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, 2002 
METHODOLOGY 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 APPROACHES 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 CONDUCTING RISK 

 ASSESSMENTS for TIER 1b and TIER 2 CHEMICALS.........................................42 
XVII. 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...................................50 
METHODOLOGY 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 Apesticide 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 based 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 pesticide 
products and as an active ingredient in other pesticide products. Since FFDCA section 408 

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

may use this tiered data screening methodology when evaluating any pesticide chemical of 

apparent low or low/moderate toxicity, regardless of whether it might be characterized as an 

active or inert ingredient. 

At this time, EPA has completed review of two tolerance exemption petitions and over 

200 tolerance reassessments for low or low/moderate toxicity chemicals using essentially the 

process described in this paper. More reviews are underway. Based on these experiences, OPP 

intends to continue its chemical-by-chemical reviews of pesticide chemicals according to the 

process described herein for the foreseeable future. However, EPA remains interested in further 

improvements in the efficiency and reliability of its process, and therefore welcomes comments 

from interested persons. 

This paper is intended to provide guidance to EPA personnel and decision-makers, and to 

pesticide registrants. The policies and process described herein are not binding on either EPA or 

pesticide registrants, and EPA may modify or disregard the process described herein where 

circumstances warrant and without prior notice. Likewise, pesticide registrants may assert that 

this process is not appropriate generally or not applicable to a specific pesticide chemical or 

situation. 

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II. BRIEF OVERVIEW of NEWLY DEVELOPED METHODOLOGY

The methodology currently being used by OPP for evaluating low or low/moderate 

toxicity chemical substances is a screening process that incorporates elements 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, clarity, consistency, and reasonableness. There is 

also a need for these decisions to be made in an efficient and cost-effective manner. 

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 will 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 chemical 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. Chemicals 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 some chemicals may be used as an inert 

ingredient in some formulations and as an active ingredient in other formulations. EPA believes 

this methodology may also be appropriate for evaluating some low toxicity chemicals regardless 

of whether they are categorized as active or inert ingredients. 

The methodology 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 preliminary Tier 

determination that is based on widely available information on chemical families and categories. 

Later as the Agency begins to review chemical-specific or surrogate information in the open 

literature, the preliminary Tier determination may be revised. 

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Tier 1 chemicals would be those of low or low/moderate toxicity for which there is 
readily available scientifically-valid information/data to make a confirmatory judgement 

concerning these chemical substances= low or low/moderate toxicity. It is anticipated that the 

rationale and justification used to make this confirmatory judgement concerning the low or 

low/moderate toxicity for these chemicals would consist of commonly or readily available 

knowledge on the lack of toxicity. This could include information such as a review of existing 

data, or a SAR (structure-activity-relationship) assessment. Tier 1a risk assessments will be 

qualitative. Tier 1b risk assessments will usually be qualitative, although for some lower toxicity 

chemical substances a quantitative risk assessment may be performed. 

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

sufficient information to assess the chemical substance=s toxicity. Given the lack of readily 

available information to classify it as a Tier 1, the chemical substance would be placed in Tier 2, 

and OPP would likely require the submission of a limited data set to characterize the hazard of 

the chemical substance. This data set would have similarities to the internationally recognized 

Organization for Economic Cooperation and Development (OECD) Screening Information Data 

Set (SIDS). The data submitted could be either existing studies that were not readily available to 

OPP or newly performed studies. Once the submitted data have been reviewed and evaluated, 

the Tier 2 determination could be revised to either Tier 1 or Tier 3. For most Tier 2 chemical 

substances, the quantitative risk assessment would integrate the results of the submitted studies, 

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

some Tier 2 chemicals could have qualitative assessments based upon the review and evaluation 

of the submitted data. 

Chemical substances which appear to have appreciable toxicity would be assigned to Tier 

3. The methodology discussed in this paper is not appropriate for making FFDCA Section 408 

safety determinations for higher toxicity chemical substances. OPP anticipates that it would need 

to review a complete (food-use) 40 CFR Part 158 database to make these safety determinations. 

It should be emphasized that a Tier determination is merely a tool used by OPP to assist 

in making its decisions on how to evaluate the risk of a chemical substance. In and of itself, the 

Tier Determination has little regulatory meaning. In fact, this methodology could be performed 

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

Page -5- 
III. BACKGROUND

Definition of Inert Ingredient

AInert ingredients@ are all ingredients contained in a pesticide product that are not Aactive 

ingredients@ as defined in 40 CFR 153.125. These substances have a very wide range of 

physical/chemical characteristics and potential toxicological effects ranging from practically 

non-toxic to effects of high toxicological concern, such as carcinogenicity. One of the most 

significant challenges EPA faced in developing a methodology for a comprehensive inert 

ingredient assessment program was determining the most appropriate procedure for evaluating 

such a diverse group of substances. 

Statutory and Regulatory Framework of Pesticide Regulation

Pesticide products are regulated under the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA), and the Federal Food, Drug, and Cosmetic Act (FFDCA). Both 

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

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

intended function without unreasonable adverse effects on the environment and its composition 

and labeling meet requirements under FIFRA section 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 emergency exemption from FIFRA requirements under section 18 of FIFRA, or 

issues a regulation exempting a pesticide from FIFRA requirements 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 section 4 also requires EPA to reevaluate all 

pesticides first registered before November 1, 1984, through a program called reregistration. 

FFDCA prohibits the introduction or delivery for introduction into interstate commerce 

of any food that is Aadulterated@ (FFDCA section 301(a)). Food is deemed adulterated if, among 

other reasons, Ait bears or contains a pesticide chemical residue that is unsafe within the meaning 

of section 408(a)@ (FFDCA section 402(a)(2)(B)). Under FFDCA section 408(a)(1), Aany 

pesticide residue in or on a food shall be deemed 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 exemption) for 

residues of a pesticide active ingredient, any inert ingredient and any metabolites and degradates 

of active or inert pesticide ingredients that are in or on a food. FQPA redefined Apesticide 

chemical@ in FFDCA section 201(q)(1) to mean: Aany substance that is a pesticide within the 

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

added a definition of Apesticide chemical residue@ in FFDCA section 201(q)(2). This term means 

any residue of a pesticide chemical or any other substance that results primarily from the 

metabolism or degradation of a pesticide chemical. This definition makes explicit the longstanding EPA interpretation that tolerances established under section 408 of the FFDCA cover 

Page -6- 
chemical compounds formed through the breakdown or metabolism of pesticidally active and 

inert ingredients of a pesticide formulation. 

FQPA significantly changed the basis for making a safety finding when establishing a 

tolerance (or tolerance exemption). Under FFDCA section 408(b)(2)(A) and (c)(2)(A), the 

Agency must find that: AThere is reasonable certainty that no harm will result from aggregate 

exposure to the pesticide chemical residue, including all anticipated dietary exposures and all 

other exposures for which there is reliable information.@ 

In addition to assessing exposure to pesticide residues in food and water, EPA must 

assess exposures to pesticide residues from non-occupational uses, such as, in and around the 

home, garden, recreational areas, and schools. Additionally, the Agency is required to assess the 

risk of a pesticide chemical exposure to infants and children using an additional 10-fold margin 

of safety to take into account potential pre-and post-natal exposures and completeness of the data 

with respect to exposure and toxicity for infants and children, unless EPA determines, based on 

reliable data, that a different margin of safety will be safe for infants 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 Atolerances and exemptions for pesticide chemical residues in effect on the day before 

the date of the enactment of the Food Quality Protection Act of 1996.@ In making its 

reassessment determination, the Agency applies a Areasonable certainty of no harm@ standard. 

While FIFRA governs the sale, distribution and use of a pesticide through a registration 

process and enforcement of the requirements on the pesticide label, FFDCA provides a direct 

means of policing pesticide residue levels in food through a tolerance or an exemption 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 exemptions have not been 

established for each of the active and inert ingredients in the formulation. 

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 Aall active and inert ingredients@ within the definition of Apesticide 

chemical@. FIFRA section 3(c)(5) requires EPA to determine, for each individual pesticide 

product, whether its composition is such as to warrant the proposed claims made for it, whether 

it will perform its intended function without unreasonable adverse effects on the environment, 

and whether, when used in accordance with widespread and commonly recognized practice, it 

will not generally cause unreasonable adverse effects on the environment. Making such findings 

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 submission of various information on the inert 

ingredients in a pesticide formulation. FIFRA section 2(n) requires that the total percentage of 

all inert ingredients be listed as part of the ingredient statement on the label, and FIFRA section 

(3)(c)(1)(D) requires the submission of Athe complete formula 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 submission of a 

battery of acute toxicity tests on the pesticide formulation (which would include both the active 

and inert ingredients), there were no specific inert ingredient data requirements. 40 CFR 

158.155(b) requires the identification and characterization of the inert ingredients in a pesticide 

formulation. Moreover, the general requirements of the FFDCA apply equally to active and inert 

ingredients. 

Summary of the Pesticide Program Risk Assessment and Risk Management Process

In evaluating possible impacts of pesticide exposures on human health and the 

environment, the Agency uses a process known as risk assessment. The National Academy of 

Sciences and EPA risk assessment guidelines define risk assessment as the process for 

analyzing scientific data to describe the form, dimension, and characteristics of risk. That is, a 

risk assessment answers the question: What is the likelihood of harm to humans or the 

environment? Risk assessments are performed in a four-step process: 

$ Hazard Identification/Assessment: determining whether a particular chemical is or is not 

linked to a particular effect 

$ Dose-Response Assessment: determining the relationship between the magnitude of the 

exposure and the probability of the particular effect occurring at a particular exposure 

$ Exposure Assessment: determining the nature and extent of the exposure 

$ Risk Characterization: a description of the nature (qualitative) and the magnitude 

(quantitative) of risk, including a discussion of the strengths and weaknesses of the 

assessment 

Once the risk assessment is complete, the conclusions of the risk assessment are used to 

make an informed risk management determination. In managing the risk, the OPP risk manager 

considers the statutory requirements and the feasibility of the risk mitigation/risk reduction 

measures. 

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: farms and feed lots, homes and schools. Some pesticide products can be used to 

fumigate soil, others to kill weeds. Some are used to prevent food spoilage or insect infestation 

after harvest. Some products are intended to be used in small, localized spots, while others are 

meant to be broadcast over a large area. Some are used to kill germs on food-contact surfaces in 

homes, restaurants and processing facilities. 

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. Examples 

of inert ingredients uses include: 

$ stickers (to increase the time that the active ingredient remains on the plant part or other 

solid surface), 

$ solvents, 

$ surfactants (to modify the surface characteristics, such as reducing the surface tension of 

water often described as wetting agents, detergents, penetrants, and emulsifiers), 

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

$ thickeners such as carrageenan and modified cellulose, 

$ propellants in aerosol dispensers; and 

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

rate of release. 

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

use of the word Ainert@ to describe a component in a pesticide product means only that 

the substance is not intended to exert a pesticidal effect (i.e., to prevent, destroy, repel 

or mitigate any pest or to function as a plant regulator, desiccant, or defoliant) in that 

product. The Ainert@ ingredient may have biological activity of its own, it may be toxic 

to humans, and it may be chemically active. However, while inert ingredients may be 

important in delivering the pesticide product in a controlled manner, they are not the ingredient 

in the formulation that is intended to prevent, destroy, repel, or mitigate the target pest. 

