-ranging exposure pattern these chem ical substances would also be of low risk concern. OPP would use the existing, scientifically valid inform ation/data to approve the use of these substances in a pesticide product. However, if the information is insufficient to make the confirmatory judgement that a substance ha s little or no toxicity and that aggregate exposures to such substance would not result in unacceptable risk, then the Tier 1a or 1b determination would be inappropriate. The preliminary Tier determination would be changed to Tier 2.

Tier 1a:

Inert ingredients that can be assessed under this tier would be those substances with a long history of safe usage. They are consider ed to be of low toxicity, and therefore even considering a wide-ranging exposure pattern woul d also be of low risk concern. Tier 1a substances would not require subm ission of any t oxicological data. It is anticipated that the rationale and justification confirm i ng the low toxicity for these chem icals could be extrem ely

lim ited and would consist of com m only or readily available knowledge on the lack of toxicity.

Tier 1a risk assessm ents would be qualitative, drawing primarily on the substances = long history of safe use, to support establishing unlim ited tolerance exemptions. In fact, nonpesticidal exposures to m a ny of these m a terials m a y be frequent and at significantly higher levels than would occur as a result of pesticidal use. The safety finding would also be based on low risk, and usually allow for establishing unlim ited tolerance exem ptions.

Exam ples of chem ical substances that are currently considered to be likely candidates for Tier 1a, that is, those chem ical substances that could receive a prelim inary Tier 1a

determ ination, are described below:

$ Com m only consum ed food item s (excluding known allergens): These are necessary to supply nutrition and there is a long history of safe use.

$ Anim al feed item s : These item s have been fed to anim als without any evidence of ill

effects. Exam ples of such m a terials woul d include corn cobs, and orange pulp/peel.

H um ans have safely consum ed m eat, m ilk, poultry and eggs produced by such anim als.

$ W eathered rocks and m i nerals, including silicates and oxides: These are the m a terials in and of the earth in which we grow our food. Exam ples of such m a terials would include

sand and lim estone. There is, thus, a long history of hum an exposure to these substances, including inadvertent dietary exposure.

Page -35- $ Polym e rs that conform to the criteria specified in the TSCA polym er exem ption (40 CFR723.250): OPPT reviewed over 12,000 polym er applications to determ ine these criteria which identify polym ers of m i nim a l toxicological concern.

$ Inert gases (argon and helium ) : These gases are chem ically inert. There are no known or suspected adverse effects. Pesticidal use of these substances is unlikely to significantly add to exposures from existing sources.

$ Atm o spheric gases (nitrogen and carbon dioxide): These are the gases that are present in

the atm o sphere that we breathe.

Tier 1b:

Inert ingredients that can be assessed under this tier would include chem ical substances

for which som e data/inform ation would be necessary to m a ke a confirm a tory judgem e nt concerning the substances = low or low/m oderate toxicity. It is anticipated that the qualitative risk

assessm ent for these chem icals would be m o re than that needed for a Tier 1a rationale and justification. The kinds and types of data to m a ke this low toxicity confirm a tory judgem e nt would vary from chem ical to chem ical. Approva l of substances in Tier 1b would be based upon

inform ation such as a review of existing, scien tifically valid data, and/or a SAR assessm ent,
rather than based on the subm ission of new studies. Use of surrogate data m a y be acceptable to

m a ke the confirm a tory judgem e nt concerning the chem ical substances = low or low/m oderate toxicity. Most Tier 1b risk assessm ents would be conducted in a qualitative m a nner assum i ng wide-ranging exposure, although quantitative risk assessm ents could also be perform e d. OPP anticipates that the FFDCA section 408 safe ty finding would also be based on low or

low/m oderate toxicity with resultant low risk, and usually allow f o r establishing unlim ited

tolerance exem ptions, although OPP m a y im pose lim itations on the tolerance exem ption, if appropriate.

Exam ples of chem ical substances that are currently considered to be likely candidates for Tier 1b, that is, those chem ical substances that could receive a prelim inary Tier 1b

determ ination, are described below:

$ FDA-approved food dyes: FDA has reviewed and evaluated the available data to support the use of Food, Drug, & Cosm etic (FD&C) dyes and Drug & Cosm etic (D&C) dyes. The exposure from the uses regulated by FDA should significantly exceed the exposures

from pesticidal uses, i.e., the uses regulated by EPA.

$ Known food allergens: These would include peanuts, tree nuts, m ilk, soybeans, eggs, fish, crustacea, and wheat. Various factors such as restrictions on post-harvest applications or inform ation on the environm ental degradation/m e tabolism of the allergen

m a y enable the Agency to m a ke a determ ination of saf e ty by preventing or m itigating dietary exposure from the pesticidal use.

$ Naturally occurring m a terials (such as hum ic acid) that are ubiquitous in the

environm ent, but are som e tim es a highly refined version of the m a terial or a synthetic

Page -36-com pound essentially identical to the naturally occurring m a terial: Exposure to the

natural m a terial is already occurring. However, if it is not possible to m a ke the

confirm a tory judgem e nt concerning the low t oxicity of the synthetic or highly refined

m a terial based on a factor such as a long history of safe usage, then the use m u st be supported by data to assure that the chem ical has little or no toxicity.

$ Chem icals that are part of the norm a l m e tabolic processes that occur in the hum an body:

This would include interm ediates of carbohydrate m e tabolism

, such as the citric acid (Krebs) cycle, and interm ediates of lipid m e tabolism

, such as lecithin. (This could also

include salts of such chem icals.) Other possible m e tabolic processes could include

form ation of lactic acid from glucose, and form ation of the non-essential am ino acids that are synthesized by the hum an body: The assessm ent would include a discussion of the

m e tabolic process and an evaluation of the existing, scientifically valid data.

$ Essential am ino acids (those not m a nufactured by the body) and som e vitam i ns: The

assessm ent would include a discussion of the m e tabolic process, an evaluation of the existing, scientifically valid data, and inform ation on the existing non-pesticidal

exposures.

