PB83-153890
PESTICIDE ASSESSMENT GUIDELINES - SUBDIVISION D: PRODUCT CHEMISTRY
G.J. Beush, et al
U.S. Environmental Protection Agency
Washington, D.C.
October 1982
U.S. DEPARTMENT OF COMMERCE
National Technical Information Service
NIB,
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I
PB83-153890-
EPA 5AQ/9-82-018
October 1, 1982
PESTICIDE ASSESSMENT GUIDELINES
SUBDIVISION D
PRODUCT CHEMISTRY
Prepared by
G.
J.
Beusch
W.
R.
Bontoyan
E.
B.
Brittin
A.
W.
Burns
J.
H.
Chen
C.
H.
Hal 1 ( retired)
W.
L.
Jordan
I.
N.
Mauer
J.
A.
Shaughnessy (retired)
Guideline Coordinator
Robert K. Hitch
Hazard Evaluation Division
Office of Pesticide Programs
U.S. Environmental Protection Agency
Office of Pesticide and Toxic Substances
Washington, D.C. 20460
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Subdivision D, a Federal Insecticide Fungicide and Rodenticide Act guideline,
was the the subject of close final review from an Agency-sponsored comittee
consisting of a representatives from industry, academia and a national environ-
mental group.
To assess its potential toxicity to humans and hazard to the environment, the
gency requires basic information on the composition of each product. For all products
his information includes a description of the manufacturing process, a discussion
>n ':he formation of product impurities and a Confidential Statement of Formula. This
;*.dtement names each intentional ingredient (both active and inert) of the product,
impurities (_> 0.1%) that are associated with the active ingredient, and an? other
product impurities that may be either toxicologically significant or environmentally
hazardous. The formulating composition (i.e., nominal concentration in percentage
by weight) is indicated and composition limits, upper and lower, are stated for the
intentionally added ingredients; upper limits, for each impurity. For products pro-
duced by an integrated-formulation system, composition data determined by an analysis
are needed for the product and in some instances for the technical chemical.
Subdivision D constitutes one volume of a twelve-part NTIS Federal Insecticide,
Fungicide and Rodenticide Act guideline series.
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FOREWORD
Subdivision D describes protocols vfoich may be used to perform
Product Chemistry testing to support the registration of pesticides
under the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA). It is a nonregulatory companion to 40 CFR Part 158, Data
Requirements for Registration. A public meeting was held in July,
1982 to accept comments on the FIFRA guidelines. Because of the
importance of the issues raised in the Subdivision D comments, a
review committee comprised of representatives of industry,
environmental groups and academia read and approved the Agency
revision. This guideline refers to requirements established in 40
CFR Part 158 so that this document can be read as a complete package
and so that the protocols may be explained in their proper context.
I &
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SUBDIVISION D: PRODUCT CHEMISTRY
TABLE OF CONTENTS
DISCUSSION PAGE
BACKGROUND AND SCOPE
A. History. 1
B. Reorganization of Guidelines Sections. 6
C. Purposes of Product Chemistry Data Guidelines. 6
II EXPLANATION OF APPROACH
A. Definitions. 8
B. The Formulators' Exemption. 11
C. Statement of Formula. 12
D. Description of Beginning Materials and Manufacturing Process. 12
E. Discussion of the Formation of Impurities. 14
F. Results of Preliminary Analyses. 15
G. Certified Limits. 15
H. Methods to Verify Certified Limits. 17
I. Physical and Chemical Characteristics. 17
J. Submittal of Samples. 18
K. Timing of Data Submissions. 18
III ISSUES IN PRODUCT CHEMISTRY
A. Information on Impurities, and Discussion on Their Formation. 20
B. Information on Manufacturing Process.' 29
C. Certified Limits. 31
D. Requirement for Analytical Methods. 36
E. Accuracy and Precision of Methods. 41
F. Deferred Submittal of Data. 42
G. Multiple Formulations. 43
/• b
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GUIDELINES
Series 60: GENERAL INFORMATION PAGE
§ 60-1 Overview. 45
(a) Scope and purpose. 45
(b) List of requirements. 45
(c) Application status and compliance. 46
§ 60-2 Definitions. 48
§ 60-3 General provisions. 49
(a) Data on the pesticide product. 49
(b) Omitting certain of the required data. 49
(c) Timing of data submissions. 50
(d) Confidential treatment of product chemistry
information. 5 1
Series 61: PRODUCT ICENTITY AND COMPOSITION
§ 61-1 Product identity and disclosure of ingredients. 51
(a) Product identity. 51
(b) Statement of formula. 51
§ 61-2 Description of beginning materials and manufacturing
process. 52
(a) Beginning materials. 52
(b) Manufacturing process. 52
(c) Changes in beginning materials or manufacturing
process. 53
§ 61-3 Discussion of the formation of impurities. 53
(a) General requirements. 53
(b) Manufacturing-use products and those end-use
products produced by an integrated formulation
system. 53
(c) End-use products not produced by an integrated
formulation system. 54
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GUIDELINES
PAGE
Series 62: ANALYSIS AND CERTIFICATION OF PRODUCT INGREDIENTS
§ 62-1 Preliminary analysis of product samples. 55
(a) When required. 55
(b) Requirements for performing sample analyses. 55
(c) Description of analytical methods and reporting of
sample analysis results. 56
(d) Identifying spectral data. 57
(e) References. 57
§ 62-2 Certification of ingredient limits. 57
(a) General. 57
(b) Manufacturing-use products and those end-use
products produced by an integrateed
formulation system. 59
(c) End-use products not produced by an integrated
formulation system. 59
(d) Certified limits for additional ingredients
and impurities. 60
§ 62-3 Analytical methods to verify certified limits. 60
(a) When required. 60
(b) Requirements for analytical methods and supporting
data. 60
(c) Description of analytical methods. 62
Series 63: PHYSICAL AND CHEMICAL CHARACTERISTICS
§ 63-1 General provisions for physical and chemical
characteristics testing. 62
(a) Summary of test requirements. 62
(b) Test methods and the "References" paragraphs. 62
(c) General reporting requirements. 63
(d) General references. 63
§ 63-2 Color. 65
§ 63-3 Physical state. 65
§ 63-4 Odor. 66
§
63-5 Melting point.
66
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GUIDELINES
§ 63-6 Boiling point.
§ 63-7 Density, bulk density or specific gravity.
§ 63-8 Solubility.
§ 63-9 Vapor pressure.
§ 63-10 Dissociation constant.
§ 63-11 Octanol/water partition coefficient.
§ 63-12 £H.
§ 63-13 Stability.
§ 63-14 Oxidizing or reducing action.
§ 63-15 Flammability.
§ 63-16 Explodability.
§ 63-17 Storage stability.
§ 63-18 Viscosity.
§ 63-19 Miscibility.
§ 63-20 Corrosion characteristics.
§ 63-21 Dielectric breakdown voltage.
67
67
68
69
69
70
70
71
72
72
73
73
74
75
75
76
series 64: OTHER PRODUCT CHEMISTRY REQUIREMENTS
§ 64-1 Submittal of samples.
76
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I. BACKGROUND AND SCOPE
A. History.
1. Product Chemistry guidelines. Guidelines proposing data require-
ments for product chemistry information were first proposed by the
Agency on June 25, 1975 in 40 FR 26802. The guidelines published
at that time also included data requirements for pther types of
studies, sudi as studies to evaluate environmental chemistry (fate),
fish and wildlife hazard, human hazard, and product performance.
Ihese proposed guidelines described the kinds of information required
by the Agency to determine whether a particular pesticide should
be registered.
The interested public submitted more than 80 sets of comments
on the 1975 proposed guidelines. Based on a review of these comments
and extensive Agency consideration, EPA reproposed the product
diemistry guidelines as part of Subpart D of Part 163 in Title 40 of
the Code of Federal Regulations (43 FR 29696, July 10, 1978). At the
same time, EPA also reproposed the Introduction (Subpart B), Environ-
mental Chemistry guidelines (then also part of Subpart D), and the
guidelines for hazard evaluation to protect wildlife and aquatic
organisms (Subpart E).
In response to the 1978 proposals ("1978 proposed guidelines"),
the Agency again received over 80 sets of comments. The Agency has
considered these comments in developing the final Product Chemistry
guidelines. In general, EPA has revised Subdivision D to clarify the
guidelines, to enhance the quality of the data that would be submitted,
and to reduce the burden on applicants or registrants (to the extent
that this could be done while still assuring that EPA obtained the
needed information).