Prior to the creation of EPA, the Food and Drug Administration (FDA) had the 

responsibility for establishing pesticide residue tolerances under section 408 of FFDCA. The 

Department of Agriculture (USDA) registered pesticides under FIFRA. USDA determined in 

1961 that all ingredients in a pesticide (then referred to as an Aeconomic poison@) are Apesticide 

chemicals@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 formulations applied to growing crops or raw agricultural commodities. Later, 

Page -9- 
in 1969, a process was established whereby persons wishing to use additional inert ingredients 

in food-use pesticides could submit 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 formulation and had been previously determined 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 time. 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, OPP published in the Federal Register (52 FR 13305) a policy 

statement on inert ingredients that established four categories of toxicological concern for the 

inert ingredients in use at the time: 

$ List 1 inert ingredients were Ainerts of toxicological concern.@ List 1 inert ingredients 

were classified on the basis of peer reviewed studies which demonstrated carcinogenicity, 

adverse reproductive effects, neurotoxicity or other chronic effects, developmental 

toxicity (birth defects), ecological effects and the potential for bioaccumulation. 

$ List 2 inert ingredients were Apotentially toxic inerts/high priority for testing.@ Many of 

these inert ingredients are structurally similar to chemicals known to be toxic; some have 

data suggesting a concern. 

$ List 3 inert ingredients were Aunknown 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 Ainerts of minimal concern.@ 

On November 22, 1989, (54 FR 48314) List 4 was further subdivided into List 4A and 

List 4B: 

$ List 4A inert ingredients are minimal risk inert ingredients. 

$ List 4B inert ingredients are Ainerts for which EPA has sufficient information to 

reasonably conclude that the current use pattern in pesticide products will not adversely 

affect public health or the environment.@

The 1987 policy also specified a minimum or base set of data that would be needed to 

assess all new inert ingredients. These data were a subset of the data requirements for pesticide 

active ingredients and included: 

Page -10- 
$ general information (use patterns, types of formulated products, and purpose of the inert 

ingredient in the formulation), 

$ eight product chemistry studies, 

$ toxicity studies 

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

$ dermal subchronic (non-food uses) 

$ rat developmental toxicity study 

$ mutagenicity studies 

$ for outdoor uses only, four ecotoxicity studies 

$ acute fish toxicity 

$ acute invertebrate toxicity 

$ acute bird toxicity 

$ 8-day bird toxicity 

$ for outdoor uses only, five environmental fate studies 

$ hydrolysis 

$ aerobic soil metabolism

$ 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 assessment in which the 

toxicity information was compared with the expected dietary exposure (usually a worst-case 

estimate) to determine 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 formulations. Accordingly, EPA would generally determine that no 

additional data were needed to support the inert ingredient use of the substance.

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V. IMPACT of FQPA on the INERT REGULATORY PROGRAM

FQPA included specific amendments to FFDCA section 201(q)(1)) that defined an inert 

ingredient as a pesticide chemical. Thus, the FQPA standard of Areasonable certainty of no 

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

exemption. 

EPA=s regulations at 40 CFR part 180 do not specify exactly what data must be submitted 

with a petition to establish a tolerance or an exemption from the requirement of a tolerance. 

Section 180.7(b) identifies in general terms the types of information needed for approval of a 

tolerance or tolerance exemption. Within this regulatory framework, EPA makes decisions 

about what data are needed on a chemical-by-chemical basis, and acquires them through either 

FFDCA or FIFRA. For pesticide chemicals currently subject to a tolerance or exemption, or 

contained in a registered pesticide product, EPA may 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 submission of a comprehensive array of test data on the pesticide active ingredient (see 

40 CFR part 158), which provide the basis for EPA to make the section 408 safety finding in 

regard to that active ingredient. 

 In the 1987 policy statement 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 statement stated that in its chemical-specific 

deliberations EPA could conclude that some or all of these studies are unnecessary, or might 

deem additional data necessary to fully assess the risks. Since the enactment of the FQPA, 

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

exemption for an inert ingredient that the base set of data described in the 1987 policy statement 

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 Aall other exposures for which there is reliable 

information,@ 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 completeness 

of the data with respect to exposure and toxicity for infants and children. The 1987 inerts policy 

Page -12- 
requested the submission of only a single developmental toxicity study, and no reproductive 

toxicity study. A single developmental toxicity study is generally considered insufficient 

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

sensitivities of infants and children. 

The 1987 base set of data is no longer appropriate; however, the 1987 inert ingredient 

policy also Acategorized 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 remain in 

existence, continue to be used by the Agency, and will be updated. 

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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 million 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 modifying the current inerts review process to ensure 

compliance with FQPA, EPA considered whether it was appropriate to simply require a 

complete Part 158 data set to support the use of an inert ingredient in a pesticide. EPA examined 

the proposition that if a Part 158 data set was necessary to support decision-making on an active 

pesticide ingredient, then the same data set should also be necessary for the other ingredients in a 

pesticide formulation. 

Inert ingredients are not intended to poison or repel pest organisms; therefore, with some

exceptions, inert ingredients generally do not possess the same kind of biological activity as 

substances used as active ingredients in pesticides. Biologically active chemicals are those that 

are capable of altering an organism=s biological processes. Many chemicals have such activity. 

Inert ingredients are not generally used for their biological activity per se, but are used in 

pesticide formulations primarily for their physical/chemical characteristics. Active ingredients, 

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

in a manner that can significantly impact 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 human 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 substance that can kill a complex biological system 

such as a rodent, insect or plant can also be potentially hazardous to human health. For 

example, it is no surprise that organophosphate pesticides (such as chlorpyrifos and diazinon) 

and carbamate insecticides (such as carbaryl) can interfere with the human nervous system. The 

40 CFR Part 158 data requirements and the current paradigm for assessing Aconventional 

pesticides@ was created for conventional active ingredients. Registrants of active ingredients 

have the option of requesting waivers of data requirements that they believe to be inappropriate. 

Similarly, the existing Part 158 data requirements are not always necessary to assess the risk of 

the lower toxicity inert ingredients. 

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EPA also considered whether a complete Part 158 data set would be sufficient to support 

the safety findings required by FFDCA for inert ingredients. In evaluating this proposition, EPA 

found that, when outlining the data requirements for pesticide active ingredients, the general 

assumption had been made 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 time that Part 158 

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

sources in its risk assessments. 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 existing 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 finding? 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 additional studies could provide the quality 

and quantity of data appropriate to support a safety finding. 

In establishing a policy of relying on the 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 set, 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 scientifically sound pesticide chemical hazard/risk 

assessments, as well as the legal requirements 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 information on some 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 make the safety findings prescribed 

in FIFRA and FFDCA. 

Page -15- 
VII. ADDITIONAL CONSIDERATION: ALTERNATIVE APPROACHES FOR 

 DETERMINING DATA REQUIREMENTS USED by VARIOUS REGULATORY 

 PROGRAMS 

As part of the development of this approach, OPP also examined various regulatory 

systems elsewhere. OPP was particularly interested in understanding how other 

regulatory bodies dealt with similar circumstances; 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 Administration (FDA)

Some of the same substances used as inert ingredients in pesticide products are also 

considered by FDA under its administration of FFDCA. These substances may have uses as 

food additives (both direct and indirect), cosmetics, dietary supplements, human drugs, and color 

additives, as well as animal drugs and animal feed itemsBall 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 emulsification. 

Since 1982, FDA has used the concept of tiered testing requirements to obtain 

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

the assumption that the degree of effort expended to reduce uncertainty about the safety of a 

direct food additive or color additive should relate in some 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 assessment of direct food additives and color 

additives are provided in an FDA Center for Food Safety and Applied Nutrition (CFSAN) 

document entitled AToxicological Principles for the Safety Assessment of Direct Food Additives 

Used in Food.@ This document (often referred to as the ARedbook@) sets out guidelines based on 

a system of tiered information recommendations for additives in food and describes how FDA 

determines which toxicity tests are recommended to assess the safety of direct food additives. 

The Redbook delineates the toxicology information deemed appropriate for assessing the safety 

of direct food additives and color additives. The FDA approach incorporates information about 

expected human exposure and chemical structure/activity relationships into initial AConcern 

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

recommended 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 information about the 

metabolism, chemical composition, and toxicity of the additive. Recommendations for minimum

testing are associated with each Concern Level, and these recommendations 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 may come into contact with food as 

part of packaging or processing equipment, but are not intended to be added directly to food. 

They are also known as food contact substances. 

Historically, FDA has based its recommendations for toxicity data to support the safe use 

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

estimated 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 cumulative 

estimated dietary intake (CEDI) to greater than 1 part per million (ppm) or, in the case of

biocides, to greater than 200 parts per billion (ppb) are the levels at which FDA has historically 

requested more comprehensive 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 measure 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 human health generally require longer term and more specialized 

toxicity testing to support their safe use. 

Cosmetic Regulation: FDA is only able to regulate cosmetics after products are released 

to the marketplace. Cosmetic ingredients, with the exception of color additives, are not reviewed 

or approved by FDA before they are sold to the public. FDA cannot require companies to do 

safety testing of their cosmetic products before marketing. If, however, the safety of a cosmetic 

product has not been substantiated, the product's label must read: "WARNING: The safety of 

this product has not been determined." FDA does not have the authority to require 

manufacturers to register their cosmetic establishments, file data on ingredients, or report 

cosmetic-related injuries. 

Dietary Supplement Regulation: FDA regulates dietary supplements under a different set 

of regulations than those covering "conventional" foods and drug products. The dietary 

supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is 

marketed. FDA is responsible for taking action against any unsafe dietary supplement product 

after it reaches the market. Generally, manufacturers do not need to register with FDA or get 

FDA approval before producing or selling dietary supplements. Manufacturers must make sure 

that product label information is truthful and not misleading. 

Human Drug Regulation: FDA evaluates drugs (including prescription drugs, over-thecounter drugs and generic drugs) under FFDCA to determine 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. commercialization. The data gathered during the animal studies and human 

clinical trials of the Investigational New Drug phase become part of the application. 

The inactive components 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 maintains a list of Aapproved@ excipients), FDA will first determine 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 

requirements. FDA generally considers a weight of the evidence type approach when 

determining the need for additional toxicological testing of drug excipients. 

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

Under the Toxic Substances Control Act (TSCA) in order to require that testing be 

performed on a chemical, the Agency must either find that, among other things, the chemical 

A...may present an unreasonable risk to human health or the environment...@ or A...is or will be 

produced in substantial quantities, and such substance either enters or may reasonably be 

anticipated to enter the environment in substantial quantities or there is or may be significant or 

substantial human exposure to the substance...@ The latter finding has been termed an >exposurebased finding= and allows EPA the option to require testing if certain production volume and 

exposure triggers are met. 