$ Natural fatty acids: These are long hydrocarbon chains that are attached to a carboxyl group (-COOH ) and are formed during digestion of dietary fat . Fatty acids are transported from the gut into the blood stream and are also released from adipose tissue

when fat is m e tabolized in the body. The assessm ent would include a discussion of the

m e tabolic process, and an evaluation of the existing, scientifically valid data.

$ Derivatives of natural fatty acids that m a y be considered are:

$ Fatty acid esters that occur when the fatty acid joins with another hydrocarbon chain (fatty acid chain-COO-R2)

$ Mono-, di-, and triacyl glycerols (also known as triglycerides). One, two, or three fatty acids are joined (through an ester linkage) to glycerol (an alcohol)

$ Salts of fatty acids

$ Modifications of sim p le and com p lex carbohydrates: The assessm ent would include a

SAR assessm ent.

$ Gum s (m any are derived from plants, seaweed or algae): An evaluation of the existing, scientifically valid data would be necessary to m a ke the confirm a tory judgem e nt that little or no toxicity is associated with exposure to these substances.

$ W a xes: These are water-insoluble solid esters of higher fatty acids with long-chain fatty alcohols and generally have m i nim a l to no derm al penetration. The assessm ent would include an evaluation of the existing, scientifically valid data and/or a SAR assessm ent to

m a ke the confirm a tory judgem e nt that little or no toxicity is associated with exposure to

these substances.

Page -37-$ Com m on m i neral acids: These could include hydrochloric, sulfuric, sulfurous, carbonic, nitric, nitrous, phosphoric, phosphorous, hydrogen brom ide, and hydrogen iodide. Existing, scientifically valid data should supply sufficient inform ation to characterize the toxicity of these acids. Most acids could not be considered as low toxicity substances; however, these acids are usually used in pesticide products to adjust the pH of the

form ulated product. Given the sm all am ounts that are used, the resultant risk should be

low.

$ Com m on hydroxides: These could include sodi um , potassium , and calcium hydroxide. Existing, scientifically valid data should supply sufficient inform ation to characterize the toxicity of these bases. Most bases could not be considered as low toxicity substances; however, these bases are usually used in pesticide products to adjust the pH of the

form ulated product. Given the sm all am ounts that are used, the resultant risk should be

low.

$ Salts of certain inorganic acids and bases: This could include various salts such as

am m onium , sodium , potassium , calcium , m a gne sium , zinc, iron, barium , or alum inum

, but would not include salts such as cadm i um or chrom i um . The assessm ent would include an evaluation of existing, scientifically valid data to dem onstrate that little or no toxicity is associated with exposure to these substances. A SAR assessm ent m a y be necessary for som e of the salts to assess ecotoxicity concerns.

$ Aliphatic acids (RCOOH), alcohols (ROH), aldehydes (R-CO-H), (R1-COO-R2), and ketones (R1-CO-R2): The C range - the length of the hydrocarbon chain - would need to

be determ ined. Som e of these chem icals have been approved by FDA as GRAS or as

direct food additives. The assessm ent would include an evaluation of existing, scientifically valid data and/or a SAR assessm ent to m a ke the confirm a tory judgem e nt that little toxicity is associated with exposure to these substances.

$ Rosins: These are the m a terials left after turpentine is rem oved from tree resins. The

assessm ent would include an evaluation of existing, scientifically valid data and/or a

SAR assessm ent to m a ke the confirm a tory judgem e nt that little or no toxicity is associated with exposure to these substances.

$ Lignins: These are derived from wood. The assessm ent would include an evaluation of existing, scientifically valid data and/or a SAR assessm ent to m a ke the confirm a tory judgem e nt that little or no toxicity is associated with exposure to these substances.

Page -38-$ Cellulose: This is the m a jor com p lex carbohydrate in plants. Cellulose, per se , m a y actually be Tier 1a; however, m odifications of cellulose are m o re likely to be Tier 1b.

The assessm ent would include a SAR assessm ent.

$ Flower and vegetable oils/essential oils: These are natural com ponents of plants that provide distinctive odor or flavor. For som e of these oils, an evaluation of existing, scientifically valid data and/or a SAR assessm ent could be used to m a ke the confirm a tory judgem e nt that little or no toxicity is associated with exposure to these substances. For other substances, the safety finding would acknowledge the use pattern, which is a low percentage of m o st form ulations. Given the sm all am ounts that are needed to provide the distinctive odor or flavor, the resultant risk should be low.

$ Chem icals for which a scientific assessm ent already has been perform e d by an expert panel: These assessm ents can be docum ented in the form of a m onograph, a selfaffirm ed GRAS determ ination, or an FDA evaluation. The Agency would conduct a

stream lined review of the work of the panel to validate the panel = s review, to understand and evaluate the differences in the use patterns, and to locate the additional inform ation
necessary to m a ke the safety finding.

Page -39-XIV. DESCRIPTION of TIER 2 ASSIGNMENTS

Chemical substances that cannot be readily assigned to Tier 1 (see Unit XIII) or Tier 3 (see Unit XV) would be initially assigned to Tier 2. If the confirmatory judgement cannot be made that a chemical s ubstance has little or no toxicity, then a

minimum data set to characterize the toxici ty would be needed to evaluate such

substances. This data would consist of a A screening @ data set which would have sim ilarities to the internationally recognized SIDS data set (see the Appendix).