2. Change from the 0.01 Percent Requirement to a 0.1 Percent
Requirement. The 1978 proposed guidelines proposed the identification
and quantification of each substance in the pesticide product,
including added ingredients and/or impurities, greater than or equal
to 0.01 percent of the product by weight. The Agency received many
public comments objecting to this requirement. Forty-four percent
of the comments received on the product chemistry guidelines opposed
the Agency's proposed requirement for quantitative data on product
ingredients (inerts and impurities) equal to or greater than 0.01
percent by weicfrt. The ccmmenters also said that the quality control
procedures associated with maintaining the certified composition
limits for all of the product ingredients would be excessive.
Actually, however, the 0.01 percent requirement was placed only on
manufacturing-use products and products produced by an integrated
formulation system; the requirement for other formulated products was
less demanding.
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Most of the canmenters also said that the costs of certifying
product composition to the proposed 0.0 1 percent level would be ex-
tremely high, amounting to more than 10 percent of the total develop-
ment costs of a typical pesticide. The estimates varied widely
and were dependent upon cost estimates for developing methodology
to detect eadi impurity (§7,000 to $25,000) and the number of
product impurities.
Companies formulating with polymeric materials, or with oils
containing perhaps hundreds of minor components, pointed out the
problem of analytical closure (viz., the determined ingredients do
not add to 10 0 percent, often with a difference of a few percentage
points) and considered it virtually impossible to account for all
components present in quantities greater than or equal to 0.01 percent
by weight. They also stressed that previously the Agency had frequently
been concerned with product impurities of toxicological significance
at levels considerably less than 0.01 percent, and they urged the
Agency to limit the 0.01 percent requirement to only those impurities.
Although supporting the Agency's concern about trace quantities
of highly toxic impurities, several of these canmenters proposed, as
an alternative approach, the development of quantitative methodology
for only those impurities having sufficient toxic activity to be
potentially hazardous to man and the environment. Many such comments
were offered in conjunction with the proposed requirements for
certification of limits. Three examples of these many comments
follow:
<1) A more reasonable requirement would be to request
applicants to advise the Agency on biologically active
ingredients that could likely be present in the product at
levels that could affect product safety.
(2) The certification of limits, therefore, must be
selectively aimed at and limited to the active ingredient
content and those impurities known to represent a toxicological
hazard at the levels found.
(3) These limits should be set only for the active ingre-
dient and potentially highly toxic impurities.
The Agency is in agreement with the ideas set forth by these cam-
menters but has decided not to ask for biological-screening data at
this time because of the many subsantial issues raised to these tests
by the public. Instead, the Agency will rely upon the information and
data submitted under other guideline sections (i.e., Manufacturing
process, Discussion of the formation of impurities, Preliminary analy-
sis of products) to provide adequate data on product composition.
Based on a review of this data, applicants would be required to provide
analytical methodology suitable for monitoring the commercial product
both for the active ingredients and for impurities that are of toxi-
cological concern or environmentally hazardous.
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Table 1. Organization of product chemistry topics in current
guidelines and 1978 proposed guidelines.
DESIGNATED AND REDESIGNATED SECTIONS
Guideline Sections and Paragraphs
Subject Current Proposed in July 1978
GENERAL INFORMATION
Scope of data requirements 60-1(a)
List (or location) of requirements -1(c)
163.60-1(a)
-2(a)
DEFINITIONS 60-2(a) thru (m) 163.61-1(a) thru (c
163.40-2(a),(c),(d)
GENERAL PROVISIONS (requirements)
Data on pesticide product 60-3(a)
Requests for waivers -3(b)
Explanations for excluding data 163.61-2 (e)
Tech. grade of the active ingredient -2(b)
Timing of data submission -3(c)
Data for products not in production -3(c)(1) -2(c)
Contents of deferral request -3(c)(2)
Notification requiring deferred submittal -3(c)(3)
Nature of data submittals -2(d)
Confidential treatment of data -3(e)
PRODUCT IDENTITY AND DISCLOSURE C? INGREDIENTS
Product identity 61-1(a) 163.61-3(a)
Formula of technical chemical -3(b)
Statement of formula -1(b) -3(c)
Name and certified limits for added
ingredients -1(b)(1) .....
Name and certified limits for impurities -1(b)(2)
Purpose -1(b)(3)
Chemical name and CAS-Registry number -1(b)(4) -3(c)(1)
Other names, formulae, molecular Wt., etc. -1(b)(5) -3(c)(2)-(6)
DESCRIPTION OF BEGINNING MATERIALS AND MANUFACTURING PROCESS
Beginning materials
Submittal of registration number
of manufacturing-use product
Name and address of producer
Names of beginning materials
Specifications, etc.
All other information
Manufacturing process
Batch or continuous
Amounts and order of addition
Equipment
61 -2(a)
-2(a)(1)
-2(a)(2)(i)
-2(a)(2)(ii)
-2(a) (2) (in)
-2(a)(2)(iv)
-2(b)
-2(b)(1)
-2(b)(2)
-2(b)(3)
63.61-4(a )
3(a)
-4(b)
-4(b)
-4(b)
-4(b)
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Table 1 (continued)
Phys ical condi tions
Reactions
Flow chart
Duration of steps
Purification
Quality control
Changes
-2(b)(4) -4(b)
-2(b)(5) -4(b)
-2(b)(6) -4(b)
-2(b)(7)
-2(b)(8) -4(b)
-2(b)(9) -4(b)
-2(c)
DISCUSSION ON FORMATION OF IMPURITIES
General requirements 61-3(a) 163.61-5
Manufacturing-use products and end-use -3(b)
products from integrated formulation
system
Impurities greater than 0.1% (expected) -3(b)(1)
Other impurities (found) -3(b)(2)
All other end-use products -3(c)
ANALYSIS OF PRODUCT SAMPLES
When required
Requirements
Selection of samples
Number of samples
Batch choice
Intervals choice
Additional samples
Ingredients to look for
Selection of method
Additional requirements
Methods and reporting of results
Methods description
Precision and accuracy of method
Reporting results
Identifying spectral data
-1(a)
» • • • *
-Kb)
163.61-7(a) (1
-1(b)(1)
-7(b)(1
-1(b)(1)(i)
-7(b)(1
-1
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Table 1 (continued)
analytical methods to verify certified limits
When required
62-3(a)
• • • * •
Requirement for analytical methods
-3(b)
163.61-7(a)(1)
Substances requiring methods
-3(b)(1)
-7(a)(2)-(4)
Manufacturing-use products and end-use
-3 (b) (1) (i)
-7(a)(2),(3
)
products from integrated formulation
sys tem
All other end-use products
-3(b)(1)(ii)
-7(a)(4)
Additional ingredients
-3(b)(1)(iii)
-7(a)(5)
Waivers
-3(b)(2)
• • « « •
Precision and accuracy of methods
-3(b)(3)
-7(a)(1)
validation studies
-3(b)(4)
-7(a)(1)
Method description and reporting
-3(c)
-7(a)(1)
PHYSICAL AND CHEMICAL CHARACTERISTICS
General provisions
63-1
163.61-8(a)
, (b), ( c)
Color
-2
-8(c)
1)
Physical state
-3
-8(c)
7)
Odor
-4
-8(c)
2)
Melting point
-5
-8(c)
3)
Boiling point
-6
-8(c)
9)
Density, bulk density, or specific gravity
-7
-8(c)
8)
Solubility
-8
-8(c)
4)
Vapor pressure
-9
-8(c)
10)
Dissociation constant
-10
-8(d)
Octanol/water partition coefficient
-11
-8(c)
6)
pH
-12
-8(c)
11 )
Stability
-13
-8(c)
5)
Oxidizing or reducing action
-14
-8(c)
12)
Flammability
-15
-8(c)
13)
Explodabili ty
-16
-8(c)
15)
Storage stability
-17
-8(c)
13)
Viscosity
-18
-8(c)
17)
Miscibility
-19
-8(c)
16)
Corrosion characteristics
-20
-8(c)
18)
Dielectric breakdown voltage
-21
-8(c)
19)
SUBMITTAL CF SAMPLES
64-1
163.61-9
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B. Reorganization of Guidelines Sections.
In order to present the revised Product Chemistry guidelines m
a more logical sequence, the Agency has rearranged and renumbered the
sections and their individual requirements. Table 1 indicates the
sections and principal paragraphs of the current guidelines and their
designations in guidelines proposed in 1978.