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

submission of a Premanufacture Notification (PMN), although if toxicity data are in the 

>possession and control= of the submitter, these data must be presented at the time of the PMN 

submission. Since, in general, little or no data are received with a PMN, hazard assessments for 

the subject chemical depends heavily on models, structure-activity relationships (SAR) based on 

analogous chemicals, or data on the subject chemical retrieved from public databases or 

reference material. Using the available information, both human health and ecotoxicity concerns 

are identified. Levels of concern are generally described by terms such as high, moderate, or 

low. After the hazard assessment has been performed, then an exposure assessment, based upon 

the scenarios most appropriate to the chemical, is completed. 

Almost 90 percent of the PMNs submitted to the program complete the review process 

without being restricted or regulated in any way. If the Agency determines that a new chemical 

substance may pose a risk to health or the environment, and lacks sufficient toxicological 

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

submitter to manufacture or import the new substance under specified conditions (risk-based 

consent order). The order may require development of additional test data as a pre-condition of 

its termination. In the absence of a risk finding and sufficient toxicological data, and faced with 

the potential for substantial human or environmental 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 determines that a new substance 

will present an unreasonable risk, section 5(f) of TSCA allows EPA to prohibit the manufacture, 

processing, or distribution in commerce of the substance. 

Office of Pesticide Programs (OPP): Conventional Pesticide Active Ingredients

Historically, OPP=s focus has been primarily on conventional pesticide active ingredients 

which are generally synthetic/manufactured chemicals 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 pesticidal uses of the substance will account for 

virtually all exposures. Because of this presumption, the Agency has linked data 

requirements to the expected exposures associated 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 requirements that they 

believe are not necessary. The Agency examines the information submitted to support the 

waiver and determines whether to grant the request. 

Office of Pesticide Programs (OPP): Biological Pesticides

Biological pesticides or biopesticides are almost exclusively derived from naturally 

occurring materials (animals, plants, bacteria, and certain minerals). Biopesticides are generally 

considered to be inherently less toxic to humans than conventional pesticides. Biopesticides are 

often effective in very small quantities and decompose quickly. Due to the relatively specific 

nature of their pesticidal effects, biopesticides generally affect only the target pest and closely 

related organisms. 

Biopesticides include the following three categories: microbial, plant, and 

biochemical 

$ Microbial pesticides , which include a microorganism (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 material necessary for the production of the 

pesticidal substance. 

$ Biochemical pesticides which are naturally occurring substances or synthetic compounds 

essentially identical to natural substances that control pests by non-toxic mechanisms. 

This would include substances such as insect sex pheromones that interfere with mating 

as well as various scented plant extracts that attract insect pests to traps. 

Since biopesticides generally tend to pose lower risks to humans than conventional 

pesticides, the Agency generally requires much less data concerning human dietary toxicity and 

exposure to register a biopesticide than to register a conventional pesticide. Not only are the 

data requirements 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) 

Office of Pesticide Programs (OPP): Antimicrobial Pesticides

Antimicrobial pesticides, such as disinfectants and sanitizers, are defined in FIFRA 

section 2(mm)(1)(A) as pesticides that are intended to "(i) disinfect, sanitize, reduce, or mitigate 

growth or development of microbiological organisms; or (ii) protect inanimate objects, industrial 

processes or systems, surfaces, water, or other chemical substances from contamination, fouling, 

or deterioration caused by bacteria, viruses, fungi, protozoa, algae, or slime." FIFRA section 

3(h)(3)(A)(ii)(III) requires that EPA Aconform the degree and type of review to the risks 

and benefits presented by antimicrobial pesticides 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 microbes. The data requirements for each 

antimicrobial use category are commensurate with the potential exposure and risks associated 

with that use pattern, including the need to demonstrate the effectiveness of the formulation with 

respect to controlling the public health pest. In some cases requirements are tiered so that higher 

exposures or higher potential risks require a second level of data. The amount 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 methodology for determining the data needs, characterizing the hazard, and 

determining the risk of inert ingredients must be flexible enough to apply to a broad range of 

possible use patterns including those of conventional pesticides, biopesticides, and antimicrobial 

pesticides. EPA believes that a screening process that incorporates elements of a tiered data 

approach is appropriate due to the wide differences in toxicity among inert ingredients. 

The terms Ainert ingredient@ and Aactive ingredient@ as used under FIFRA refer to the 

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

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

the same standard as an active ingredient, that is, Aa reasonable certainty of no harm.@ However, 

the statute does not stipulate that there is only one risk assessment approach that could be used 

by the Agency when making these assessments. 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 assessment approach would also be inappropriate. The Agency intends 

to use the methodology described in this paper for reassessing some of the 870 inert ingredient 

tolerance exemptions as required by FFDCA section 408(q) by the August 2006 deadline, as 

well as processing petitions for new inert ingredients for use in pesticide formulations for use on 

food or feed, and reviewing new inert ingredients proposed for non-food formulations. 

FIFRA distinguishes active pesticide ingredients from other ingredients in the 

formulation. Active ingredients are always identified on the pesticide label. List 1 inert 

ingredients are listed as part of the formulation. But the identities of other inert ingredients in a 

pesticide formulation are not normally listed on the label. Therefore, as part of its review of an 

application for pesticide registration, the Agency must determine 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 information on 

the concentration, purpose, and mode of action of the ingredient in the formulation. This 

distinction must be made on a product-by-product basis since some substances are used as an 

active ingredient in one pesticide product and an inert ingredient in another pesticide product. 

The following are examples of chemicals, that have uses as both an active ingredient and an inert 

ingredient. 

$ Ethanol is a disinfectant and microbiocide (an active ingredient) at high 

concentrations. Ethanol is also a powerful solvent; therefore, a small amount of 

ethanol could be used to dissolve another chemical, which could then be added to 

the formulation. At much lower concentrations, ethanol cannot function as a 

disinfectant or microbiocide (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 

cosmetics. As an inert ingredient it is used as a dye to color the pesticide product. 

It is also an active ingredient, an algicide. When 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 modify the surface characteristics of a solution) in 

pesticide formulations. When used in this capacity, canola oil would be an inert, 

rather than an active, ingredient. 

FIFRA also requires the Agency to determine whether a pesticide product as a whole, 

including the active ingredients and all other ingredients poses an unreasonable risk to humans 

or the environment. FQPA amended FFDCA to stipulate that, when establishing tolerances or 

exemptions from the requirement of a tolerance for pesticide chemical residues, the Agency must 

be reasonably certain of no harm from exposures to pesticide chemical residues in or on food. A 

chemical substance=s hazard characterization is a function of toxicity, not whether the chemical 

is considered to be an inert or an active ingredient. 

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

characterize the hazard rather than the chemical substance=s classification as an active or inert 

ingredient in a pesticide product. For those low toxicity food-use pesticide chemicals for which 

only a minimum toxicology database is deemed necessary, a Areasonable certainty of no harm@

finding could be accomplished in the qualitative sense, particularly for those pesticide chemicals 

for which an exemption from a tolerance would be granted. 

OPP has always set different data requirements under FIFRA for broad categories of 

pesticides (e.g., antimicrobial public health pesticides, conventional pesticides, biopesticides). 

In regard to FFDCA data requirements, OPP has concluded that it is appropriate to make a 

similar distinction between chemical residues of high toxicity and those of low or low/moderate 

toxicity. OPP believes that this distinction is of far greater significance to dietary risk than the 

purely functional distinction between chemicals= roles as Ainert@ or Aactive@ ingredients in any 

particular pesticide product, and that the data needed should reflect the expected risks. This 

methodology was originally developed for evaluating inert ingredients. However, under the 

appropriate circumstances, OPP proposes to use this methodology to establish exemptions from

the requirement of a tolerance based on the toxicity of the chemical substance, not on its use as 

an inert or active ingredient. 

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

In addition to relying on existing chemical information/data to make the initial Tier 

determinations, OPP intends to use existing chemical information/data in its efforts to make a 

confirmatory judgement concerning a chemical=s low or low/moderate toxicity provided the 

information/data can provide sufficient, credible information to make a safety finding. As 

previously discussed, if the confirmatory judgement concerning a chemical substance=s low or 

low/moderate toxicity cannot be made, then the use of this methodology is not appropriate. The 

determination as to whether or not the existing chemical information/data are acceptable for 

assessing the hazard of a particular chemical substance will be made by OPP on a chemical-bychemical basis as part of the overall review and evaluation process of each chemical. 

OPP has used and will continue to use this methodology on a chemical-by-chemical 

basis. But, even considering the pilot projects that have been undertaken by OPP that have 

included the search for and use of existing information/data, this is still the beginning stages of

process development, and totally comprehensive guidance on the types and sources of 

information/data that could be used to make the confirmatory judgement concerning the low or 

low/moderate toxicity of a chemical is not possible at this time. However, OPP can provide 

some basic principles of data acceptability and a description of how OPP would attempt to locate 

existing, scientifically-valid data. 

First of all, the information/data must be relevant. The types of information/data needed 

are those that address endpoints that are relevant to evaluating a chemical=s toxicity and then 

performing a risk assessment. This would include ecotoxicity and human health effect 

endpoints, environmental fate endpoints and physical-chemical property endpoints. 

Second, the information/data must be of sufficient quality and quantity. It must 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 Harmonized Test 

Guidelines. These guidelines contain many parameters of toxicity (e.g, studies that address 

human health endpoints would generally need to report the number of organisms 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). Conformance to these parameters 

result in studies which provide scientifically adequate data that can be used to determine a doseresponse relationship, which is critical for performing a quantitative risk assessment. 

Considering the considerable amount of testing that has been conducted on many 

chemicals, there could be existing information/data which may not have been generated in 

accordance with OPPTS test guidelines. However, many of these studies have been vetted in 

peer review or have undergone a formal review process. These vetted, peer-reviewed studies can 

significantly inform the risk assessment process for low or low/moderate toxicity chemicals. 

Page -23- 
Thus, in its review and evaluation process, OPP would focus on the credibility and scientific 

validity of the information/data, not on whether the existing information/data is a guideline 

study. 

The data that would be most 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 time-frame is offered as a guideline: 

an older study could still provide valuable information.) It should be ascertained that the study 

would provide an appropriate amount of information on how the study was conducted, and what 

data were obtained, as well as the conclusions that were drawn. The Agency requires sufficient, 

credible information with which to make its decision, not an overwhelming amount of 

information. 

There are numerous 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 

chemical information/data. 

OPP begins its search for chemical information/data with electronically searchable 

databases that can be accessed via government operated (.gov), publicly available websites. 

These databases contain inventories of scientifically peer-reviewed data on a large number of 

chemicals. The National Library of Medicine maintains 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 Information System), CCRIS (Chemical Carcinogenesis Research 

Information 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 terms used with a site 

such as NLM Gateway, otherwise hits on hundreds of journal articles are possible. 

The National Toxicology Program (NTP) conducts chemical bioassays on a number of 

substances. Summary 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/National Institute for Occupational Safety and 

Health), such as that on a Chemical Sampling Information 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 World Health 

Organization. The IARC evaluates chemical bioassays and the IARC website, www.iarc.fr/, 

contains summary reports of those bioassays reviewed by IARC. 