Page -40-XV. EXAMPLES of TIER 3 ASSIGNMENTS

For substances that are known or suspected of having significant toxicity, OPP anticipates that it would not be able to m a ke the section 408 safety finding without a com p lete (food-use) Part 158 database. Such substances would be evaluated in a m a nner substantially

sim ilar to the approach for active ingredients in conventional pesticides, i.e. a quantified risk

assessm ent considering aggregate exposures to determ ine if the risk exceeds the Agency = s level of concern. Generally, these are chem icals for which the Agency suspects m a y involve significant toxicity and/or exposure concerns, such as endocrine disruption, carcinogenicity, developm ental and reproductive effects, ecotoxicity, persistence/bioaccum u lation and/or significant derm al penetration. These chem icals m a y have already been classified as List 1

A inerts of toxicological concern @ or List 2 A potentially toxic inerts/high priority f o r testing @

. Usually, registrants whose products contain Tier 3 chem icals would be required to provide these data via a FIFRA section 3(c)(2)(B) Data Call-In (DCI) Notice.

Exam ples of chem ical substances that m i ght have prelim inary Tier 3 determ inations are

described below:

$ Phthalates are possible endocrine disrupters, and som e have been evaluated by the National Toxicology Program for developm ental/reproductive effects.

$ Petroleum hydrocarbons are currently being evaluated by the Agency. Approxim a tely 110 chem icals have been identified that are currently used in pesticide products. These chem icals would be grouped and a representative

chem ical(s) would be selected for each group. It is expected that these chem icals would be referred to the Inert Ingredient Focus Group (see Unit XVIII) before the

DCI is issued to determ ine the data requirem e nts.

$ Preservatives (usually referred to as A in-can @ preservatives as they protect the

form ulated product from m i crobial degradation before use) are oftentim es active ingredients. Many of the active ingredients used as in-can preservatives have only been registered for non-food uses, whereas the inert ingredient use could include use on food-crops.

$ Chem icals with significant derm al absorption can carry the active ingredient in an unpredictable m a nner into workers = bodies (im p acting the worker assessm ent), and plants and anim als tissues (im p acting tolerances). An exam ple would be

dim e thyl sulfoxide (DMSO).

$ Chem icals, such as herbicide safeners (which increase the tolerance of the desired crop to the herbicide). Many of these safeners are structurally

related to and have sim ilarities in biological activity to that of an active ingredient

.

Page -41-$ Chem icals that are structurally sim ilar to chem icals of toxicological concern

$ Ethylene glycol ethers, especially short chain ethylene glycol ethers, are developm ental and reproductive toxicants.

Page -42-XVI. WEIGHT-of-the-EVIDENCE EVALUATION for CONDUCTIN G RISK

ASSESSMENTS for TIER 1b and TIER 2 CHEMICALS

The ordinary process for assessing the dietary risks of pesticide active ingredients entails extensive data review and evaluation, m u ltiple peer-reviews, and m u ch docum entation. EPA believes the decision process for low or low/m oderate risk substances can be accom p lished in a

sim p ler, less intensive m a nner, and therefore has been exploring the use of a stream lined process that would reduce the extent of review, consultation and docum entation needed to support such a

risk assessm ent. At this tim e, OPP anticipates that Tier 1b and Tier 2 chem icals will be reviewed

as described below:

Tier 1b

For a Tier 1b chem ical, an evaluation of existing, scientifically valid data and/or the SAR

assessm ent (described below) m a y be the only inform ation considered by OPP. The inform ation

m

u st provide a sufficient basis to m a ke a confirmatory judgement on the low or low/moderate toxicity of the chemical substa nce. Aggregate exposure will be considered qualitatively. If the information is not suffi cient, to support a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, then the Tier determination would be changed to Tier 2.

Tier 2

Review and evaluation of Tier 2 chem ical s would integrate a body of evidence that includes (1) a SAR (structure-activity-relationship) assessm ent, (2) an evaluation of existing, scientifically-valid inform ation/data, and (3) the Tier 2 screening data set. Based upon these

three sources of inf o rm ation OPP will determ ine whether the chem ical substance m eets the statutory criteria for a tolerance exem ption. If the Agency does not in its review and evaluation identify any effects of concern, then it should be possible to establish or reassess a tolerance

exem ption for the chem ical. However, if an effect of concern is noted during the review and evaluation process then additional targeted testing related to that effect would be requested or the

chem ical could be taken to Tier 3.

The Structure-Activity-Relationship (SAR) Assessm ents

There are various SAR assessm ent processes. The one described below was developed by OPPT as a tool for quickly assessing and predicting toxicity and environm ental fate in the

absence of chem ical-specific data. OPPT scientists assess a chem ical = s structural sim ilarity to

chem icals for which data are available. For hum an health, this process can be used to assess the potential for absorption and m e tabolism

, m u tagenicity, carcinogenicity, developm ental and reproductive effects, neurotoxicity, system ic effects, im m unotoxicity, and sensitization and irritation. This is generally perform e d as a qualitative assessm ent; although, if a robust data base were available on an analogous chem ical, an endpoint would be chosen by OPPT and a quantitative risk assessm ent conducted. OPPT also perform s an ecotoxicity and environm ental

Page -43-fate assessm ent often using m odeling data. In perform i ng these assessm ents, OPPT assesses specif i c use patterns based on inf o rm ation supplied by the subm itter as well as OPPT = s professional judgem e nt of future potential exposures.

The reliability of this approach as a m e thod of assessing potential hum an and

environm ental risks has been exam ined in the Project on the Evaluation of (Quantitative) Structure Activity Relationships (EPA 743-R-94-001), conducted in cooperation with the European Union (EU). Given only chem ical stru cture inform ation, OPPT assessed 140 chem icals using their SAR assessm ent process. The results of their assessm ents were then com p ared to the

A base set @ data that the EU had received on each chem ical. The results indicated that the SAR

assessm ents were A on target @ 90% of the tim e for aquatic toxicity, and roughly 80% of the tim e for hum an health effects. For hum an health, the approxim a tely 20% that were not A on target @

were overestim ates, i.e., an overly conservative estim ate of the chem ical = s toxicity. In fact, the

SAR assessm ent for only one chem ical was considered to have underestim ated the chem ical = s toxicity. It should be noted that the data set required by the EU provides screening level

inform ation and does not address potential developm ental, reproductive, neurotoxic, and carcinogenic effects. Nevertheless, based on this study and on the expertise of the OPPT SAR

Team , OPP believes that SAR analysis is an effective tool for predicting toxicity and thus identifying chem icals which m a y present specific risk concerns and/or for which the value of generating additional data would be low.