C. Purposes of Product Chemistry Data Guidelines.
The Agency intends that the guidelines provide meaningful
information to applicants, registrants/ and the general public
regarding the product chemistry data requirements for registration
of a pesticide. Such guidance should enable the members of the
pesticide industry to plan their research programs using test methods
acceptable to the Agency, and to anticipate the costs as well as the
time involved in preparation and approval of an application for
registration. Toward these ends, these guidelines specify: the
conditions under which each data requirement is applicable; the
standards for acceptable testing, stated with as much specificity as
the current scientific disciplines can provide; and the information
required in a test report. The guidelines also suggest circumstances
under which an applicant should consult with the Agency before
initiating a test. In addition, the guidelines provide examples of
acceptable protocols for conducting the required testing, and cite
- in sections on specific tests - published literature which provides
information useful for designing tests.
The Agency believes that adherence to this subdivision will
result in reliable data to support applications for registration, and
will accelerate and upgrade the Agency's review and evaluation of
registration applications.
Data submitted to meet the requirements for Product Chemistry
of this subdivision fall into two major categories: information on
product composition and information on specific chemical and physical
characteristics of pesticide chemicals and products.
1• Product composition. Data on product composition include
information about the beginning materials and manufacturing process
(§ 61-2), the discussion on formation of impurities (§ 61-3), the
results of preliminary analysis of product samples (§ 62-1), the
explanation of how the certified limits were determined (§ 62-2), and
the description of and validation data for analytical methods for
ingredients (§ 62-3). These data support the conclusions expressed
in the statement of formula required by § 61-1.
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Product composition data are used in several ways. First, EPA
reviews the composition of a product to determine vAiether the product
contains any ingredient in an amount which may cause unreasonable
adverse effects on the environment. This review is based on infor-
mation available to EPA from the public literature and its own files
about the toxicity and environmental effects of ingredients. This
is the primary use of product composition data.
EPA also uses product composition data when reviewing applica-
tions for conditional registration. FIFRA § 3(c)(7)(A) authorizes
the conditional registration of products vAiich are "identical or
substantially similar to any currently registered pesticide.. .or
differ only in ways that would not significantly increase the risk
of unreasonable adverse effects on the environment..." In nearly
every case, this determination involves an examination of an appli-
cant's product and a canparison with the canposition of currently-
registered products.
Finally, EPA compares data on product canposition with infor-
mation on the composition of materials used in toxicity tests and
other kinds of studies. This comparison indicates which ingredients
in a pesticide product have been evaluated by a particular study,
and might lead to a conclusion that another study is needed.
Based on its conclusions concerning the environmental charac-
teristics and toxic properties of the pesticide, EPA can impose
appropriate use restrictions, labeling requirements, special packag-
ing requirements, or other needed requirements.
2. Physical and chemical characteristics. Data on the physical and
chemical characteristics of pesticide chemicals and products are
presented in §§ 63-2 through -21. These data are obtained from
relatively simple and inexpensive measurements, observations, or
tests. Some characteristics confirm or provide supportive information
on the identity of ingredients and products. This is particularly
true for determinations of color, odor, physical state, melting and
boiling points, density, specific gravity, solubility, vapor pressure,
and pH. In addition, such data provide information vAiich is useful
in reviewing the manufacturing or formulating process used to produce
the chemical or product. Marked raising or lowering of pH, melting
or boiling points, vapor pressure, density, specific gravity, or
solubility, for example, may provide-evidence of significant changes
in manufacture or formulation, and could indicate the need to
investigate product composition further.
Other information - color, odor, physical state, pH, and visco-
sity - is needed by the Agency to respond to emergency requests for
identification of unlabeled pesticides involved in accidents or
spills. Physicians, hospitals, and poison control centers also request
such information from time to time when apparently-poisoned victims
(or their families or acquaintances) cannot identify specific pesticide
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products to which the victims have been exposed. This has often been
the case when pesticides are removed from their original containers.
Certain other physical and chemical characteristics data are
used directly in hazard assessment. These include stability, oxidizing
and reducing action, flammability, explodability, storage stability,
corrosion, and dielectric breakdown voltage. EPA requires a study
of the corrosion characteristics of a pesticide to evaluate the effect
of the product formulation on the container; if the pesticide is
highly corrosive, then lids, liners, seams, or container sides may
be damaged causing the contents to leak during storage, transportation,
handling, or use. The storage stability study provides data on change
(or lack of change) in product composition over time; if certain
ingredients decompose, obviously other new chemicals are formed whose
toxicity and other characteristics need to be considered. This
situation is also true, to some extent, for data needed on stability
of technical chemicals. Depending on the results of those tests, EPA
may impose requirements for precautionary label statements.
Finally, certain data required in this series are needed as
basic or supportive evidence in initiating or evaluating studies
required by other disciplines. For example, the octanol/water
partition coefficient is used as a criterion in determining whether
certain fish and wildlife toxicity studies (in Subdivision E) must
be conducted. Data on vapor pressure are used directly in determi-
nation of reentry intervals for products that may be used in situa-
tions where residues in air pose a potential hazard (Subdivision
K). Data on viscosity and miscibility provide supportive information
on tank mix proposals (examined more extensively in Subdivision N)
and spray application instructions (of special concern in Subdivision
H).
II. EXPLANATION OF APPROACH
This part of the Discussion explains the approach and concept
of the Product Chemistry guidelines. After explaining terms that are
used throughout the discussion and the guidelines, this part describes
and explains the purposes of the specific major substantive requirements,
beginning with the requirement to submit a statement of formula.
A. Definitions.
The Administrator is authorized by FIFRA to regulate pesticide
products distributed in commerce. The term "pesticide product" is
defined in 40 CFR 162.3(hh) as a pesticide which is offered for
distribution and use; the term includes not only the pesticidal
substance or mixture, but also the labeled container and supplemental
labeling. The Product Chemistry guidelines divide all pesticide
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products into two categories: "end-use products" and "manufacturing-
use products." Section 60-2 (b) defines end-use product _1/ as "a
pesticide product intended to be labeled with instructions for
direct use or application for pesticidal purposes." A "manufactur-
ing-use product," defined in § 60-2(g), is "any pesticide product
other than an end-use product." Thus, manufacturing-use products
are, as the term implies, used in the production of end-use products,
primarily through reformulation, i.e., mixing the manufacturing-use
product with different chemical substances such as solvents or
diluents bo form new pesticide products. Usually manufacturing-use
products contain a high concentration of the active ingredient.
Such manufacturing-use products are often referred to as "technical
grade products." The term "manufacturing-use product" also applies
to products which are repackaged either into smaller containers or
with different labeling.
All pesticides are composed of one or more substances. For
regulatory purposes these substances are classified either as active
ingredients, intentionally-added inert ingredients, or impurities.
The term "active ingredient" is defined by FIFRA sec. 2(a) as:
(1) In the case of a pesticide other than plant
regulator, defoliant, or desiccant, an ingredient viiich
will prevent, destroy, repel, or mitigate any pest;
(2) In the case of a plant regulator, an ingredient
which, through physio logical action, will accelerate or
retard the rate of growth or rate of maturation or
otherwise alter the behavior of ornamental or crop plants
or the produce thereof;
(3) In the case of a defoliant, an ingredient which
will cause the leaves or foliage to drop from a plant;
and
(4) In the case of a desiccant, an ingredient which
will artificially accelerate the drying of plant tissues.
In short, the active ingredients in pesticides are the substances
which directly produce the intended pesticidal effect.
FIFRA sec. 2(m) defines "inert ingredient" as "an ingredient
which is not active." Inert ingredients are divided into two
groups: those which are intentionally added to the pesticide and
_V The term "end-use product" replaces the term "formulated product"
used in the proposed Product Chemistry guidelines. [See § 40-2(b)
of proposed Subpart B, and also § 30-2(b)(6) of current subdivision
A.]
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those vfriicii are not, i.e., impurities. Intentionally-added inert
ingredients are any ingredients, other than active ingredients,
vrtiich are intentionally included in a pesticide for some useful
purpose. [See § 60—2(f).] Intentionally-added inert ingredients
include wetting agents, emulsifiers, surfactants, aerosol propel-
lents, diluents, solvents, stabilizers, and the like.
Finally, pesticides contain "impurities," substances "other than
an active ingredient or an intentionally-added inert ingredient."
[See § 60-2(c).] Impurities include sudi substances as unreacted
starting materials, side reaction products, contaminants, and
degradation products.