Page -24- 
Another source of information would be EPA=s High Production Volume (HPV) 

Challenge Program which is part of the Agency=s Office of Pollution Prevention and Toxics 

(OPPT) Chemical Right-to-Know Initiative. (www.epa.gov/chemrtk/volchall.htm) This 

voluntary program was developed to collect and make publicly available a baseline set of health 

and environmental data (hazard information) on the industrial chemicals that are the most widely 

used in the United States, i.e., those produced or imported into the U.S. in amounts greater than 1 

million pounds per year. This baseline or screening data set is consistent with the international 

Organization for Economic Cooperation and Development (OECD) HPV SIDS Program, and 

represents an internationally agreed upon set of tests that can screen chemicals for potential 

hazards. Sponsors of HPV chemicals under the HPV Challenge Program have agreed to gather 

and assess the adequacy of existing information/studies and, if adequate information does not 

exist, to develop the needed data. The sponsors prepare robust summaries of the data (both 

existing and newly developed data), which are then posted on the Agency=s ChemRTK Web Site. 

 

Depending on the level of detail in the data summaries, the voluntarily submitted 

information could be useful to OPP=s decision-making process. It is possible that some robust 

summaries could be used as is, or, in other cases, that the original study could be submitted to 

OPP for review and evaluation. The HPV Program has issued a guidance document 

ADetermining the Adequacy of Existing Data@ (www.epa.gov/chemrtk/datadfin.htm). This 

guidance document should be helpful to those wishing to submit data to OPP. 

EPA=s Voluntary Children=s Chemical Evaluation Program (VCCEP) is also part of the 

Agency=s Chemical Right-to-Know Initiative and will focus on industrial chemicals to which 

children are likely to be exposed. The goal of this voluntary program is to gather and/or develop 

both chemical hazard and exposure information that can then be carefully evaluated to ensure 

that children are adequately protected from potential risks associated with exposure to industrial 

and commercial chemicals. No submissions have yet been received; however, these submissions 

could also eventually provide information that could be useful to OPP=s decision-making 

process. 

EPA=s TSCA Section 4 Testing Program addresses industrial chemicals and has required 

by rule the development of a range of health and environmental effects data on several hundred 

industrial chemicals. Full study reports are submitted to the Agency. Summaries of the testing 

results are posted on the Agency=s website at www.epa.gov/opptintr/chemtest/4top.htm.

Generally, OPP would not attempt to search further than the above sources. However, 

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

exemption to locate and identify existing information/data which could then be provided to OPP. 

 For example, there could be a scientific assessment that was performed by an expert panel. 

These could include assessments performed by various trade associations and documented in the 

form of a monograph, or a self-affirmed GRAS (generally recognized as safe) determination. 

There are also evaluations that were performed by FDA to evaluate a dye or to affirm a 

Page -25- 
GRAS substance. Many of these assessments are based on peer-reviewed data. However, FDA=s 

 GRAS determination relates to the use of a particular chemical substance in food, and can 

specify limitations on the food-use pattern. Additionally, FDA does not consider the possible 

presence of the chemical in drinking water, or in other products that can be used in and around 

the home, as EPA is required to do under FFDCA section 408. Under FIFRA, the Agency must 

also consider ecological effects of the chemical when sprayed on a agricultural field. Thus, the 

FDA GRAS determination can provide valuable information, which can then be supplemented 

by other existing, scientifically-valid information/data. 

Most formulators of pesticide products purchase the chemical substances that are then 

incorporated into pesticide products. Therefore, another possible source of data is the 

manufacturer/supplier who could submit these data to OPP. 

In conclusion, it should be remembered that those persons wishing to establish or 

maintain a tolerance or tolerance exemption have the responsibility of providing sufficient and 

adequate information, appropriate to conducting a hazard and risk assessment, to the Office of 

Pesticide Programs. In the absence of sufficient information to support an FFDCA section 408 

safety determination, EPA may deny or revoke a tolerance or exemption from the requirement 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 assessment, 

of the chemical substance. Toxicity is the driving force in determining tier placement. However, 

risk, the basis for the FQPA safety finding, is a function of both hazard and exposure. The 

exposure assessment can potentially impact the type of risk assessment to be performed. It is 

also possible that chemical substances of low toxicity could need submission of additional 

toxicity and/or exposure data if the exposure assessment indicated the potential for extremely 

high exposure. 

In the typical human health risk assessment performed by the Office of Pesticide 

Programs for a conventional active ingredient the methodology for performing the exposure 

assessment relies on an extensive data set and modeling. Exposure assessments for dietary, 

drinking water, residential, and occupational exposures can be performed in a tiered fashion to 

refine the exposure estimates. Performance of probabilistic (Monte Carlo) simulations for 

dietary exposure are routinely performed. The different kinds of exposures for each active 

ingredient are well-documented. Each new use of the active ingredient is documented in a new 

risk assessment to make sure that the Agency=s level of concern is not exceeded and that the 

FQPA safety finding can continue to be made. The result of the quantified risk assessment is 

that tolerances with specific numerical limitations are established under FFDCA. 

This screening/tiered methodology is different, because tolerance exemptions are 

different from numerical tolerances. For the low or low/moderate toxicity substances that will 

be considered, the intent is to determine whether tolerance exemptions are appropriate. 

Establishment of a tolerance exemption can be unlimited (no restrictions), or can have some

specific types of limitations such as indicating that the chemical substance would only be used as 

a surfactant or a limitation on the percent of the chemical substance in the formulation. Once a 

tolerance exemption has been established, there is no limitation on the amount of residues of the 

chemical substance that could be present in food or feed, and the chemical substance has the 

potential to be used in any pesticide product, applied to any crop, at any percent in the 

formulated pesticide product (subject only to the limitations as discussed above, if present). 

Thus, as pesticide products exit and enter the market place, the use patterns for any particular 

chemical substance with a tolerance exemption can change. 

Given this potential for shifting use patterns, it is necessary to examine a wide range of 

use patterns. The need to assume wide-ranging, constantly-changing exposure scenarios (instead 

of having specific, well-defined exposures) for tolerance exemptions necessitates a unique 

approach for both dietary (food and drinking water) exposures and residential exposures. Rather 

than conducting a separate exposure assessment for every conceivable scenario, representative 

exposure estimates will be used to account for a wide range of potential uses. 

Page -27- 
Under this methodology exposure assessments will be conducted in either a qualitative or 

quantitative manner. A qualitative exposure assessment would yield a qualitative risk 

assessment, that would discuss both the potential pesticidal exposures and the non-pesticidal 

exposures, as can best be determined. 

Risk assessments for most Tier 1 chemical substances would be performed in a 

qualitative manner. The risk assessment would focus on the low toxicity of the chemical 

substance which would be combined in a qualitative manner with the understanding of the 

exposure assessment. The combination of low toxicity 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 chemical substance. However, if concerns were identified during the 

performance of the qualitative risk assessment, there would be the option of switching to a 

quantitative risk assessment. 

Under this screening/tiered methodology, quantitative risk assessments 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 methodology will be 

based on conservative estimates of the potential high-end exposures that could occur. Bounding 

level exposure estimates would be generated for dietary (food and drinking water) and 

residential (dermal and inhalation) exposures. 

OPP has already developed one bounding level exposure estimate for dietary exposure 

resulting from pre-harvest uses of a chemical substance. The modeling assumed that the 

Achemical@ would be used on all crops, that 100% of all crops would be treated with the 

Achemical@, that residue levels could be as high as the highest established tolerance levels for 

each commodity, and that secondary residues in meat, milk, poultry and eggs could occur. These 

inputs were then combined with the consumption information used in all OPP dietary modeling. 

Dietary exposure estimates were then generated for acute and chronic scenarios for various 

population subgroups. At this time, additional bounding level exposure estimates are being 

developed for other routes of exposure. 

The resulting exposure estimates would be compared to the hazard data to determine 

whether any risk concerns exist. This qualitative comparison would not involve mathematical 

operations to add up the exposures. It would not be scientifically valid to try to quantify risk 

based on these bounding level exposure assessments because their conservative assumptions 

would overstate the risk. If, based on the qualitative comparison, there are no risk concerns, then 

no further assessment would be conducted, and the tolerance exemption would be established. 

However, it is always possible during the performance of either a qualitative or 

quantitative risk assessment that risk concerns could be identified. Once these concerns have 

been identified, then under this methodology there are various actions that could be taken. As 

previously stated, the determination could be made to shift from a qualitative to a quantitative 

risk assessment, or there could be a request for information to better characterize either the 

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hazard or the exposure. Under FFDCA, to establish either a tolerance or tolerance exemption, 

the Agency must find that Athere is a reasonable certainty of no harm@. In the absence of 

sufficient information to support an FFDCA section 408 safety determination, EPA may deny or 

revoke a tolerance or exemption from the requirement of a tolerance. 

Under this methodology, consideration will also be given to ecotoxicity and worker 

exposures. These exposures are not expressly considered when establishing tolerance 

exemptions 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 organisms or to those persons who may 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 determinations. 

As OPP reassesses the 870 inert ingredient tolerance exemptions List reclassifications are 

also being performed (see Unit IV for List descriptions). All tolerance exemptions that have 

been reassessed are by definition List 4. However, OPP must 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 safety of the chemical 

(such as very low toxicity or practically non-toxic) considering the widely available information 

on the chemical=s known properties, and a history of safe use under reasonable circumstances. 

List 4A substances are recognized as safe for use in all pesticide products subject only to good 

agricultural practices or good manufacturing practices. Classification as a List 4A inert 

ingredient is a high standard to meet. As an example, substances of high acute toxicity are 

usually not considered for classification to List 4A. The critical distinction between List 4A 

minimal risk substances and other substances, is that the Agency does not define how, where, 

when or in what manner the substance can be used. Any reasonably foreseeable use of these 

substances is not expected to present a risk to humans. 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 home, to a child in a day-care center, 

or when ingesting a food commodity that has been treated. In making 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 chemical substances, a quantitative worker exposure assessment, 

as performed in the active ingredient higher toxicity paradigm, would not be performed. 

However, as part of the FIFRA registration process the Agency requires the submission of six 

acute end-product toxicity tests. These tests are the basis for labeling language for the first aid 

statement, determine the types of protective equipment such as gloves and respirators, and affect 

the decision on whether or not the product can be used in and around the home. This approach 

to worker protection is only possible due to the lower toxicity of the chemical substances that are 

considered under this screening/tiered methodology. 

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XI. COORDINATION with OTHER DATA GENERATION PROGRAMS at EPA

It is entirely possible that a chemical substance could be regulated by the Office of 

Pesticide Programs (OPP) as a pesticide chemical, as either an inert or an active ingredient, and 

that same chemical could also be regulated by the Office of Pollution, Prevention and Toxics 

(OPPT) under the New Chemicals Program (NCP) or as an existing chemical subject to TSCA 

Section 4 test rules. Or, the chemical substance could be the focus of data 

collection/development efforts such as the High Production Volume (HPV) Challenge Program

or the Voluntary Children=s Chemical Evaluation Program (VCCEP). These are very different 

Programs. 