Search f o r Existing Scientif ically Valid Data

This was discussed in Unit IX. The Agency will review and evaluate this inform ation.

Results of the Agency = s Review and Evaluation of the Screening Data Set.

The screening level studies for Tier 2 chem icals (toxicity, environm ental fate, ecotoxicity, and product chem istry) would be reviewed by the disciplinary specialists to

determ ine if any adverse effects were present. Exam ples of adverse effects, for a toxicity study, could be organ lesions, m a lform a tions (m issing lim bs or cleft palette), or reduction in im plant indices. OPP would not request that any additional studies (targeted testing) be subm itted, if : (1)

no adverse effects observed at the m a xim u m tested dose (depending on the dose level), or no

adverse effects observed in anim als tested at a dose level of 1000 m g /kg/day, and (2) no

concerns are raised from the SAR assessm ent or the evaluation of existing, scientifically valid data. If adverse effects are observed or if other concerns are identified, then under Tier 2 targeted testing would be requested. Targeted testing would address only the m o st sensitive observed adverse effects in the screening studies , and would typically call for subm ission of a guideline study(s) to address the effect of concern. However, it is also possible for OPP to

determ ine based on the results of the screening level studies and/or the targeted testing that placem ent in Tier 3 would be appropriate.

W e ight-of-the-Evidence Evaluation

Page -44-As previously discussed, a chem ical substance would be determ ined to be Tier 2 i f a confirmatory judgement cannot be made concerning the chemical substance = s low or low/moderate toxicity using commonly available information and/or an evaluation of existing, scientifically valid data. Therefore, for a Tier 2 chem ical, at least the SAR assessm ent and the Tier 2 screening data set m u st be ava ilable for consideration during the weight-of-theevidence evaluation. An SAR assessm ent is a powerful predictive tool that exam ines all toxicological disciplines. Thus, it m a y be possi ble for the SAR to support the findings from the screening-level com b ined repeated dose/developm ental/reproductive toxicity study. Together with the evaluation of existing, scientifically va lid data (if available) OPP would evaluate the potential f o r increased sensitivity f o r inf a nts and children that is considered when m a king the safety finding under FFDCA. In a weight-of-the-evidence evaluation, all these sources of

inform ation/data are considered and then used to characterize the hazard associated with the use of an inert ingredient.

Page -45-XVII. EVALUATION of the FQPA 10X SAFETY FACTOR WHEN CONDUCTING

RISK ASSESSMENTS for LOWER TOXICITY CHEMICALS

A primary consideration in implementation of the FQPA safety factor provision is assessing the degree of concern regarding the potential for pre-and postnatal effects. On February 28, 2002, the Agency issued a Guidance Document entitled

A Determination of the Appropriate FQPA Safety Factor(s) in Tolerance Assessment,

which is available at http://www.epa.gov/pesticides/trac/science/#10-fold.

Because substances that m a y be considered to be Tier 1 pose m u ch lower risks than conventional active ingredients, EPA considers a different evaluation process of the FQPA 10X safety factor to be appropriate for such substances. FFDCA section 408 provides that EPA shall apply an additional tenfold m a rgin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the com p leteness of the data base unless

EPA concludes that a dif f e rent m a rgin saf e ty will be saf e f o r inf a nts and children. Tier 1

chem icals will be those of low or low/m oderate toxicity and the risk assessm ent usually will be qualitative. Because the criteria for a Tier 1 determ ination preclude evidence of significant toxicity, a saf e ty f actor analysis would not be used and the FQPA 10X saf e ty f actor will be unnecessary. If there were inform ation associating significant reproductive or developm ental

effects with a chem ical substance with a prelim inary Tier 1 determ ination, then the chem ical substance could undergo a quantitative risk assessm ent, or would be changed to Tier 2 or Tier 3.

For chem icals that m a y be considered to be Tier 2, the FQPA 10X safety factor cannot be

rem oved or reduced without the subm ission of som e type of developm ental or reproductive data. For quantitative Tier 2 risk assessm ents, OPP would determ ine an actual num ber f o r the

children = s health safety factor. The determ ination would be based on the com p leteness of the screening toxicity database and the SAR assessm ent. For a Tier 2 chem ical, the determ ination to

rem ove, reduce, or retain the 10X would be m a de in a two-step process. The first step considers only the toxicity of the chem ical. If, (1) the SAR assessm ent does not indicate the potential for reproductive and/or developm ental effects or sensitivity, and (2) the available toxicity data, both

the subm itted study(ies) and an evaluation of existing, scientifically valid data, do not indicate any developm ental/reproductive concerns or sensitivity, then the 10X m a y be rem oved based only on toxicity.

The second step in the process considers the exposure com ponent of the risk assessm ent. As previously explained, a bounding estim ate/LOC (lev el of concern) approach would be used to address dietary and residential exposures. After the bounding estim ates are perform e d, the 10X will be reconsidered in light of the available inform ation on exposure and the inform ation from the bounding estim ate/LOC (level of concern).

Page -46-XVIII. ROLE of the INERT INGREDIENT FOCUS GROUP

To expedite the screening and review of low toxicity inert ingredients, OPP form ed an Inert Ingredient Focus Group (IIFG). The IIFG has the prim ary role for reviewing and evaluating Tier 1 and Tier 2 chem ical substances. It is a senior level interdivisional group,

whose m e m b ers possess expertise in the various scientific and regulatory disciplines necessary for perform i ng a risk assessm ent as well as m a king risk m a nagem e nt decisions. Generally, the IIFG would not perf orm the initial science reviews or the prelim inary risk assessm ents, but

would evaluate those reviews and assessm ents as a group. Thus, the IIFG would sim u ltaneously

f u lf ill the roles of all the disciplinary and review com m ittees that would ordinarily participate in assessing the risk of a conventional pesticide active ingredient, as well as being responsible for

m a king the risk m a nagem e nt evaluations.