In recent years, EPA has becane increasingly concerned about
impurities in pesticides, particularly impurities associated with an
active ingredient. The term "impurity associated with an active
ingredient," defined at § 60-2(d), means:
(1) Any impurity present in the technical grade of the
active ingredient (e.g. , a substance carried over from a
beginning material, or from an intermediate, and impurities
formed through side reactions or by degradation of the
active ingredient); and
(2) Those impurities ich form in a pesticide pro-
duct through reactions between the active ingredient and
other substances in the product, or in the packaging of
the product.
[The reasons for using this definition and for imposing stricter
requirements on this group of impurities are explained in part III.A.
of this Discussion.]
The definition of "impurity associated with an active ingredient"
includes another term, "technical grade of the active ingredient,"
which also appears frequently in the Product Chemistry guidelines.
This term [see § 60-2(i)], vAiich is used interdiangably with "technical
chemical," means a material:
which contains an active ingredient? .. .which is produced
on a commercial or pilot plant scale (though it may never
be held for sale); and...to which no inert ingredient has
been deliberately added....
Finally, the Definitions section at § 60-2 (e) defines the term
"integrated formulation system" as:
a process for producing an end-use product through the use
of any substance vAiich contains an active ingredient and
which :
(1) Is not a registered manufacturing-use product; or
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(2) Was produced or acquired in a manner that does
not permit its inspection by the Administrator under sec.
9(a) of FIFRA, prior to its use in the process.
In other words, this term includes, but is not limited to, any pro-
cess for producing a pesticide product that would contain an
active ingredient which is not present as the result of using a
registered pesticide product purchased from another. End-use
products not produced by an integrated formulation system are
unlikely to contain any impurities associated with an active ingre-
dient other than those impurities already identified in connection
with registration of a product used to make such an end-use product.
The purpose, then, of including this definition is to distinguish
between the two types of end-use products {those produced by an
integrated formulation system and those which are not), and to
allow the Agency to impose less stringent requirements on products
which are not produced by such a system. (See parts II.E., F.,
G., and H. of this Discussion.)
B. The Formulators' Exemption.
FIFRA sec. 3(c)(2)(D) provides that:
No applicant for registration of a pesticide who
proposes to purchase a registered pesticide from another
producer in order to formulate such purchased pesticide
into an end-use product shall be required to -
(i) sutniit or cite data pertaining to the safety of
such purchased product; or
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the purchased product, the applicant is covered by the formulators'
exemption. The primary result of the formulators' exemption is to
lessen the data requirements for companies that simply use a regis-
tered pesticide to make their end-use products.
C. Statement of Formula.
The most important section in the Product Chemistry guidelines
is contained in § 61-1, Product identity and disclosure of ingredients.
This section discusses the submission procedures for the statement
of formula identifying each active ingredient, each intentionally-
added inert ingredient, and, in certain cases, impurities that may
be present in the product while it is being distributed in commerce.
Identification of an ingredient includes a variety of information:
for all ingredients, the chemical name and Chemical Abstracts Service
(CAS) number; for active and intentionally-added inert ingredients,
the purpose or function of the ingredient; and for active ingredients,
the molecular, structural, and empirical formulas, the molecular
weight (or range), as well as other means of identification.
In addition to identifying the ingredients in his product, the
applicant must also provide certified limits for the ingredients
listed in the statement of formula. Upper and lower certified limits
must be established for each active ingredient and each intentionally-
added inert ingredient. In addition, for some types of products, an
upper certified limit must be established for certain impurities.
(See part II.G. of this Discussion.) The upper certified limit is the
maximum (and the lower certified limit is the minimum) amount of the
ingredient that will be present in the product at any time while it
is in commerce.
Finally, § 61-1 requires an applicant to identify his product
by the product name and trade name(s) (if different). In addition,
the guidelines request (but do not require) the company code number
assigned to the product.
The purposes of the requirements in this section are to obtain
a comprehensive listing of the ingredients that may be present in a
product and the amounts of such ingredients and to assemble in one
section of an application all of the major types of identifying
information on a product and its ingredients. The composition
information will be used primarily in subsequent evaluations of the
safety of the product. (See part I.D. of this Discussion.) The
identifying information will be used as an aid in locating data in
the public literature concerning the human health and environmental
properties of the product and/or its ingredients.
D. Description of Beginning Materials and Manufacturing Process.
Most of the other sections of the Product Chemistry guidelines
are intended to produce data to support the information contained in
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the statement of formula required by § 61-1. The first of these data
requirements are contained in § 61-2, concerning descriptions of
beginning materials and the manufacturing process.
The most basic pieces of information needed to determine the
composition of a pesticide product are the identity and, so far as
feasible, the composition of the materials used to produce the
product. Section 61-l(a) requires an applicant to identify each
"beginning material" 2/ used to produce his product and to supply
certain information (if available to the applicant) on the beginning
material. Specifically, the applicant is required to submit a copy
of available technical specifications by which the supplier of a
beginning material describes its composition, properties, and/or
toxicity as well as any other information available to the applicant
concerning the composition of the beginning material. If a beginning
material is a registered pesticide product, it is sufficient simply
to identify the product by its registration number.
The requirements concerning the description of beginning materials
represent a significant change from the proposed Product Chemistry
guidelines. In the proposal, an applicant would have been required
to provide "the identity and the percent composition by weight of
each substance present in the material [and] the expected variation
in composition (to the extent that this information is reasonably
ascertainable)..." Not only was this proposed requirement vague, but
it could also have been interpreted as requiring applicants to perform
difficult and expensive chemical analyses of beginning materials.
To eliminate these potential problems, the Agency rewrote the section
to state that an applicant is required to submit only the information
(of the types specified) which is available to him. The section does
not require an applicant to perform periodic chemical analyses of his
beginning materials.
The next kind of information necessary to evaluate the composition
of a pesticide is a description of the manufacturing process used to
make the product. Section 61-2 specifies the kind of information
which should be contained in this description. Among other things,
the description should include: a statement of the order in which
beginning materials are added and their relative amounts; a description
of the physical conditions controlled during the manufacturing process;
a description of any purification procedures; and a description of
any quality control measures. In addition, the applicant must provide
a flow chart showing the intended chemical reactions occurring during
each step of the process.
2/ The term "beginning material" is defined in § 60-2(b) and means
replaces "starting material" which is generally understood to
apply only to raw materials. As used in the Product Chemistry
guidelines, "beginning material" has a broader meaning; it includes
all materials, whether raw or processed, used in the manufacturing
or formulating process.
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Together, the descriptions of beginning materials and of the
manufacturing process identify the major variables affecting the
composition of a pesticide product. EPA's diemists can review this
information along with information required by other sections to
determine whether the applicant's product will contain the ingredients
and conform to the certified limits listed in the statement of
formula.
E. Discussion of the Formation of Impurities.
Section 61-3 addresses the applicant's submission of a discus-
sion based on chemical theory of the impurities that may be present
in his pesticide products and to explain how sudi impurities may
be formed. Applicants are required to address impurities \Aiich
either have been detected by analysis of samples of the product or
are expected to be present in quantities equal to or greater than
0.1 percent of the product.
EPA expects the theoretical discussion to serve several functions.
EPA will learn viiat kinds of impurities the applicant expects will
be present in his product as it is distributed in commerce. EPA can
independently evaluate this information to determine vdiether other
impurities might be present in the product. In addition, the
thoroughness of the theoretical discussion can indicate how reliable
other pieces of information supplied by the applicant might be.
Finally, the list of impurities generated by the theoretical discus-
sion becomes the basis for the sample analysis requirements contained
in 40 CFR § 158.24.
This section of the guidelines states expressly that the dis-
cussion is to be based on the information concerning beginning
materials and manufacturing process required by § 61-2. It also
specifies the particular kinds of chemical reactions viiich must
be considered and discussed. Different requirements in this latter
respect are established for end-use products not produced by an
integrated formulation system and all other products (end-use
products produced by an integrated formulation system and manu-
facturing-use products). See § 61-3(b)(1) and (c)(1). Applicants
seeking to register end-use products not produced by an integrated
formulation system are subject to less stringent requirements since
the impurities associated with an active ingredient in such a pro-
duct will almost always be the impurities present in the pesticide
products used to manufacture their products. Thus, for these
applicants, the theoretical discussion should focus on possible
reactions between the active ingredient and other ingredients in
the pesticide when such information is known. Applicants seeking
to register other kinds of products must discuss the possibility
of chemical reactions involving other substances, e.g., reactions
between intentionally-added inert ingredients.