$ OPP is a regulatory program that operates under FFDCA and FIFRA. Without EPA=s 

prior approval, a pesticide product cannot be offered for sale or distribution in the United 

States. Registrants of pesticide products must submit the necessary data to maintain their 

registration to OPP for review and evaluation. There can be statutory deadlines. 

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

manufacture of new industrial chemicals. There are no pre-set data requirements; 

therefore, the program relies heavily on the use of SAR (structure-activity-relationship) 

to assess human and environmental toxicity. The NCP has successfully used SAR to 

assess over 35,000 chemical substances since its inception. 

$ EPA=s TSCA Section 4 Testing Program addresses industrial chemicals and has required 

by rule the development of a range of health and environmental effects data on several 

hundred industrial chemicals. Full study reports are submitted to the Agency. 

Summaries of the testing results are posted on the Agency=s website. 

$ HPV is a voluntary program that was designed with significant stakeholder input. 

Sponsors of HPV chemicals under the HPV Challenge Program have agreed to gather 

and assess the adequacy of existing information/studies and, if adequate information does 

not exist, to develop the needed data. Robust summaries and test plans are prepared by 

the sponsors and are posted on the Agency=s website. The adequacy of the data is 

determined based on robust summaries of key studies for the various endpoints. 

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

chemical hazard and exposure information 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 programmatic similarities. The common theme among these Programs is 

the critical need to collect/develop data. Each of the Programs has a tiered approach to 

characterizing its data needs. There is a functional similarity 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 

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

Page -30- 
assure that the three programs operate efficiently and productively while supporting each other=s 

efforts. However, it is entirely possible that the same or similar data could be evaluated in a 

somewhat different manner under these different Programs. 

Coordination could involve the following types of scenarios: 

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

chemicals that are used in pesticide products. However, in most cases, the overlapping VCCEPsponsored chemicals are those inert ingredients of potentially higher toxicity and therefore would 

not be assessed using OPP=s screening/tiered methodology described herein. Pesticide 

formulators are encouraged to work with the manufacturer/supplier of the VCCEP chemicals that 

are incorporated in their formulation to provide input for preparation of the VCCEP exposure 

profiles. Since some of the VCCEP chemicals 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 

manufacturers/suppliers would have already identified and/or generated some of the data 

required under the DCI. These data could be reviewed and evaluated, and then be used in a risk 

assessment to support OPP=s regulatory decision. 

Another area of overlap, that has already occurred is with the HPV Program; some

chemicals sponsored under HPV are also used as either inert or active ingredients in pesticide 

products. In one case the HPV robust summaries had been recently posted on the internet. A 

comparison of the robust summaries with the data submitted to OPP indicated for the most part 

that it was the same data, and there was general agreement on the selection of doses and 

endpoints in the various studies. In another case, OPP was able to review the robust summaries 

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

robust summaries submitted to OPPT. OPP=s data were conducted on the chemical of interest 

and its calcium and sodium salts. The robust summaries were conducted on the chemical of 

interest and two derivatives. Also present was a rationale including metabolic arguments as to 

the appropriateness of the use of the derivatives. OPP is moving forward on its regulatory 

decision based on the data submitted to OPP, with consideration of the information submitted to 

OPPT. OPP=s regulatory decision is based on the information available at the time the decision 

is made. However, any 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 informed of any new data submitted and in particular the status of any assessments of

overlapping chemicals in their respective Programs. 

OPP and OPPT staff will also coordinate on development of methodologies for assessing 

exposure and on common documentation. Currently submissions of data to OPP are the studies. 

 OPPT receives full studies under its regulatory Programs. However, robust summaries are 

Page -31- 
submitted to some OPPT Programs. Those persons submitting data to OPP for chemicals that 

are also sponsored under HPV or VCCEP are encouraged to also submit robust summaries of the 

data to OPPT. 

For chemicals of lower toxicity that can be appropriately addressed under this 

screening/tiered methodology, OPP anticipates in many cases, that the data submitted voluntarily 

to the HPV or VCCEP Programs could significantly inform its decisions. However, if a 

chemical is also used as a pesticide inert ingredient, and more 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 time to provide the appropriate data for assessing human health risk as required by 

the FQPA amendments to FIFRA and FFDCA. Although data satisfying the FIFRA DCI would 

generally meet 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. 

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XII. PRELIMINARY TIER DETERMINATION 

 The methodology currently being used by OPP is a screening process that incorporates 

elements of a tiered data approach. EPA tiers many of its data requirements. Under most 

tiered systems, the decision to continue to test 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 determination begins in a preliminary manner, 

focusing on the toxicity, the hazard characterization, of the chemical substance and an 

understanding of the types of assessments (qualitative or quantitative) possible for each tier. As 

the existing, scientifically-valid information/data on a particular chemical substance is reviewed 

and evaluated, the Agency may revise its tier determination.

 OPP=s preliminary tier determination is based on the available information on the 

chemical substances= potential toxicity. This can include not only the existing, scientificallyvalid information/data but also a judgement made by OPP based on structural similarities and 

chemical families and categories, such as, alcohols or fatty acids. 

The Tiers are briefly described below: 

Tier 1a: Chemical substances that can be assessed under this tier would be those substances with 

a long history of safe usage. They are considered 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 justification confirming the low toxicity for these chemicals could be 

extremely limited and would consist of commonly or readily available knowledge on the lack of 

toxicity; therefore, Tier 1a chemical substances would not require submission of any 

toxicological data. 

Tier 1b: Chemical substances that can be assessed under this tier would include chemicals for 

which some information/data would be necessary to make the confirmatory judgement 

concerning the substances= low or low/moderate toxicity. Confirmation of the low or 

low/moderate toxicity of substances in Tier 1b would be based upon information such as a 

review of existing, scientifically valid information/data (see Unit IX) and/or a SAR (structureactivity-relationship) assessment. The qualitative exposure and risk assessment for these 

chemicals would be more than that needed for a Tier 1a rationale and justification. However, it 

is also possible that a quantitative risk assessment similar to that performed for Tier 2 may be 

performed. 

Tier 2: Generally, Tier 2 chemical substances would be those for which OPP does not have and 

could not locate sufficient existing, scientifically-valid information/data to assess a chemical 

substance=s toxicity. If the toxicity of the chemical cannot be determined, a Tier 1 determination 

Page -33- 
is not possible. For these Tier 2 chemical substances, OPP would request the submission of a 

limited 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 similarities to the internationally recognized 

OECD screening information data set (SIDS). (see the Appendix) The Tier 2 hazard assessment 

would integrate the results of the submitted studies, a SAR assessment, and any existing, 

scientifically valid data (if available). Generally, Tier 2 exposure and risk assessments will be 

quantitative. 

Tier 3: OPP would request for Tier 3 chemical substances the submission of a complete (fooduse) 40 CFR Part 158 database, that is, a data set comparable to the data required to evaluate a 

conventional active ingredient intended for food use. Under Tier 3, List 1 and some List 2 inert 

ingredients would be evaluated in a similar manner to that of an active ingredient. These are 

chemicals that EPA suspects may involve significant toxicity and/or exposure concerns, such as 

endocrine disruption, carcinogenicity, neurotoxicity, developmental and reproductive effects, 

ecotoxicity, persistence/bioaccumulation and/or significant dermal penetration. 

In summary, the preliminary tier determination would be based on the available 

information. During a chemical=s review and evaluation, and as additional information is 

received, the Agency can revise the tier determination either up or down. Thus, it is possible that 

a preliminary Tier 1b determination could go to Tier 2, or the reverse. 

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

exemption increases as the level of toxicity increases. The intent of this screening process is not 

only to assure that each chemical is adequately assessed, but also to focus the Agency=s 

resources on those chemicals of potentially higher toxicity and therefore potentially higher risk. 

 Under this methodology OPP anticipates needing the complete 40 CFR Part 158 data set only 

for those chemical substances of significant toxicological concern such as List 1 or some List 2 

inert ingredients. However, this screening/tiered methodology will provide sufficient 

information to allow the Agency to distinguish the lower toxicity chemicals from the higher 

toxicity chemicals as well as provide sufficient information for the characterization and 

assessment of lower toxicity chemicals. 

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

Tiers 1a and 1b would make use of existing information to make a confirmatory 

judgement concerning a chemical substance=s low or low/moderate toxicity, and therefore even 

considering a wide-ranging exposure pattern these chemical substances would also be of low risk 

concern. OPP would use the existing, scientifically valid information/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 has 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 considered to be of low toxicity, and therefore even 

considering a wide-ranging exposure pattern would also be of low risk concern. Tier 1a 

substances would not require submission of any toxicological data. It is anticipated that the 

rationale and justification confirming the low toxicity for these chemicals could be extremely 

limited and would consist of commonly or readily available knowledge on the lack of toxicity. 

Tier 1a risk assessments would be qualitative, drawing primarily on the substances=

long history of safe use, to support establishing unlimited tolerance exemptions. In fact, nonpesticidal exposures to many of these materials may 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 unlimited tolerance exemptions. 

Examples of chemical substances that are currently considered to be likely candidates for 

Tier 1a, that is, those chemical substances that could receive a preliminary Tier 1a 

determination, are described below: 

$ Commonly consumed food items (excluding known allergens): These are necessary to 

supply nutrition and there is a long history of safe use. 

$ Animal feed items: These items have been fed to animals without any evidence of ill 

effects. Examples of such materials would include corn cobs, and orange pulp/peel. 

Humans have safely consumed meat, milk, poultry and eggs produced by such animals. 

$ Weathered rocks and minerals, including silicates and oxides: These are the materials in 

and of the earth in which we grow our food. Examples of such materials would include 

sand and limestone. There is, thus, a long history of human exposure to these substances, 

including inadvertent dietary exposure. 

Page -35- 

$ Polymers that conform to the criteria specified in the TSCA polymer exemption (40 CFR 
723.250): OPPT reviewed over 12,000 polymer applications to determine these criteria 

which identify polymers of minimal toxicological concern. 

$ Inert gases (argon and helium): These gases are chemically inert. There are no known or 

suspected adverse effects. Pesticidal use of these substances is unlikely to significantly 

add to exposures from existing sources. 

$ Atmospheric gases (nitrogen and carbon dioxide): These are the gases that are present in 

the atmosphere that we breathe. 

Tier 1b:

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

for which some data/information would be necessary to make a confirmatory judgement 

concerning the substances= low or low/moderate toxicity. It is anticipated that the qualitative risk 

assessment for these chemicals would be more than that needed for a Tier 1a rationale and 

justification. The kinds and types of data to make this low toxicity confirmatory judgement 

would vary from chemical to chemical. Approval of substances in Tier 1b would be based upon 

information such as a review of existing, scientifically valid data, and/or a SAR assessment, 

rather than based on the submission of new studies. Use of surrogate data may be acceptable to 

make the confirmatory judgement concerning the chemical substances= low or low/moderate 

toxicity. Most Tier 1b risk assessments would be conducted in a qualitative manner assuming 

wide-ranging exposure, although quantitative risk assessments could also be performed. OPP 

anticipates that the FFDCA section 408 safety finding would also be based on low or 

low/moderate toxicity with resultant low risk, and usually allow for establishing unlimited 

tolerance exemptions, although OPP may impose limitations on the tolerance exemption, if 

appropriate. 