The types of decisions m a de by the IIFG would vary based upon the substance(s) being considered and the type of risk assessm ent being perform e d. At m o st IIFG m eetings, the group would consider inert ingredients. However, som e active ingredients, especially those that can also be used as inert ingredients, for which there is existing scientifically valid data that could be

used to m a ke the confirm a tory judgem e nt concerning the substances = low or low/m oderate toxicity would also be considered for evaluation by the IIFG.

Som e exam ples of the possible decisions that would be m a de by the IIFG are listed

below:

$ Determ ining the prelim inary Tier determ ination as well as changes to this determ ination

$ Determ ining the adequacy of the substances = database for perform i ng a risk assessm ent

$ Evaluating the extra factor for the protection of infants and children

$ Determ ining for those substances = whose database are inadequate, the additional

inform ation/studies needed

$ Judging the adequacy of the risk assessm ent perform e d for approving the use of the

substance with or without lim itations

$ Identifying effects of concern and then determ ining the need for targeted testing

$ Identifying the data needed prior to the issuance of a Data Call-In Notice

$ Determ ining appropriate List placem ent (such as 4A) for an inert ingredient

The current process begins by selecting a chem ical substance for review. The next steps, perform e d by various OPP staff, would be intern et searches, data review and evaluation, and

docum ent preparation. If necessary and appropriate, an SAR assessm ent would be prepared.

Page -47-IIFG would review the evaluations, and then determ ine the nature and extent of the risk

assessm ent. OPP staff would then perform a prelim inary risk assessm ent. The IIFG would then

review and evaluate this risk assessm ent. For each Tier, the elem ents listed below com p rise a possible sequence of events:

Tier 1a:

$ Consider the available inform ation and/or reviews and evaluate whether the prelim inary determ ination as Tier 1a is appropriate

$ Form ulate a rationale indicating the substance = s (or group of substances = ) low toxicity based on readily available inform ation which can include factors such as a long history of safe use

$ Determ ine whether the rationale is sufficient and appropriate considering a wide-ranging exposure pattern

$ Determ ine whether the inert ingredient should be classified as List 4A or

4B

$ Prepare a Decision Mem o capturing the basis upon which the decision was

m a de, which can then be used to prepare tolerance reassessm ent
docum e n t s , F e d e r a l R e g i s t e r Notices, or other docum ents necessary to
form alize the decision.

Tier 1b:

$ Consider the available inform ation and/or reviews and evaluate whether the prelim inary determ ination as Tier 1b is appropriate

$ Evaluate the results of searches f o r existing scientif ically-valid data to

determ ine the adequacy of the database

$ If necessary and appropriate, have a SAR assessm ent prepared

$ Form ulate a rationale indicating the low or low/m oderate toxicity based on

the review of the existing scientif ically valid data and/or the SAR

assessm ent

$ Consider a wide-ranging exposure pattern, and understand the nonpesticidal exposures of the chem ical substance

$ Determ ine whether a qualitative risk assessm ent or a quantitative risk

assessm ent should be perform e d, or that the substance should be shifted to

Tier 2

$ Determ ine whether the inert ingredient should be classified as List 4A or

4B

$ Prepare a Decision Mem o capturing the basis upon which the decision was

m a de, which can then be used to prepare tolerance reassessm ent
docum e n t s , F e d e r a l R e g i s t e r Notices, or other docum ents necessary to
form alize the decision.

Tier 2:

Page -48-$ Consider the available inform ation and/or reviews and evaluate whether the prelim inary determ ination as Tier 2 is appropriate

$ Evaluate the results of searches f o r existing scientif ically-valid data to

determ ine the adequacy of the substances = database

$ Understand the non-pesticidal exposures of the chem ical substance

$ If necessary and appropriate, have a SAR assessm ent prepared

$ Determ ine whether the subm itted data are suf f i cient and appropriate f o r

m a king a decision, whether targeted testing is necessary, or whether there are significant risk concerns and that the substance should be shifted to

Tier 3

$ Consider and then integrate the existing scientif ically valid data, the SAR

assessm ent, and the reviews of the subm itted data

$ Select doses and endpoints for use in risk assessm ent

$ Determ ine the appropriate safety factor for the protection of infants and

children

$ Perform the bounding level/LOC assessm ents

$ Determ ine whether the inert ingredient should be classified as List 4A or

4B

$ Prepare a Decision Mem o capturing the basis upon which the decision was

m a de, which can then be used to prepare tolerance reassessm ent
docum e n t s , F e d e r a l R e g i s t e r Notices, or other docum ents necessary to
form alize the decision.

Tier 3:

The IIFG would have little involvem e nt with Tier 3 chem icals. The IIFG would m a ke

the Tier 3 determ ination. Once this determ ination has been m a de, the chem ical would be referred to the appropriate regulatory m a nager in one of OPP = s regulatory divisions.

Description of the Documentation

IIFG decision documents will contain: (1) the chemical name, and CAS Reg. No., (2) the requested action (e.g., tolerance exe mption petition, tolerance reassessment), (3) the names of those present at the meeting (member, presenter, observer), (4) a
discussion of the information/data reviewed and evaluated and/or a discussion of the risk of the chemical substance, and (5) recommendations from the IIFG to the management of the appropriate regulatory division.