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F. Results of Preliminary Analyses.
Section 62-1, concerning preliminary analysis of product samples,
is intended bo allow an applicant to confirm the conclusions reached
in the theoretical discussion. This section requires applicants to
report the results of analyses of a representative set of samples (at
least five) of the product. The analyses must be designed to measure
the amount of active ingredient present in the product and to identify
and quantify (if present) any impurity associated with an active
ingredient tfiich is expected (based on the theoretical discussion)
to constitute 0.1 percent or more of the product. On a case-by-case
basis EPA may require applicants to analyze product samples for other
ingredients or to provide identifying spectral data.
The requirements for analysis of product samples apply only to
manufacturing-use products and end-use products produced by an
integrated formulation system. Once again, end-use products not
produced by an integrated formulation system are sub]ect to less
stringent requirements. Applicants seeking to register such products
will be required to provide the results of sample analysis only on
a case-by-case basis.
Applicants are permitted to use any analytical method they
consider appropriate. The analytical methods used to satisfy the
requirements of this section will not be evaluated by the more
rigorous standards concerning reproducibility, accuracy, and pre-
cision applicable to the "verification" methods required by § 62-3.
Applicants are, however, required to describe each method in detail
and to state its precision and accuracy.
G. Certified Limits.
Section 62-2 requires applicants to explain how they determined
the certified limits for the ingredients in their products. In ad-
dition, this section establishes certain requirements concerning
certified limits and explains that certified limits are used in
two ways. First, EPA reviews the composition of pesticide products
to determine whether the product will cause unreasonable adverse
effects on the environment. This review will involve, among other
things, an evaluation of the upper bound of the toxicity of a
product, that is, the toxicity of a product if the most hazardous
ingredients were present m the product at the upper certified
limits set for such ingredients. Second, certified limits will
become the basis for future enforcement actions. FIFRA sec. 12(a)
(1) (C) states that it is unlawful to sell or distribute:
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any registered pesticide the composition of which differs
at the time of its distribution or sale from its composition
as described in the statement required in connection with
its registration under section 3.
The "statement required in connection with its registration" is the
statement of formula required by § 61-1. Once a statement of formula
containing certified limits has been submitted for a product, each
quantity of the pesticide in commerce must conform to the composition
described in the statement of formula (i.e., the amount of each
ingredient must fall within the certified limits) or the product
will be considered in violation of FIFRA sec. 12(a)(1)(C).
The section states that a certified limit is valid as long as
the product is in commerce or until a specific expiration date stated
on the label. Thus, an applicant needs to predict how long his product
is likely to remain in commerce and what storage conditions may occur
during that period. Based on this information and his knowledge of
chemistry, the applicant then needs to establish certified limits
that take into account possible degradation of the product's
ingredients. If an applicant expects his product to contain one or
more ingredients that degrade rapidly, the applicant can place a
specific expiration data on the label of the product and a statement
that the product shall not be used after that date.
In response to public comments, EPA has added a new paragraph,
§ 62-2 (a)(4), to this section specifically asking applicants to set,
for intentionally-added ingredients and impurities, limits based on a
consideration of product variability. The limits stated should not
greatly exceed those actually occuring in the product when normal
quality assurance procedures are used in the production process. At
the same time, the stated ranges should define product composition
sufficiently for the Agency to determine its suitability for
registration.
Finally, this section specifies the ingredients for which
certified limits are required. For manufacturing-use products and
those end-use products produced by an integrated formulation system,
the applicant must report upper and lower certified limits for active
ingredients and intentionally-added inert ingredients and upper
certified limits for impurities associated with an active ingredient
which were found or theorized to be present m quantities equal to
or greater than 0.1 percent of the product. Once again, for reasons
discussed earlier, end-use products not produced by an integrated
formulation system are subject to less stringent requirements. These
products are only required.to provide upper and lower certified limits
for active and intentionally-added inert ingredients; upper certified
limits for the impurities in those products are not routinely re-
quired. Of course, on a case-by-case basis EPA may require addi-
tional certified limits.
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H. Methods bo Verify Certified Limits.
Section 62-3 requires applicants to submit an analytical method
for detecting and measuring the quantity of each active ingredient
(and certain impurities) in their products. These methods must be
capable of determining vAiether the ingredient falls within its certi-
fied limits and also be suitable for use in state federal enforcement
programs. Therefore, the applicants must submit data to establish
the precision and accuracy of these methods.
Since such methods can usually be adapted to formulated pro-
ducts, the requirement for verification methods applies only to
manufacturing-use products and end-use products produced by an inte-
grated formulation system. As with other requirements, EPA may
require, on a case-by-case basis, methods for additional ingredients
(e.g., low level impurities or intentionally-added inerts) or
additional products (e.g., end-use products not produced by an
integrated formulation system).
In response to public comments, EPA has added paragraph (b)(3)
(iii) of § 62-3 to provide guidance on the precision of verifica-
tion methods. The guidance is based on the standards generally
endorsed by the American Association of Official Analytical Chemists
(AOAC); these standards, merely reflect the prevailing state of
the art in analytical chemistry. In any case, EPA stresses that
the paragraph only contains guidance; it does not establish criteria
that will automatically result in rejection of a method vAiich does
not achieve the recommended precision.
I. Physical and Chemical Characteristics.
Sections 63-1 through -2 1 contain requirements to submit data
on the physical and chemical characteristics of a pesticide product
and its ingredients, particularly the active ingredient. These data
requirements are subject to the formula tors' exemption contained in
FIFRA sec. 3(c)(2)(D). (See part II.B. of this Discussion.) These
requirements have a variety of purposes. Some characteristics, such
as explcsiveness and flammability, are directly related to hazards
to humans. EPA requires data on other characteristics, e.g., solu-
bility and viscosity, to assess the behavior of the product when
it is used. Still other properties like color, density, and odor
are used to identify the pesticide in emergency situations. Finally,
some characteristics, such as melting and boiling points, are rele-
vant to the review and evaluation of the manufacturing process.
The Agency requires applicants to add warning statements to
their product labels on the basis of these physical and chemical
characteristic. Some of the labeling requirements appear in 40
CFR 162.10(h) (2) (in), and others will appear eventually in proposed
labeling regulations. EPA may also require changes in use directions
based on the results of physical and chemical characteristic tests.
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For the most part, the physical and chemical characteristics
covered by these sections are determined routinely for all pesticide
Products. Moreover, these characteristics are usually determined
with testing techniques which were standardized years ago and are
now widely used. Each of these guidelines sections contains a
"References" paragraph vAiich cites standardized testing techniques,
usually published by the Organization of Economic Cooperation and
Development (OECD) and the American Society for Testing and Materials
(ASTM). While EPA recommends that these protocols be used, EPA
will accept determinations made using other techniques, so long as
the techniques are validated and the specific test standards in
the appropriate sections are satisfied.
J. Submittal of Samples.
The last section of the Product Chemistry guidelines is § 64-1.
Titled Submittal of samples, this section requires that a sample of
an analytically-pure grade of each active ingredient and the technical
grade of each active ingredient in a product be submitted to EPA.
It is usually sufficient for only one applicant to submit the analy-
tical grade sample, and for all other applicants seeking to register
a pesticide product containing that active ingredient to rely on
the first applicant's submission. However, the same approach does
not work with regard to submission of technical diemicals. Each
and every producer of a technical grade of an active ingredient
(TGAI) is required to submit a sample and each applicant must
specify viiich TGAI is used to formulate his product.
The purpose of the requirements to submit samples is for EPA to
have a small quantity of a known substance which EPA can then use in
validating its enforcement results and in making comparisons between
similar products manufactured by different producers.
K. Timing of Data Submissions.
Information on the composition of a pesticide product is essential
for EPA to decide whether to approve applications to register pesticide
products. Ideally, before approving a registration, EPA would like
to receive all of the information required by these Product Chemistry
guidelines based on the the product as it will be distributed m
commerce. Practically, however, this is not always feasible, parti-
cularly ^hen a company is seeking to expand its production into a
new type of pesticide.
Section 60-3 (a) states that product chemistry data shall be
derived from testing with commercially-produced pesticides. Yet when
a company is developing a new pesticidal active ingredient or trying
to enter the market for a registered active ingredient, the company
may be unwilling to build commercial-scale facilities until EPA has
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approved its application for registration. In such cases, the
applicant's product chemistry data could only be based on material
produced on a pilot scale. EPA will accept such data for purposes
of evaluating applications as provided in § 60-3(c). If registration
is granted, EPA will also impose requirements and a schedule for
submitting data based on commercial production.