Examples of chemical substances that are currently considered to be likely candidates for 

Tier 1b, that is, those chemical substances that could receive a preliminary Tier 1b 

determination, are described below: 

$ FDA-approved food dyes: FDA has reviewed and evaluated the available data to support 

the use of Food, Drug, & Cosmetic (FD&C) dyes and Drug & Cosmetic (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, milk, soybeans, eggs, 

fish, crustacea, and wheat. Various factors such as restrictions on post-harvest 

applications or information on the environmental degradation/metabolism of the allergen 

may enable the Agency to make a determination of safety by preventing or mitigating 

dietary exposure from the pesticidal use. 

$ Naturally occurring materials (such as humic acid) that are ubiquitous in the 

environment, but are sometimes a highly refined version of the material or a synthetic 

Page -36- 
compound essentially identical to the naturally occurring material: Exposure to the 

natural material is already occurring. However, if it is not possible to make the 

confirmatory judgement concerning the low toxicity of the synthetic or highly refined 

material based on a factor such as a long history of safe usage, then the use must be 

supported by data to assure that the chemical has little or no toxicity. 

$ Chemicals that are part of the normal metabolic processes that occur in the human body: 

This would include intermediates of carbohydrate metabolism, such as the citric acid 

(Krebs) cycle, and intermediates of lipid metabolism, such as lecithin. (This could also 

include salts of such chemicals.) Other possible metabolic processes could include 

formation of lactic acid from glucose, and formation of the non-essential amino acids that 

are synthesized by the human body: The assessment would include a discussion of the 

metabolic process and an evaluation of the existing, scientifically valid data. 

$ Essential amino acids (those not manufactured by the body) and some vitamins: The 

assessment would include a discussion of the metabolic process, an evaluation of the 

existing, scientifically valid data, and information 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 metabolized in the body. The assessment would include a discussion of the 

metabolic process, and an evaluation of the existing, scientifically valid data. 

$ Derivatives of natural fatty acids that may 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 simple and complex carbohydrates: The assessment would include a 

SAR assessment. 

$ Gums (many are derived from plants, seaweed or algae): An evaluation of the existing, 

scientifically valid data would be necessary to make the confirmatory judgement that 

little or no toxicity is associated with exposure to these substances. 

$ Waxes: These are water-insoluble solid esters of higher fatty acids with long-chain fatty 

alcohols and generally have minimal to no dermal penetration. The assessment would 

include an evaluation of the existing, scientifically valid data and/or a SAR assessment to 

make the confirmatory judgement that little or no toxicity is associated with exposure to 

these substances. 

Page -37- 
$ Common mineral acids: These could include hydrochloric, sulfuric, sulfurous, carbonic, 

nitric, nitrous, phosphoric, phosphorous, hydrogen bromide, and hydrogen iodide. 

Existing, scientifically valid data should supply sufficient information 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 

formulated product. Given the small amounts that are used, the resultant risk should be 

low. 

$ Common hydroxides: These could include sodium, potassium, and calcium hydroxide. 

Existing, scientifically valid data should supply sufficient information 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 

formulated product. Given the small amounts that are used, the resultant risk should be 

low. 

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

ammonium, sodium, potassium, calcium, magnesium, zinc, iron, barium, or aluminum, 

but would not include salts such as cadmium or chromium. The assessment would 

include an evaluation of existing, scientifically valid data to demonstrate that little or no 

toxicity is associated with exposure to these substances. A SAR assessment may be 

necessary for some 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 determined. Some of these chemicals have been approved by FDA as GRAS or as 

direct food additives. The assessment would include an evaluation of existing, 

scientifically valid data and/or a SAR assessment to make the confirmatory judgement 

that little toxicity is associated with exposure to these substances. 

$ Rosins: These are the materials left after turpentine is removed from tree resins. The 

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

SAR assessment to make the confirmatory judgement that little or no toxicity is 

associated with exposure to these substances. 

$ Lignins: These are derived from wood. The assessment would include an evaluation of 

existing, scientifically valid data and/or a SAR assessment to make the confirmatory 

judgement that little or no toxicity is associated with exposure to these substances. 

Page -38- 
$ Cellulose: This is the major complex carbohydrate in plants. Cellulose, per se, may 

actually be Tier 1a; however, modifications of cellulose are more likely to be Tier 1b. 

The assessment would include a SAR assessment. 

$ Flower and vegetable oils/essential oils: These are natural components of plants that 

provide distinctive odor or flavor. For some of these oils, an evaluation of existing, 

scientifically valid data and/or a SAR assessment could be used to make the confirmatory 

judgement 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 most formulations. Given the small amounts that are needed to provide the 

distinctive odor or flavor, the resultant risk should be low. 

$ Chemicals for which a scientific assessment already has been performed by an expert 

panel: These assessments can be documented in the form of a monograph, a selfaffirmed GRAS determination, or an FDA evaluation. The Agency would conduct a 

streamlined 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 information 

necessary to make 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 substance has little or no toxicity, then a 

minimum data set to characterize the toxicity would be needed to evaluate such 

substances. This data would consist of a Ascreening@ data set which would have similarities 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 make the section 408 safety finding without a complete 

(food-use) Part 158 database. Such substances would be evaluated in a manner substantially 

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

assessment considering aggregate exposures to determine if the risk exceeds the Agency=s level 

of concern. Generally, these are chemicals for which the Agency suspects may involve 

significant toxicity and/or exposure concerns, such as endocrine disruption, carcinogenicity, 

developmental and reproductive effects, ecotoxicity, persistence/bioaccumulation and/or 

significant dermal penetration. These chemicals may have already been classified as List 1 

Ainerts of toxicological concern@ or List 2 Apotentially toxic inerts/high priority for testing@. 

Usually, registrants whose products contain Tier 3 chemicals would be required to provide these 

data via a FIFRA section 3(c)(2)(B) Data Call-In (DCI) Notice. 

Examples of chemical substances that might have preliminary Tier 3 determinations are 

described below: 

$ Phthalates are possible endocrine disrupters, and some have been evaluated by the 

National Toxicology Program for developmental/reproductive effects. 

$ Petroleum hydrocarbons are currently being evaluated by the Agency. 

Approximately 110 chemicals have been identified that are currently used in 

pesticide products. These chemicals would be grouped and a representative 

chemical(s) would be selected for each group. It is expected that these chemicals 

would be referred to the Inert Ingredient Focus Group (see Unit XVIII) before the 

DCI is issued to determine the data requirements. 

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

formulated product from microbial degradation before use) are oftentimes 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. 

$ Chemicals with significant dermal absorption can carry the active ingredient in an 

unpredictable manner into workers= bodies (impacting the worker assessment), 

and plants and animals tissues (impacting tolerances). An example would be 

dimethyl sulfoxide (DMSO). 

$ Chemicals, 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 similarities in biological activity to that of an active 

ingredient.

Page -41- 
$ Chemicals that are structurally similar to chemicals of toxicological concern 

$ Ethylene glycol ethers, especially short chain ethylene glycol ethers, are 

developmental and reproductive toxicants. 

Page -42- 
XVI. WEIGHT-of-the-EVIDENCE EVALUATION for CONDUCTING 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, multiple peer-reviews, and much documentation. EPA 

believes the decision process for low or low/moderate risk substances can be accomplished in a 

simpler, less intensive manner, and therefore has been exploring the use of a streamlined process 

that would reduce the extent of review, consultation and documentation needed to support such a 

risk assessment. At this time, OPP anticipates that Tier 1b and Tier 2 chemicals will be reviewed 

as described below: 

Tier 1b

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

assessment (described below) may be the only information considered by OPP. The information 

must provide a sufficient basis to make a confirmatory judgement on the low or 

low/moderate toxicity of the chemical substance. Aggregate exposure will be considered 

qualitatively. If the information is not sufficient, 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 chemicals would integrate a body of evidence that 

includes (1) a SAR (structure-activity-relationship) assessment, (2) an evaluation of existing, 

scientifically-valid information/data, and (3) the Tier 2 screening data set. Based upon these 

three sources of information OPP will determine whether the chemical substance meets the 

statutory criteria for a tolerance exemption. 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 

exemption for the chemical. 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 

chemical could be taken to Tier 3. 

The Structure-Activity-Relationship (SAR) Assessments 

There are various SAR assessment processes. The one described below was developed 

by OPPT as a tool for quickly assessing and predicting toxicity and environmental fate in the 

absence of chemical-specific data. OPPT scientists assess a chemical=s structural similarity to 

chemicals for which data are available. For human health, this process can be used to assess the 

potential for absorption and metabolism, mutagenicity, carcinogenicity, developmental and 

reproductive effects, neurotoxicity, systemic effects, immunotoxicity, and sensitization and 

irritation. This is generally performed as a qualitative assessment; although, if a robust data base 

were available on an analogous chemical, an endpoint would be chosen by OPPT and a 

quantitative risk assessment conducted. OPPT also performs an ecotoxicity and environmental 

Page -43- 
fate assessment often using modeling data. In performing these assessments, OPPT assesses 

specific use patterns based on information supplied by the submitter as well as OPPT=s 

professional judgement of future potential exposures. 

The reliability of this approach as a method of assessing potential human and 

environmental risks has been examined 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 chemical structure information, OPPT assessed 140 chemicals 

using their SAR assessment process. The results of their assessments were then compared to the 

Abase set@ data that the EU had received on each chemical. The results indicated that the SAR 

assessments were Aon target@ 90% of the time for aquatic toxicity, and roughly 80% of the time 

for human health effects. For human health, the approximately 20% that were not Aon target@

were overestimates, i.e., an overly conservative estimate of the chemical=s toxicity. In fact, the 

SAR assessment for only one chemical was considered to have underestimated the chemical=s 

toxicity. It should be noted that the data set required by the EU provides screening level 

information and does not address potential developmental, 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 chemicals which may present specific risk concerns and/or for which the value of 

generating additional data would be low. 

Search for Existing Scientifically Valid Data

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

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

The screening level studies for Tier 2 chemicals (toxicity, environmental fate, 

ecotoxicity, and product chemistry) would be reviewed by the disciplinary specialists to 

determine if any adverse effects were present. Examples of adverse effects, for a toxicity study, 

could be organ lesions, malformations (missing limbs or cleft palette), or reduction in implant 

indices. OPP would not request that any additional studies (targeted testing) be submitted, if: (1) 

no adverse effects observed at the maximum tested dose (depending on the dose level), or no 

adverse effects observed in animals tested at a dose level of 1000 mg/kg/day, and (2) no 

concerns are raised from the SAR assessment 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 most sensitive 

observed adverse effects in the screening studies, and would typically call for submission of a 

guideline study(s) to address the effect of concern. However, it is also possible for OPP to 

determine based on the results of the screening level studies and/or the targeted testing that 

placement in Tier 3 would be appropriate. 