Page -49-Description of the Databases

Given the streamlined nature of this process, it is particularly important to capture chemical-specific information and decisions in searchable databases. This would allow the IIFG to compare new actions with previous decisions. OPP will establish an internal Agency searchable st ructure database containing the following information: (1) chemical name (common and CA Index Name), and CAS Reg. No., (2) structure, (3) petition number(s), (4) MRIDs, (5) exposure information such as types of formulations, (6) molecular formula, (7) human health toxicity - description of the data base and summary of review and evaluation, (8) ecotox summary, (9) fate summary, (10) water modeling estimates, (11) other information as well as the conclusions of the IIFG with rationale. There will also be an internal database to capture the complete IIFG decision document(s) as well as any other do cuments that were generated in support of

the decision.

Page -50-XIX. OPPORTUNITIES for REGISTRANTS and PETITIONERS

A person who has petitioned the Agency to grant an exem ption f r om the requirem e nt of a tolerance for an inert ingredient not currently used in pesticide products or a person who has

subm itted inform ation to the Agency to support a particular tolerance exem ption as part of

tolerance reassessm ent m a y subm it data on its own initiative, and m a y in certain cases be required to subm it certain additional data. In all these instances, the Agency needs the subm itted

inform ation to be properly form atted. The Agency needs sufficient credible inform ation with

which to m a ke its decision, not an overwhelm ing am ount of inform ation.

As discussed the IIFG = s first task is a prelim inary tier determ ination. Proponents of a

tolerance exem ption are encouraged to propose a prelim inary tier determ ination to OPP.

Recom m e ndations that are based on existing scientifically-valid inform ation/data, and that clearly explain the factual basis for the recom m e nded Tier determ ination, are those m o st likely to provide the inform ation that could expedite the IIFG = s Tier determ ination. Subm itters should carefully consider the exam ples given in this docum ent as well as evaluations perform e d by the IIFG in preparing their recom m e ndation for prelim inary Tier determ ination.

For substances believed to be Tier 1:

$ For those chem ical substances subject to tolerance reassessm ent, OPP expects that for

m a ny of these chem icals there would be su f f i cient, credible scientif ically-valid

inform ation/data through the internet. Therefore, tolerance reassessm ents for m a ny Tier

1 chem ical substances would be perform e d by OPP without the need for subm issions

from those proponents of the tolerance reassessm ent.

$ For a chem ical substance f o r which a petitioner is seeking approval of a new inert ingredient (tolerance exem ption petition), petitioners should provide the Agency with the

results of their search f o r existing scientif ically valid inf o rm ation/data. Petitioners would then develop a rationale which explains why a tolerance exem ption should be established

for this low or low/m oderate toxicity substance. Petitioners should also prepare a

sum m a ry to be used in the Notice of Filing which would include the above inform ation.

For substances believed to be Tier 2 and 3:

$ For chem ical substances subject to tolerance reassessm ent, proponents of a tolerance

exem ption should anticipate OPP = s need for m o re inform ation. Given that OPP = s lack of credible scientifically-valid inform ation/data can be the reason for a Tier 2 determ ination,

if

no inf o rm ation has been subm itted to the Agency f o r a Tier 2 chem ical substance, then the Agency would issue a FIFRA section 3(c)(2)(B) Data Call In (DCI)

Page -51-Notice for the required inform ation or request inform ation under FFDCA 408(f) for the Tier 2 screening data set. For m o st Tier 3 chem icals, OPP will need the com p lete 40 CFR

Part 158 data set.

$ For a tolerance or tolerance exem ption petition, the Agency will not be able to grant the petition unless there are suf f i cient data to determ ine that there is a reasonable certainty

that no harm will result from aggregate exposure to the pesticide chem ical residue. The

subm ission should include studies (form a tted according to PR Notice 86-5), and the

results of the search f o r existing scientif ically valid inf o rm ation/data, and a sum m a ry to be used in the Notice of Filing, which will include discussions of the studies, the other

uses of the chem ical, and estim ates of endpoints for use in risk assessm ent.

The Agency would conduct an initial evaluation of the subm ission including the

subm itters = recom m e ndation for Tier determ ination. The subm itter will be inform ed as to the

com p leteness of the subm ission and whether any deficiencies have been identified.