The conditional registration program authorized by FIFRA sec.
3(c)(7) also affects the timing of product chemistry data submissions.
In general terms, the conditional registration program allows EPA to
approve the registration of a product even though the application
does not contain (or reference) all of the data needed by EPA to
determine whether the pesticide would cause unreasonable adverse
effects on the environment. Instead, EPA needs to determine that
the applicant's product is the same as, or is substantially similar
to, a currently-registered product [FIFRA sec. 3(c)(7)(A)] or
that it only proposes to add a new use to those already approved
for currently-registered products [FIFRA sec. 3(c)(7)(B>].3/
In either case, EPA must also determine that use of the applicant's
product would not substantially increase the risk of unreasonable
adverse effects.
FIFRA sec. 3(c)(7) provides generally that EPA may issue
conditional registrations without requiring applicants to submit data
that current registrants of similar products have not been required
to submit. Many current registrants have not submitted data which
would satisfy these Product Chemistry guidelines. Thus, EPA is
authorized to issue conditional registrations without first obtaining
comprehensive product chemistry data, so long as it,has adequate
information to make the statutorily-required determinations. The
Agency has concluded, however, that the information on product
composition is necessary to determine whether an applicant's product
is identical or substantially similar to a currently-registered
product. Therefore, EPA has decided to require applicants for
conditional registration to provide most of the data specified in
these guidelines. The existing regulations on conditional registration,
40 CFR § 162.18-2(c)(1) and (d)(1), establish requirements for product
chemistry data, and § 60-1(c) of the Product Chemistry guidelines
describes those requirements.
3/ In certain limited circumstances, FIFRA sec 3(c)(7)(C) allows EPA
to register products containing active ingredients not present in
any previously-registered product.
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III. ISSUES IN PRODUCT CHEMISTRY
Many useful comments were supplied to the Agency as a result
of the proposal of the Product Chemistry guidelines in 1978. These
comments suggested many changes to improve the proposal and identi-
fied issues that had to be resolved before these guidelines could
be published. Additional issues and further upgrading were evident
during internal Agency review and revision of these guidelines. In
responding to these issues, the Agency has generally developed less
burdensome requirements than were originally proposed, has required
data and information that applicants could more easily obtain, and
has clarified those requirements which commenters found ambiguous.
At the same time, EPA has established requirements which will pro-
vide product chemistry information that is adequate to assess the
safety of pesticides.
The major issues raised by reviewers of the proposed Product
Chemistry guidelines involved the following general topics:
- Information on impurities.
- Submittal of a theoretical discussion on formation of impurities.
- Development of certified limits for product ingredients and
impurities.
- Submittal of information on manufacturing process.
- Submittal of analytical methods.
- Timing of submittal of certain data.
A. Information on Impurities, and Discussion on Their Formation.
The 1978 guidelines proposed several requirements specifically
aimed at better delineation of unintentional substances in pesticide
products, including (principally) impurities, reaction products,
and degradates. These requirements were developed as a result of
finding dioxins, ethylene thiourea, N-nitrosamines, and several
other hazardous substances as impurities or degradates in a number
of widely-used pesticide products. The proposed guidelines required,
among other things:
- A discussion on formation of unintentional ingredients in a
product;
- A declaration and certification of upper limits for each impurity,
reaction product, and degradate known to be present or reasonably
identifiable as present in the product;
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- Analytical methods for detecting and measuring each identifiable
impurity present m quantities of 0.01 percent (of the weight of
the product) or more;
- A statement of formula identifying each reasonably identifiable
substance in the technical chemical and listing the presence of
each by percentage weight or as ppm; and
- Name and structural formula (if available) for each impurity,
reaction product, or degradate.
These proposed requirements elicited many comments. The major
issues and the Agency response and action to each are explained
below.
1. Information on impurities. Comments - Concern was expressed
about what is "reasonably identifiable"; that it was impossible
to satisfy the identification requirements in some cases, and
that, in many other cases, such identification information was not
particularly useful. Some commenters stated that the number of
chemicals which might be "reasonably identifiable" is exceedingly
large, and that EPA should not require extensive identifying infor-
mation on such a potentially long list of substances. There was
concern that many small and medium-sized formulators would be
unable to afford the costs of determining the identifying informa-
tion required by the guidelines. A suggestion was offered that
routine analysis of such product conponents should be at the 0.1
percent level rather than at the 0.01 percent level, and that
additional analyses to determine whether other components were
present should be required only when the impurities are highly
toxic.
Responses - In response to these concerns and comments, the
Agency made a number of significant revisions in the guidelines.
In addition, EPA has provided more comprehensive explanation of
those proposed requirements that were retained for the current
guidelines. A discussion of the actions taken and the reasons for
retaining certain of the proposed requirements is provided in the
following paragraphs.
EPA has concluded that there is no reason to require a charac-
terization of the technical grade of each active ingredient to
support the registration of a pesticide product and accordingly
has deleted the provision which is the subject of some of the
above comments. The requirement was included in the proposed
product chemistry guidelines as an indirect way of identifying
some of the impurities which were associated with the active ingre-
dient. A number of changes in the guidelines have been made that
improve the nature of this data requirement without requiring more
data than are actually needed for Agency review and decision-making.
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One of these changes was instituted by directing attention to
impurities associated with the active ingredient, the major source
of toxicity in most pesticide products. In order to clarify which
impurities are considered associated with an active ingredient,
EPA has added to the current product chemistry guidelines a defini-
tion of the term "impurity associated with an active ingredient."
[See § 60-2(f) and the explanation provided in the Discussion at
Part II.A.] The description of the manufacturing process addressed
by § 61-2 and the discussion of the formation of impurities addressed
by § 61-3 still provide the basis for determining which impurities
fall within the scope of the above definition.
In response to the comments about the volume and value of data
that could be generated to meet some of the requirements regarding
impurities, the Agency agrees that the proposed guidelines would
have required identifying information on a long list of substances,
some of which were never likely to be in a pesticide product and
others of which would be present in very small toxicologically-
insignificant amounts. The Agency recognizes that the proposed
requirement would have been burdensome and that it would have
provided information which would be only occasionally useful to the
Agency.
Accordingly, the Agency now requires identifying information
on substances "which might reasonably be identifiable as present in
the pesticide product...and those reaction products and degradation
products known or theorized to be formed..." The primary purpose
of the requirement to provide identifying information is to make
available for easy reference and use by the Agency a nearly complete
list of the different ways a chemical substance is identified. The
Agency can then use these different pieces of information to collect
additional knowledge about the effects of the substances, principally
through computerized literature searches. The Agency now requires
identifying information only for those ingredients for which a
certified limit must be established. (See § 61.1(b) of the current
guidelines.) Basically, the Agency now requires certified limits
(and thus identifying information) only for two groups of product
components:
- Those ingredients (active and inert) deliberately included m
the product; and
- Those impurities which are present in quantities greater than
0.1 percent or, if less, present in potentially hazardous amounts.
These requirements encompass relatively few product components
compared to all "reasonably identifiable" components for which
limits would have been required in the 1978 proposed guidelines.
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The Agency's approach is that, in addition to active ingredients
and intentionally-added inert ingredients, the requirement applies
to impurities which are expected to be present in the pesticide and
which are potentially hazardous because they are associated with
the active ingredient.
The revision of proposed § 163.61-3(c) (now § 61-1(b) in the
current guidelines) imposes far fewer requirements on the formulator
of an end-use product than the proposal. Under the current
guidelines, most formulators will only need to supply identifying
information on the intentionally-added inert ingredients in their
product. The Agency thinks such identifying information is readily
available. Thus the requirements for statement of formula should
no longer be considered burdensome. A more detailed explanation
follows regarding the new requirements in relation to types of
impurities in manufacturing-use products and in end-use products of
the typical type and those produced by an integrated formulation
system.
One of EPA's primary concerns in developing the product
chemistry guidelines is to require information which permits the
Agency to evaluate the possible hazards of impurities associated
with the manufacture of the active ingredients in pesticide products.
In particular, the Agency has concluded that it needs to know both
the identity of such impurities and the amount of each impurity in
a product. In contrast, the Agency is not ordinarily concerned
about the identity or amount of impurities which are associated
with the intentionally-added inert ingredients in a product.