Weight-of-the-Evidence Evaluation

Page -44- 
As previously discussed, a chemical substance would be determined to be Tier 2 if 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 chemical, at least the SAR assessment 

and the Tier 2 screening data set must be available for consideration during the weight-of-theevidence evaluation. An SAR assessment is a powerful predictive tool that examines all 

toxicological disciplines. Thus, it may be possible for the SAR to support the findings from the 

screening-level combined repeated dose/developmental/reproductive toxicity study. Together 

with the evaluation of existing, scientifically valid data (if available) OPP would evaluate the 

potential for increased sensitivity for infants and children that is considered when making the 

safety finding under FFDCA. In a weight-of-the-evidence evaluation, all these sources of 

information/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 

ADetermination 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 may be considered to be Tier 1 pose much 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 margin of safety for infants and children in the case of threshold 

effects to account for prenatal and postnatal toxicity and the completeness of the data base unless 

EPA concludes that a different margin safety will be safe for infants and children. Tier 1 

chemicals will be those of low or low/moderate toxicity and the risk assessment usually will be 

qualitative. Because the criteria for a Tier 1 determination preclude evidence of significant 

toxicity, a safety factor analysis would not be used and the FQPA 10X safety factor will be 

unnecessary. If there were information associating significant reproductive or developmental 

effects with a chemical substance with a preliminary Tier 1 determination, then the chemical 

substance could undergo a quantitative risk assessment, or would be changed to Tier 2 or Tier 3. 

For chemicals that may be considered to be Tier 2, the FQPA 10X safety factor cannot be 

removed or reduced without the submission of some type of developmental or reproductive data. 

 For quantitative Tier 2 risk assessments, OPP would determine an actual number for the 

children=s health safety factor. The determination would be based on the completeness of the 

screening toxicity database and the SAR assessment. For a Tier 2 chemical, the determination to 

remove, reduce, or retain the 10X would be made in a two-step process. The first step considers 

only the toxicity of the chemical. If, (1) the SAR assessment does not indicate the potential for 

reproductive and/or developmental effects or sensitivity, and (2) the available toxicity data, both 

the submitted study(ies) and an evaluation of existing, scientifically valid data, do not indicate 

any developmental/reproductive concerns or sensitivity, then the 10X may be removed based 

only on toxicity. 

The second step in the process considers the exposure component of the risk assessment. 

As previously explained, a bounding estimate/LOC (level of concern) approach would be used to 

address dietary and residential exposures. After the bounding estimates are performed, the 10X 

will be reconsidered in light of the available information on exposure and the information from

the bounding estimate/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 formed an 

Inert Ingredient Focus Group (IIFG). The IIFG has the primary role for reviewing and 

evaluating Tier 1 and Tier 2 chemical substances. It is a senior level interdivisional group, 

whose members possess expertise in the various scientific and regulatory disciplines necessary 

for performing a risk assessment as well as making risk management decisions. Generally, the 

IIFG would not perform the initial science reviews or the preliminary risk assessments, but 

would evaluate those reviews and assessments as a group. Thus, the IIFG would simultaneously 

fulfill the roles of all the disciplinary and review committees that would ordinarily participate in 

assessing the risk of a conventional pesticide active ingredient, as well as being responsible for 

making the risk management evaluations. 

The types of decisions made by the IIFG would vary based upon the substance(s) being 

considered and the type of risk assessment being performed. At most IIFG meetings, the group 

would consider inert ingredients. However, some 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 make the confirmatory judgement concerning the substances= low or low/moderate 

toxicity would also be considered for evaluation by the IIFG. 

Some examples of the possible decisions that would be made by the IIFG are listed 

below: 

$ Determining the preliminary Tier determination as well as changes to this determination 

$ Determining the adequacy of the substances= database for performing a risk assessment 

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

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

information/studies needed 

$ Judging the adequacy of the risk assessment performed for approving the use of the 

substance with or without limitations 

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

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

$ Determining appropriate List placement (such as 4A) for an inert ingredient 

The current process begins by selecting a chemical substance for review. The next steps, 

performed by various OPP staff, would be internet searches, data review and evaluation, and 

document preparation. If necessary and appropriate, an SAR assessment would be prepared. 

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

assessment. OPP staff would then perform a preliminary risk assessment. The IIFG would then 

review and evaluate this risk assessment. For each Tier, the elements listed below comprise a 

possible sequence of events: 

Tier 1a: 

$ Consider the available information and/or reviews and evaluate whether 

the preliminary determination as Tier 1a is appropriate 

$ Formulate a rationale indicating the substance=s (or group of substances=) 

low toxicity based on readily available information which can include 

factors such as a long history of safe use 

$ Determine whether the rationale is sufficient and appropriate considering 

a wide-ranging exposure pattern 

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

4B 

$ Prepare a Decision Memo capturing the basis upon which the decision was 

made, which can then be used to prepare tolerance reassessment 

documents, Federal Register Notices, or other documents necessary to 

formalize the decision. 

Tier 1b:

$ Consider the available information and/or reviews and evaluate whether 

the preliminary determination as Tier 1b is appropriate 

$ Evaluate the results of searches for existing scientifically-valid data to 

determine the adequacy of the database 

$ If necessary and appropriate, have a SAR assessment prepared 

$ Formulate a rationale indicating the low or low/moderate toxicity based on 

the review of the existing scientifically valid data and/or the SAR 

assessment 

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

$ Determine whether a qualitative risk assessment or a quantitative risk 

assessment should be performed, or that the substance should be shifted to 

Tier 2 

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

4B 

$ Prepare a Decision Memo capturing the basis upon which the decision was 

made, which can then be used to prepare tolerance reassessment 

documents, Federal Register Notices, or other documents necessary to 

formalize the decision. 

Tier 2:

Page -48- 
$ Consider the available information and/or reviews and evaluate whether 

the preliminary determination as Tier 2 is appropriate 

$ Evaluate the results of searches for existing scientifically-valid data to 

determine the adequacy of the substances= database 

$ Understand the non-pesticidal exposures of the chemical substance 

$ If necessary and appropriate, have a SAR assessment prepared 

$ Determine whether the submitted data are sufficient and appropriate for 

making 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 scientifically valid data, the SAR 

assessment, and the reviews of the submitted data 

$ Select doses and endpoints for use in risk assessment 

$ Determine the appropriate safety factor for the protection of infants and 

children 

$ Perform the bounding level/LOC assessments 

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

4B 

$ Prepare a Decision Memo capturing the basis upon which the decision was 

made, which can then be used to prepare tolerance reassessment 

documents, Federal Register Notices, or other documents necessary to 

formalize the decision. 

Tier 3:

The IIFG would have little involvement with Tier 3 chemicals. The IIFG would make 

the Tier 3 determination. Once this determination has been made, the chemical would be referred 

to the appropriate regulatory manager 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 exemption 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 structure 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 documents 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 exemption from the requirement of a 

tolerance for an inert ingredient not currently used in pesticide products or a person who has 

submitted information to the Agency to support a particular tolerance exemption as part of 

tolerance reassessment may submit data on its own initiative, and may in certain cases be 

required to submit certain additional data. In all these instances, the Agency needs the submitted 

information to be properly formatted. The Agency needs sufficient credible information with 

which to make its decision, not an overwhelming amount of information. 

As discussed the IIFG=s first task is a preliminary tier determination. Proponents of a 

tolerance exemption are encouraged to propose a preliminary tier determination to OPP. 

Recommendations that are based on existing scientifically-valid information/data, and that 

clearly explain the factual basis for the recommended Tier determination, are those most likely 

to provide the information that could expedite the IIFG=s Tier determination. Submitters should 

carefully consider the examples given in this document as well as evaluations performed by the 

IIFG in preparing their recommendation for preliminary Tier determination. 

For substances believed to be Tier 1: 

$ For those chemical substances subject to tolerance reassessment, OPP expects that for 

many of these chemicals there would be sufficient, credible scientifically-valid 

information/data through the internet. Therefore, tolerance reassessments for many Tier 

1 chemical substances would be performed by OPP without the need for submissions 

from those proponents of the tolerance reassessment. 

$ For a chemical substance for which a petitioner is seeking approval of a new inert 

ingredient (tolerance exemption petition), petitioners should provide the Agency with the 

results of their search for existing scientifically valid information/data. Petitioners would 

then develop a rationale which explains why a tolerance exemption should be established 

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

summary to be used in the Notice of Filing which would include the above information. 

For substances believed to be Tier 2 and 3: 

 

$ For chemical substances subject to tolerance reassessment, proponents of a tolerance 

exemption should anticipate OPP=s need for more information. Given that OPP=s lack of 

credible scientifically-valid information/data can be the reason for a Tier 2 determination, 

if no information has been submitted to the Agency for a Tier 2 chemical substance, then 

the Agency would issue a FIFRA section 3(c)(2)(B) Data Call In (DCI) 

Page -51- 
 Notice for the required information or request information under FFDCA 408(f) for the 

Tier 2 screening data set. For most Tier 3 chemicals, OPP will need the complete 40 CFR 

Part 158 data set. 

$ For a tolerance or tolerance exemption petition, the Agency will not be able to grant the 

petition unless there are sufficient data to determine that there is a reasonable certainty 

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

submission should include studies (formatted according to PR Notice 86-5), and the 

results of the search for existing scientifically valid information/data, and a summary to 

be used in the Notice of Filing, which will include discussions of the studies, the other 

uses of the chemical, and estimates of endpoints for use in risk assessment. 

The Agency would conduct an initial evaluation of the submission including the 

submitters= recommendation for Tier determination. The submitter will be informed as to the 

completeness of the submission and whether any deficiencies have been identified. 