Page -52-Data Specifications Comparison TableDATASPECIFICATIONSforHPV ChallengeProgram(SIDS Data Set)DATASPECIFICATIONSfor1987Inert IngredientData SetOPPDRAFT DATA SPECIFICATIONSspecifically forTier 2 Lower Toxicity Pesticide ChemicalsHuman HealthSAR Assessment and Literature Search1aScreening Level1bTargeted Testing Level1cAcute Toxicity(e.g., OECD 425)usually submittednot requirednot requiredin vitroMammalian CellChromosomeAberration(e.g., OECD 473 orOPPTS 870.5375)ORin vivoCytogenetics(Mammalian BoneMarrow ChromosomeAberration)(e.g., OECD 475 orOPPTS 870.5385)ORin vivoMammalianErythrocyteMicronucleus Test(OECD 474 or OPPTSStructural ChromosomalAberration Test(OPP 84-2)Other Genotoxic Effects(OPP 84-4)1din vivoCytogenetics(Mammalian Bone Marrow ChromosomeAberration)(OPPTS 870.5385)ORin vivoMammalian Erythrocyte Micronucleus Test(OPPTS 870.5395)possible targeted testing:Combined chronic toxicity/carcinogenicity(OPPTS 870.4300)Page -1-870.5395)Gene Mutation -BacterialSalmonella typhimuriumreverse mutation assay(Ames)(OECD 471 or OPPTS870.5100)ORGene Mutation -Mammalian(Mouse lymphoma,Chinese hamster ovary,or Chinese hamster V79)cells in culture forwardgene mutation assay(OECD 476 or OPPTS870.5300)Gene Mutation Test(OPP 84-2)Gene Mutation - BacterialSalmonella typhimuriumreverse mutation assay (Ames)(OPPTS 870.5100)ANDGene Mutation - Mammalian(Mouse lymphoma, Chinese hamster ovary, or Chinesehamster V79) cells in culture forward gene mutation assay(OPPTS 870.5300)possible targeted testing:Combined chronic toxicity/carcinogenicity(OPPTS 870.4300)Repeat Dose Toxicity(e.g., OECD 407 orOPPTS 870.3050;) orcombined with areproductive/developmental toxicity study (e.g.,OECD 422; or OPPTS870.3650)90-day Oral Rat(OPP 82-1)90-day Oral Dog(OPP 82-1)Subchronic Dermal(OPP 82-2 or -3)Developmental Rat(OPP 83-3)Combined Repeated Dose withDevelopmental/Reproductive Screen with Neurotoxicityand Immunotoxicity Components(OPPTS 870.3650)1epossible targeted testing:Developmental Study in Non-Rodents(OPPTS 870.3700)Reproduction and Fertility Effects(OPPTS 870.3800)90-Day Oral Toxicity in the Rat with Neurotoxicityand/or Immunotoxicity Endpoints(OPPTS 870.3100, 870.6200, 870.7800)Developmental Neurotoxicity(OPPTS 870.6300)not requirednot requiredEndocrine Disruptor Screening Program(EDSP)TBDTBDEnvironmental Fate2Page -2-OUTDOOR USESTier 1OUTDOOR USESBased on results of Tier 1INDOOR USESnot requirednot requiredSAR AssessmentPhotodegradation inWater(OPP 161-2)Photodegradation in Water(OPPTS 835.2240)Photodegradation(to be determined byestimation)Photodegradation in Soil(OPP 161-3)Photodegradation(to be determined byestimation)Photodegradation in Soil(OPPTS 835.2410)not requiredStability in water(e.g., OECD 111;OPPTS 835.2110)Hydrolysis(OPP 161-1)Hydrolysis as a function of pH(OPPTS 835.2110)not requiredNAKoc or Kd(OPP 163-1)Sediment and Soil Adsorption/Desorption for Parent andDegradates(OPP 163-1)not requiredTransport(Via modeling)not requirednot requirednot requiredBiodegradation(e.g., OECD 301 or 302)not requirednot requirednot requirednot requirednot requirednot requiredAerobic Aquatic Metabolism(OPP 162-4)not requirednot requiredAerobic soil metabolism(OPP 162-1)Aerobic Soil Metabolism(OPP 162-1)(based on results of Tier 1testing)Anaerobic Soil Metabolism(OPPTS 835.4200 )ORAnaerobic AquaticMetabolismnot requiredPage -3-Page -4-(OPPTS 835.4400)not requirednot requiredOther testing as requireddependent on the usepatternOther testing as requireddependent on the use patternOther testing as required dependent on the use patternEcotoxicity3OUTDOOR USESLevel 1OUTDOOR USESBased on results of Level 1:criteria to be developedINDOOR USESfor which there is an effluentTier 1 Based on results of Level 1not requirednot requiredSAR AssessmentAcute Toxicity to Fish(e.g., OECD 203;OPPTS 850.1075)Acute 96hr Fish LC50(OPP 72-1)Fish Acute Toxicity Test,Freshwater(one species - RainbowTrout)(OPPTS 850.1075)3aFish Acute Toxicity Test,Freshwater(one species -Bluegill)(OPPTS 850.1075)Fish Acute Toxicity Test,Marine(OPPTS 850.1075)Fish Early Life StageToxicity Test(OPPTS 850.1400)Fish Acute ToxicityTest, Freshwater(one species - RainbowTrout)(OPPTS 850.1075)3aFish Acute Toxicity Test,Freshwater(one species -Bluegill)(OPPTS 850.1075)Fish Acute Toxicity Test,Marine(OPPTS 850.1075)Fish Early Life Stage ToxicityTest(OPPTS 850.1400)required only in cases ofsignificant exposureAvian Oral LD50(OPP 71-1)8-Day Avian Dietary(OPP 71-2)Avian Dietary ToxicityTest(one species - BobwhiteQuail)(OPPTS 850.2200)3bAvian Dietary Toxicity Test(one species - other thanBobwhite Quail)(OPPTS 850.2200)not requiredToxicity to AquaticPlants (Algae)not requiredAlgal Toxicity - Tier 2(4 species)not requiredAlgal Toxicity - Tier 2(4 species)not required(e.g., OECD 201;OPPTS 850.5400)(OPPTS 850.5400)Aquatic Plant ToxicityTest - Tier 2usingLemna spp.(OPPTS 850.4400)(OPPTS 850.5400)Aquatic Plant ToxicityTest - Tier 2usingLemna spp.(OPPTS 850.4400)Acute Toxicity toAquatic Invertebrates(Daphnia)(e.g., OECD 202,formerly 202a; OPPTS850.1010)48-Hr LC50 or EC50 inDaphnia(OPP 72-2)Acute Toxicity to AquaticInvertebrates (Daphnia)(OPPTS 850.1010)not requiredAcute Toxicity toAquatic Invertebrates(Daphnia)(OPPTS 850.1010)not requiredDaphnid ChronicToxicity Test(when appropriate)(e.g., OECD 211,formerly 202b; OPPTS850.1300)not requirednot requiredDaphnid Chronic ToxicityTest(when appropriate)(OPPTS 850.1300)Daphnid ChronicToxicity Test(when appropriate)(OPPTS 850.1300)not requirednot requirednot requirednot required3cTerrestrial Plant Toxicity,Seedling EmergenceTier 1 or 210 species(OPPTS 850.4225)Terrestrial Plant Toxicity,Vegetative VigorTier 1 or 210 species(OPPTS 850.4250)not requirednot requirednot requiredHoney Bee Acute Contact Toxicity(OPPTS 850.3020)not requirednot requirednot requiredOther testing as requireddependent on the useOther testing as requireddependent on the use patternOther testing asrequired dependent onOther testing as requireddependent on the use patternPage -5-patternthe use patternPhysical/Chemical Properties - Product Chemistry4not requiredOPP 61-1Product Identity and Composition(OPPTS 830.1550)Melting Point(e.g., OECD 