There are two reasons for treating the two classes of
impurities differently. First, EPA's historical experience is
that most of the impurities in pesticide products which have pre-
sented risks to humans and the environment have been associated
with the pesticidally-active ingredients. For example, TCDD (2,3,
7,8-tetrachlorodibenzo-£-dioxin), one of the most toxic chemicals
known, is an impurity produced in the manufacture of the herbicide
2,4,5-T. Ethylene thiourea (ETU), a known carcinogen, is a degra-
dation product of the active moiety ethylene(bis)dithiocarbamate
present in several widely used fungicides. Second, and perhaps
more importantly, chemical theory suggests that chemically similar
substances are often likely to produce similar biological effects.
Since active ingredients are intended to kill, repel, or otherwise
significantly affect biological organisms, it follows that impurities
which are associated with such ingredients may also be biologically
active.
To understand the difference in requirements for the two
classes of end-use products, it is also necessary to note the
requirements imposed on manufacturing-use products. The registra-
tion application for manufacturmguse products must contain a
certified upper limit for each impurity associated with an active
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ingredient present in quantities greater than 0.1 percent. (See
§ 62-2(b) of the current guidelines.) The guidelines may also
require an analytical method to verify each such limit. [See §
62—3{b)(1) (iii) of the current guidelines.]
With this information, it is easy to understand why EPA
imposes less stringent requirements on end-use products which are
not produced by an integrated formulation system. Simply, those
end-use products, by definition, are manufactured or formulated
from manufacturing-use products over which the Agency has adequate
control. Thus, end-use products not produced by an integrated
system normally would not contain any impurities associated with
the active ingredient except those introduced from the manufacturing-
use product. If needed, the Agency could in most cases calculate
the percentage of such impurities in the end-use product based on
the quantity of the impurities in the manufacturing-use product and
the amount of the manufacturing-use product used. Similarly, the
Agency can often adapt the analytical methodology developed for the
manufacturing-use product for use on the end-use product. Accordingly,
little purpose would be served by imposing on registrants of end-use
products not produced by an integrated formulation system the require-
ments for data on the manufacturing impurities associated with an
active ingredient.
End-use products produced by an integrated formulation system,
however, contain active ingredients whose presence in the product is
not the result of using a purchased manufacturing-use product.
Consequently, the Agency has no indirect method of controlling the
amount of impurities contained in these products. Therefore, the
Agency imposes the Requirements to certify an upper limit for each
impurity associated with an active ingredient and to develop analy-
tical methods to verify the limits. In short, imposing these
requirements on end-use products produced by an integrated formula-
tion system is the only way the Agency has to obtain the information
it needs to evaluate the safety of these products.
Finally, the Agency notes that these requirements really are
not as burdensome as some commenters suggest. Most manufacturers
who use an integrated formulation system also produce manufacturings
use products containing the active ingredients which are present
in their end-use products. Most, if not all, of the effort required
to develop the information to support the registration of the end-
use product would be needed to produce the information which supports
the registration of the manufacturing-use product. Thus, in most
cases, little additional expense results from these requirements.
2. Theoretical Discussion. Comments - A great many comments were
directed at the requirement for theoretical discussion on the forma-
tion of impurities. Some felt that EPA lacked the legal authority
to require a discussion on formation of unintentional ingredients
except when such ingredients created a threat to human health or
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the environment and that, instead, the Agency should shift the
emphasis to formation of active ingredients and intentionally-added
ingredients and focus on known reactions and processes. Several
felt the amount of theorizing about possible reactions is unlimited
and could lead to fruitless disputes with the Agency over the
completeness of the discussion. Moreover, applicants who use
materials purchased from other chemical companies felt they would
never be able to provide a satisfactory theoretical discussion
because they would not know the complete composition of the materials
they use; therefore, they argued that the requirement for a
theoretical discussion should not be imposed on companies which
formulate end-use products. They argued further that the requirement
is inconsistent with the "formulators' exemption" in FIFRA sec.
3(c)(2)(D). Finally, commenters argued that, because of the
relationship between the theoretical discussion and other requirements
in the proposed guidelines (e.g., sample analysis and certified
limits), applicants would be required to produce large amounts of
expensive and relatively useless information.
Responses - [The Agency refers the reader to part I.A. of the
Discussion on Subdivision A for a more thorough discussion of legal
authority.] The Agency considers it has the legal authority, to
require applicants to provide a discussion of the formation of
unintentional ingredients, i.e., impurities. As is clear from the
statute and legislative history, the applicant for registration of
a pesticide bears the burden of proving that the product is safe,
and that its use will not cause unreasonable adverse effects on the
environment. [See FIFRA sec. 3(c)(5) and Sen. Rep. No. 838, 92nd
Cong. 2nd Sess. p 20 (1972).] The commenter's approach would force
the Agency to prove that a pesticide presented a risk, rather than
requiring the applicant to provide data showing the absence of an
unreasonable risk. This is clearly not the intent of the Act or of
Congress. Also, the suggested approach implies that the Agency would
need to know whether a product presented a risk before the Agency
could require data to evaluate the potential of a risk. This is
illogical, for if the Agency could prove that a risk existed, it
would not need to direct the applicant to supply data to evaluate
that risk.
The Agency rejects the suggestion to deemphasize the formation
of impurities in pesticide products. EPA - and the public - is
aware that there are a substantial number of human health and
environmental hazards attributable to the presence of impurities in
pesticides. For example, EPA is currently conducting cancellation
hearings on the use of the herbicide 2,4,5-T because (among other
things) it contains the highly toxic impurity TCDD. EPA has also
directed the registrants of certain products to examine whether
certain N-nitrosamines are present in their products.
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The Agency expects the theoretical discussion to serve several
functions. One can learn from it the kinds of impurities expected
to be present in a product as it is distributed in commerce. The
Agency can independently evaluate this information to determine
whether other impurities might be present in the product. In
addition, the thoroughness of the theoretical discussion can indicate
how reliable other pieces of information supplied by the applicant
might be. Finally, the list of impurities generated by the
theoretical discussion becomes the basis for the sample analysis
requirements contained in § 62-1.
With regard to the comment about "unlimited theorizing" leading
to "fruitless disputes...over the completeness of the discussion,"
the Agency agrees in part with the comment. Proposed § 163.61-5
would have required the applicant to provide a theoretical discussion
concerning the formation of unintentional ingredients that "might
reasonably be identifiable as present" in the applicant's product.
Critics interpreted this language to require an exhaustive discussion
of virtually every known chemical reaction - however unlikely -
which might occur. Since virtually every chemical is "identifiable"
if proper analyses are performed, the proposal was understood to
require unlimited discussion.
The Agency recognizes that the language of the proposed
requirement was ambiguous, and that, if it were applied as some of
the critics interpreted it, the requirement would be quite burdensome.
Not only-would the scope of the theoretical discussion be enormous,
but the additional burdens, dependent on the list of impurities
theorized to be present, would also be overwhelming.
Rather than try to resolve questions about the proper scope of
the theoretical discussion through case-by-case review of applicant
submissions, the Agency has revised this provision. (See § 61-3 of
the current guidelines.) First, the theoretical discussion is now
limited to impurities which may be present in quantities equal to
or greater than 0.1 percent (1000 ppm). Thus, an applicant will
not need to address possible reactions that might produce a few
parts per million of an impurity, an amount which under the proposed
guidelines might "reasonably be identifiable." Second, the Agency
has listed the specific factors which must be considered in a
theoretical discussion. [See § 61-3(b) and (c) of the current
guidelines.] The factors are very broad, including, for example,
migration of components of packaging material into the product,
carryover of impurities in the beginning materials into the final
product, and possible side-reactions during the manufacturing
process. Despite the breadth of these requirements, the list does
clarify and narrow the scope of the theoretical discussion. The
Agency expects that the combination of a specific cutoff quantity,
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0.1 percent, and a list of factors to address in the discussion
will eliminate most of the ambiguity found in the proposed version
of this requirement.
The Agency also agrees with the comments concerning the
difficulty of providing a complete theoretical discussion when
there is limited information available on the composition of
beginning materials. Accordingly, the Agency has revised that
section in the current Subdivision D guidelines to provide that the
theoretical discussion "shall be based on established chemical
theory and the information submitted under § 61-2 concerning the
beginning materials and the manufacturing process used to make the
product." Section 61-2, in turn, requires an applicant to submit
only that information which is readily available on the composition
of the beginning materials. Thus, the theoretical discussion
requirements in the current guidelines accommodate many of the
critics' concerns.