Page -52- 
Data Specifications Comparison Table

DATA 

SPECIFICATIONS 

for 

HPV Challenge 

Program

(SIDS Data Set) 

DATA 

SPECIFICATIONS 

for 

1987 

Inert Ingredient 

Data Set 

OPP

 DRAFT DATA SPECIFICATIONS 

specifically for 

Tier 2 Lower Toxicity Pesticide Chemicals 

Human Health

SAR Assessment and Literature Search1a

Screening Level1b Targeted 

Acute Toxicity 

(e.g., OECD 425) 

usually submitted not required n

in vitro Mammalian Cell 

Chromosome Aberration 

(e.g., OECD 473 or 

OPPTS 870.5375) 

OR

in vivo Cytogenetics 

(Mammalian Bone 

Marrow Chromosome

Aberration) 

(e.g., OECD 475 or 

OPPTS 870.5385) 

OR

in vivo Mammalian

Erythrocyte 

Micronucleus Test 

(OECD 474 or OPPTS 

Structural Chromosomal 

Aberration Test 

(OPP 84-2) 

Other Genotoxic Effects 

(OPP 84-4) 

1d

in vivo Cytogenetics 

(Mammalian Bone Marrow Chromosome Aberration) 

(OPPTS 870.5385)

OR

in vivo Mammalian Erythrocyte Micronucleus Test 

(OPPTS 870.5395) 

possibl

Combined chron

(OP

Page -1- 
870.5395) 

Gene Mutation - 

Bacterial 

Salmonella typhimurium

reverse mutation assay 

(Ames) 

(OECD 471 or OPPTS 

870.5100) 

OR

Gene Mutation - 

Mammalian

 (Mouse lymphoma, 

Chinese hamster ovary, 

or Chinese hamster V79) 

cells in culture forward 

gene mutation assay 

(OECD 476 or OPPTS 

870.5300) 

Gene Mutation Test 

(OPP 84-2) 

Gene Mutation - Bacterial 

Salmonella typhimurium reverse mutation assay (Ames) 

(OPPTS 870.5100) 

AND

Gene Mutation - Mammalian 

 (Mouse lymphoma, Chinese hamster ovary, or Chinese 

hamster V79) cells in culture forward gene mutation assay 

(OPPTS 870.5300) 

possibl

Combined chron

(OP

Repeat Dose Toxicity

(e.g., OECD 407 or 

OPPTS 870.3050;) or 

combined with a 

reproductive/developme

ntal toxicity study (e.g., 

OECD 422; or OPPTS 

870.3650) 

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 with 

Developmental/Reproductive Screen with Neurotoxicity 

and Immunotoxicity Components 

(OPPTS 870.3650) 1e

possibl

Development

(OP

Reproductio

(OP

90-Day Oral Toxicit

and/or Imm

(OPPTS 870.3

Developm

(OP

not required not required Endocrine Disruptor Screening Program (EDSP) 

TBD 

Environmental Fate 2

Page -2- 
OUTDOOR USES

Tier 1

OUTDOOR USES

Based on results of Tier 1

IND

not required not required SAR Assessment

Photodegradation in 

Water

(OPP 161-2) 

Photodegradation in Water

(OPPTS 835.2240)

Photodegradation 

(to be determined by 

estimation)

Photodegradation in Soil 

(OPP 161-3) 

Photodegradation 

(to be determined by 

estimation)

Photodegradation in Soil 

(OPPTS 835.2410)

n

Stability in water 

(e.g., OECD 111; 

 OPPTS 835.2110)

Hydrolysis 

(OPP 161-1)

Hydrolysis as a function of pH 

(OPPTS 835.2110)

n

NA Koc or Kd 

(OPP 163-1) 

Sediment and Soil Adsorption/Desorption for Parent and 

Degradates

(OPP 163-1) 

n

Transport 

(Via modeling)

not required not required n

Biodegradation 

(e.g., OECD 301 or 302)

not required not required n

not required not required not required Aerobic Aquatic Metabolism

(OPP 162-4)

n

not required Aerobic soil metabolism

(OPP 162-1) 

Aerobic Soil Metabolism

(OPP 162-1)

(based on results of Tier 1 

testing) 

Anaerobic Soil Metabolism

(OPPTS 835.4200 )

OR

Anaerobic Aquatic 

Metabolism

n

Page -3- 
Page -4- 

(OPPTS 835.4400)

not required not required Other testing as required 

dependent on the use 

pattern

Other testing as required 

dependent on the use pattern

Other testing as requi

Ecotoxicity 3

OUTDOOR USES

Level 1

OUTDOOR USES

Based on results of Level 1: 

criteria to be developed

IND

for which 

 Tier 1 

not required not required SAR Assessment

Acute Toxicity to Fish 

(e.g., OECD 203; 

OPPTS 850.1075)

Acute 96hr Fish LC50 

(OPP 72-1) 

Fish Acute Toxicity Test, 

Freshwater 

(one species - Rainbow 

Trout) 

(OPPTS 850.1075)

3a

Fish Acute Toxicity Test, 

Freshwater 

(one species -Bluegill) 

(OPPTS 850.1075)

Fish Acute Toxicity Test, 

Marine 

(OPPTS 850.1075)

Fish Early Life Stage 

Toxicity Test 

(OPPTS 850.1400)

Fish Acute Toxicity 

Test, Freshwater 

(one species - Rainbow 

Trout) 

(OPPTS 850.1075)

required only in cases of 

significant exposure

Avian Oral LD50 

(OPP 71-1) 

8-Day Avian Dietary

(OPP 71-2) 

Avian Dietary Toxicity 

Test 

(one species - Bobwhite 

Quail) 

(OPPTS 850.2200)

3b

Avian Dietary Toxicity Test 

(one species - other than 

Bobwhite Quail) 

(OPPTS 850.2200)

n

Toxicity to Aquatic 

Plants (Algae) 

not required Algal Toxicity - Tier 2 

(4 species) 

not required Algal Toxicity - Tier 2 

(4 species) 
(e.g., OECD 201; 

OPPTS 850.5400)

(OPPTS 850.5400)

Aquatic Plant Toxicity 

Test - Tier 2 

 using Lemna spp.

(OPPTS 850.4400)

(OPPTS 850.5400)

Aquatic Plant Toxicity 

Test - Tier 2 

 using Lemna spp.

(OPPTS 850.4400)

Acute Toxicity to 

Aquatic Invertebrates 

(Daphnia) 

(e.g., OECD 202, 

formerly 202a; OPPTS 

850.1010)

48-Hr LC50 or EC50 in 

Daphnia 

(OPP 72-2) 

Acute Toxicity to Aquatic 

Invertebrates (Daphnia) 

(OPPTS 850.1010)

not required Acute Toxicity to 

Aquatic Invertebrates 

(Daphnia) 

(OPPTS 850.1010)

Daphnid Chronic 

Toxicity Test 

(when appropriate) 

(e.g., OECD 211, 

formerly 202b; OPPTS 

850.1300)

not required not required Daphnid Chronic Toxicity 

Test 

(when appropriate) 

(OPPTS 850.1300)

Daphnid Chronic 

Toxicity Test 

(when appropriate) 

(OPPTS 850.1300)

not required not required not required 3c

Terrestrial Plant Toxicity, 

Seedling Emergence 

Tier 1 or 2 

10 species 

(OPPTS 850.4225)

Terrestrial Plant Toxicity, 

Vegetative Vigor 

Tier 1 or 2 

10 species 

(OPPTS 850.4250)

n

not required not required Honey Bee Acute Contact Toxicity 

(OPPTS 850.3020)

n

not required not required Other testing as required 

dependent on the use 

Other testing as required 

dependent on the use pattern 

Other testing as 

required dependent on 

Page -5- 
pattern the use pattern 

Physical/Chemical Properties - Product Chemistry 4

not required OPP 61-1 Product Identity and Composition 

(OPPTS 830.1550)

Melting Point 

(e.g., OECD 102; 

OPPTS 830.7200)

not required Melting Point 

(OPPTS 830.7200)

Boiling Point 

(e.g., OECD 103; 

OPPTS 830.7220)

not required Boiling 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 and 

OECD 112, if 

applicable; OPPTS 

830.7840)

Solubility 

(OPP 63-8) Water Solubility - Column Elution 

Shake Flask Method 

(OPPTS 830.7840) 

OR

Water Solubility 

Generator Column Method 

(OPPTS 830.7860)

pH Value and Pka Value 

(e.g., OECD 112, if 

appropriate)

Dissociation Constant 

(OPP 63-10) 

Dissociation Constant in Water 

(OPPTS 830.7370) 

n-Octanol/Water 

Partition Coefficient 

(e.g., OECD 107, 

 OECD 117; OPPTS 

830.7560) 

Octanol/Water Partition 

Coefficient 

(OPP 63-11) 

n-Octanol/Water Partition Coefficient - Shake Flask Method (OPP

OR

n-Octanol/Water Partition Coefficient -Generator Column Method (O

OR

Page -6- 
n-Octanol/Water Partition Coefficient -Estmation by 

 Liquid Chromatography 

 (OPPTS 830.7560) 

pH Value and Pka Value 

(e.g., OECD 112, if 

appropriate)

pH 

(OPP 63-12) pH 

(OPPTS 830.7000) 

not required Contaminants 

(OPP 61-3) 

Batch Analyses 

(OPP 62-1) 

Density 

(OPP 63-7)

not required

Residue Chemistry

not required Background 

(OPPTS 860.1000)

not required Chemical Identity 

(OPPTS 860.1100) 

not required 

Description on Use 

Pattern and Type of 

Pesticide Formulation

(OPP 171-3) 

Directions for Use 

(OPPTS 860.1200) 

1a The SAR Assessment contains an evaluation of both human health and environmental parameters. The literature search can be 

available web-sites which contain scientifically peer-reviewed data. 

1b The submitted screening level studies would be reviewed to determine if any adverse effects were present. An example of an a

lesions, malformations (missing limbs or cleft palette), or reduction in implant indices. If the following criteria are met, then t

additional studies (targeted testing) to be submitted: (1) no adverse effects observed at the maximum tested dose (MTD), or (2) 

1000 mg/kg/day. 

Page -7- 

1c Targeted testing is determined by a weight-of-the-evidence evaluation that includes the following components: a structure activ
Page -8- 

information from a search of open literature, and the Tier 2 database or equivalent testing. Targeted testing addresses only the effects in the screening studies, and requires submission of a guideline study. 

1d Mutagenicity studies are needed to assess the ability of the test material or its metabolite(s) to interact directly or indirectly w

or chromosomes and the potential for adverse effects on cellular genetic material. Subsequent testing may be needed based on 

Agency in accordance with the objective and considerations for mutagenicity testing. 

The OPP guidelines specify use of OPPTS 870.5385 or OPPTS 870.5395 for chromosomal aberrations, which when combined 

mouse lymphoma assay is a total of three tests. This is the lowest number that can constitute a complete battery of genotoxicitmutation assay other than mouse lymphoma is performed, an in vitro mammalian cytogenetic assay (OPPTS 870.5375) may be needed depending on the chemical. 

1e The ACombined Repeated Dose Toxicity with Reproductive/Developmental Toxicity Screening Test,@ (OPPTS 870.3650) 

information on all aspects of reproduction and development. This toxicity study cannot not provide conclusive evidence of no effects because it does not include assessments of many aspects of developmental and reproductive toxicity that would be examstudies (OPPTS 870.3700 and 870.3800). It is a screening test which provides limited information on reproductive/developme

neurotoxicity, and/or immunotoxicity following repeated exposure over a limited time period of 28 days. The information obtaprioritize 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 (used outdoors), such as the rate of chem

rates of formation and decline of volatile and nonvolatile degradates, the accumulation of the chemical and its transformation 

physical mobility of the chemical and its transformation products in the environment. These data are also used as input data fo

lack of such data increases the need for uncertainty factors. 

3 Ecotoxicity testing is performed only for new registrations, as tolerance reassessment is performed under FFDCA only. OPP u

the potential risks of a chemical=s use(s) to nontarget plants, aquatic and terrestrial vertebrates and invertebrates, and bees. The 

evaluated to determine the potential of the chemical to cause adverse effects, and to determine whether further testing is requir

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 herbicid

information on the use pattern and on the results of the testing on the formulated product, Tier 2 testing as indicated could be ringredient. 

4 Certain physical and chemical data are needed as basic or supportive evidence in initiating or evaluating other studies. For exa

coefficient is used as one of the criteria to determine whether certain fish and wildlife toxicity or accumulation studies must be 

data can also be used as input data for the Agency=s water modeling.