102;OPPTS 830.7200)not requiredMelting Point(OPPTS 830.7200)Boiling Point(e.g., OECD 103;OPPTS 830.7220)not requiredBoiling Point(OPPTS 830.7220)Vapor Pressure(e.g., OECD 104;OPPTS 830.7950)Vapor Pressure(OPP 63-9)Vapor Pressure(OPPTS 830.7950)Water Solubility(e.g., OECD 105 andOECD 112, ifapplicable; OPPTS830.7840)Solubility(OPP 63-8)Water Solubility - ColumnElutionShake Flask Method(OPPTS 830.7840)ORWater SolubilityGenerator ColumnMethod(OPPTS 830.7860)pH Value and Pka Value(e.g., OECD 112, ifappropriate)Dissociation Constant(OPP 63-10)Dissociation Constant in Water(OPPTS 830.7370)n-Octanol/WaterPartition Coefficient(e.g., OECD 107,OECD 117; OPPTS830.7560)Octanol/Water PartitionCoefficient(OPP 63-11)n-Octanol/Water Partition Coefficient - Shake Flask Method (OPPTS 830.7550)ORn-Octanol/Water Partition Coefficient -Generator ColumnMethod (OPPTS 830.7560)ORPage -6-n-Octanol/Water Partition Coefficient -Estmation byLiquid Chromatography(OPPTS 830.7560)pH Value and Pka Value(e.g., OECD 112, ifappropriate)pH(OPP 63-12)pH(OPPTS 830.7000)not requiredContaminants(OPP 61-3)Batch Analyses(OPP 62-1)Density(OPP 63-7)not requiredResidue Chemistrynot requiredBackground(OPPTS 860.1000)not requiredChemical Identity(OPPTS 860.1100)not requiredDescription on UsePattern and Type ofPesticide Formulation(OPP 171-3)Directions for Use(OPPTS 860.1200)1aThe SAR Assessment contains an evaluation of both human healthand environmental parameters. The literature search can be conducted using publiclyavailable web-sites which contain scientifically peer-reviewed data.1bThe submitted screening level studies would be reviewed to determine if any adverse effects were present. An example of an adverse effect could be organlesions, malformations (missing limbs or cleft palette), or reduction in implant indices. If the following criteria are met,then the Agency would not require anyadditional studies (targeted testing) to be submitted: (1) no adverse effects observed at the maximumtested dose (MTD), or (2)no adverse effects observed at1000 mg/kg/day.Page -7-1cTargeted testing is determined by a weight-of-the-evidenceevaluation that includes the following components: a structure activity relationship (SAR) assessment,Page -8-information from a search of open literature, and the Tier 2 database or equivalent testing. Targeted testing addresses only the most sensitive observed adverseeffects in the screening studies, andrequires submission of a guideline study.1dMutagenicity studiesare needed to assess the ability of the testmaterial or its metabolite(s) to interact directly or indirectly with cellular DNA, RNA, proteins,or chromosomes and the potential for adverse effects on cellular genetic material. Subsequent testing may be needed based on the evidence available to theAgency in accordance with the objective and considerations for mutagenicity testing.The OPP guidelines specify use of OPPTS 870.5385orOPPTS 870.5395 for chromosomal aberrations, which when combined with the bacterial test and themouse lymphoma assay is a total of three tests. This is thelowest number that can constitute a complete battery of genotoxicity tests.If a mammalian cell genemutation assay other than mouse lymphoma is performed, anin vitromammalian cytogenetic assay (OPPTS 870.5375) is also required.Other studiesmay be needed depending on the chemical.1e TheACombined Repeated Dose Toxicity with Reproductive/Developmental Toxicity Screening Test,@(OPPTS 870.3650) does not provide completeinformation on all aspects of reproduction and development. Thistoxicity study cannot not provide conclusive evidence of no reproductive or developmentaleffects because it does not include assessments of many aspects ofdevelopmental and reproductive toxicity that would be examined in other OPPTS guidelinestudies (OPPTS 870.3700 and 870.3800). It is a screening test which provides limited information on reproductive/developmentaltoxicity, systemic toxicity,neurotoxicity, and/or immunotoxicity following repeated exposure over a limited time period of 28 days. The information obtained from this study can be used toprioritize chemicals for further testing or to determine that a chemical requires no further testing.2 Environmental fate studies are used to determine the fate characteristics of a chemical (usedoutdoors), such as the rate ofchemical degradation, the identities andrates of formation and decline of volatile and nonvolatile degradates, the accumulation of the chemical and its transformationproducts in the ecosystem, and thephysical mobility of the chemical and its transformation products inthe environment. These data are also used as input data for the Agency=s water modeling; thelack of such data increases the need for uncertainty factors.3 Ecotoxicity testing is performed only for new registrations, astolerance reassessment is performed under FFDCA only. OPP uses a tiered testing system to assessthe potential risks of a chemical=s use(s) to nontarget plants, aquatic and terrestrial vertebratesand invertebrates, and bees. The results of the Tier 1 testsareevaluated to determine the potential of the chemical to cause adverse effects, and to determinewhether further testing is required.3a An LC 50 of less than 1 ppm in the Level 1 testing could lead to Level 2 testing of one or more of the tests indicated.3b An LD50 of less than 100 mg/kg in the Level 1 testing could lead to Level 2 testing of the indicated study.3c For registration, testing is required on the formulated product: Tier 1 for products other than herbicides and Tier 2 for herbicides. Depending on the availableinformation on the use pattern and on the results of the testing on the formulated product, Tier 2 testing as indicated could be required on the technical grade inertingredient.4 Certain physical and chemical data are needed as basic orsupportive evidence in initiating or evaluating other studies. Forexample, the octanol/water partitioncoefficient is used as one of the criteria to determine whether certain fish and wildlife toxicity or accumulation studies mustbe conducted. Additionally, suchdata can also be used as input data for the Agency=s water modeling.