The Agency also agrees in part with the suggestion to impose
less stringent requirements for a theoretical discussion on an
applicant seeking to register an end-use product than on an applicant
seeking to register a manufacturing-use product. The current
guidelines have therefore been revised accordingly. For purposes
of establishing requirements for a theoretical discussion, EPA
divides pesticide products into two groups:
- Manufacturing-use products and end-use products produced
by an integrated formulation system; and
- End-use products not produced by an integrated formulation
system.
Persons seeking to register products in the latter group can provide
a less rigorous and less thorough theoretical discussion than those
seeking to register products in the former group. In general, the
difference between the two sets of requirements is that a "non-
integrated" formulator needs to address only the possible carryover
of impurities in the beginning materials and the formation of
impurities by chemical reactions involving the active ingredient
or by degradation of an active ingredient. People seeking to
register the other kinds of products must provide this information
and discuss, in addition, the possible formation of impurities as
the result of degradation of, or chemical reactions involving,
substances other than active ingredients. [See § 61-3(b) and (c)
of the current guidelines.]
The Agency, however, disagrees with the suggestion to require
no theoretical discussion for end-use products. The commenter may
have misinterpreted the Congressional intent of the 1978 amendment
to FIFRA at sec. 3(c)(2)(D). The amendment provides that a registrant
of an end-use product is exempt from the requirement to submit data
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pertaining to the safety of any registered pesticide product
purchased from another and used to manufacture his product. While
this provision does reflect a Congressional purpose to reduce the
burden on registrants of end-use products, it does not exempt them
from requirements which uniquely pertain to the safety of their
products. Since the provision concerning a theoretical discussion
requires an examination of the possible formation of impurities
during and after the manufacture of the end-use product, the data
uniquely pertain to the end-use product and hence are not covered
by FIFFA sec. 3(c)(2)(D).
In addition to revising the requirements concerning the
discussion of the formation of impurities, the Agency has also
modified the relationship between the theoretical discussion and
other sections of the product chemistry guidelines. For example,
instead of requiring applicants for registration of manufacturing-
use products to analyze samples of their products for each impurity
listed in the theoretical discussion (see proposed § 163.617), EPA
has narrowed the requirement considerably. Thus, § 62-1 of the
current guidelines requires an applicant for registration of a
manufacturing-use product or an end-use product produced by an
integrated formulation system to analyze his product for the pre-
sence of each impurity associated with an active ingredient which
is theorized to be present in a product in quantities equal to or
greater than 0.1 percent. No analysis is routinely required for
impurities not associated with an active ingredient or expected to
constitute less than 0.1 percent of the product. Moreover, analysis
is not routinely required for end-use products not produced by an
integrated system. Thus, in the current guidelines, requirements
concerning sample analysis are no longer as heavily dependent on
the theoretical discussion as they were in the proposal.
EPA has made similar changes in the section concerning certi-
fied limits. Instead of requiring a declaration and certification
of limits for each impurity theorized to be present (see proposed
§ 163.61-6), the current guidelines require upper certified limits
for impurities associated with an active ingredient which were
theorized or found to be present in the product in quantities
greater than 0.1 percent. This requirement applies only to end-use
products produced by an integrated formulation system and to
manufacturing-use products. End-use products not produced by an
integrated formulation system are not routinely required to establish
upper certified limits for impurities. If needed, the Agency could,
in most cases, calculate the percentage of such impurities m the
end-use product based on the quantity of the impurities in the
manufacturing-use product and the amount of manufacturing-use
product used. In summary, the Agency has revised the guidelines to
reduce the burdens that would have been created by the overly broad
requirements concerning discussion of impurities and other related
provisions in the proposal.
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B. Information on Manufacturing Process.
The requirement for a description of the manufacturing process
m proposed § 163.61-4 asked for identification of starting materials
and intermediate materials, as well as details of the process
itself. This proposal elicited many comments challenging the overall
approach as well as details of the requirements. Some of these
comments and EPA's responses and actions are discussed below.
Comments - Some commented that EPA would not be able to use the
information describing the manufacturing process and identifying
starting materials. They also argued that data on beginning
materials is trade secret information and, therefore, should not be
required. Moreover, it was argued that data on the composition of
beginning materials would be irrelevant to EPA, since the impurities
in them are removed during manufacture and purification processes.
Some felt that to isolate and analyze intermediate materials would
be unreasonable and expensive. Many considered that registrants,
upon meeting these requirements, would tend to be "locked" into a
single manufacturing process, and thus development of more efficient
processes would be discouraged.
Responses - The purpose of requiring information on the
composition of materials used to produce a pesticide is to make the
information available for Agency use in assessing the ingredients
which are likely to appear in a marketed product. The EPA staff
which will be assigned to review product chemistry data includes
a number of scientists who, by virtue of their training, education,
and experience, are skilled at predicting the ingredients which
could be formed by chemical reactions between beginning materials,
by degradation of substances, or through other mechanisms. The
starting point for the analysis leading to such predictions,
obviously, is a knowledge of what substances will be used to
manufacture or formulate the pesticide. Thus, the information on
beginning materials is necessary and very useful in evaluating the
safety of a pesticide.
Many producers are not fully aware of the composition of
beginning materials used to formulate or manufacture their products.
In particular, suppliers of inert ingredients are usually very
reluctant to provide detailed information on the composition of
their chemicals. Because of the difficulty that would be involved
in obtaining detailed information on the composition of beginning
materials, EPA decided to revise proposed § 163.61-4 (now § 61-2(a)
in the final guidelines). EPA revised the section to require, an
applicant to submit any information he has concerning the composition
of the beginning materials. The revised provision does not require
applicants to analyze samples of beginning materials or to request
the supplier of a beginning material to send information to EPA.
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The Agency disagrees, however, with the assertion that
information on impurities in the beginning materials is irrelevant
because the impurities are removed during manufacture. The Agency
thinks that it is not uncommon for some products to contain impuri-
ties which carry over from the beginning materials into the final
product. Moreover, it is important to know what impurities an
applicant is trying to remove so that the Agency can assess the
appropriateness of any purification procedures for removing such
impurities.
The Agency has deleted the requirements for data on intermediate
materials. The possibility that these materials might remain in the
product as marketed must be addressed as part of the discussion on
the formation of impurities required by § 61-3 of the current
guidelines.
FIFRA authorizes EPA to require submission of trade secret
information which is necessary to evaluate the safety of a pesticide
product. (See sees. 3 and 10 of the Act.) The statute also requires
that trade secret information generally may not be disclosed to the
public and establishes severe criminal penalties for any Federal
employee who discloses trade secret information. [See FIFRA sec.
10(f).] The current product chemistry guidelines indicate in § 60-
3(e) that information required by the guidelines will be treated as
trade secrets to the extent provided by FIFRA sec. 10. EPA has
established strict internal procedures to ensure that; trade secret
information is not inadvertently released. Finally, the Agency has
been receiving and reviewing trade secret information for years and
believes that the combination of statutory sanctions and internal
procedures has provided (and will continue to provide) adequate
protection for trade secret information submitted to the Agency.
The Agency disagrees with the comment that the requirement of
proposed § 163.61-4(b) would "lock" a producer into using a specific
manufacturing process. To clarify this view, however, EPA has
added a new paragraph to the current guidelines which explains what
a registrant is required to do if he wants to change the manufacturing
process. The new paragraph, at § 61-2(c), states, in part:
(c) Changes in beginning materials or manufacturing
process. Any registrant who changes his beginning materials,
who discovers additional information concerning his
beginning materials, or who changes his manufacturing
process must report that information to the extent required
by FIFRA sec. 6(a)(2). If the change or information
indicates that the certified limits established in
accordance with § 62-2 no longer apply to the product,
the registrant must apply to amend the registration of
his product to establish new certified limits.
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This paragraph allows a registrant to change his beginning materials
or his manufacturing process whenever he wants. If the changes
would be pertinent to whether the terms of the registration of the
product should be modified, or to whether the product's registration
should be cancelled or suspended, the information regarding the
change must be reported. [See "Enforcement Policy Regarding Failures
to Report Information under Section 6(a)(2) of the Federal Insecticide,
Fungicide and Rodenticide Act," 44 FR 40716 (July 12, 1979)]. In
addition, if the changes would produce products with a composition
that no longer conformed to the certified limits established for
the product, the registrant would be required to amend his registration
to set new limits.
EPA expects that many, perhaps most, changes in the manufacturing
process would not be required to be reported under § 61-2(c). Like-
wise, because EPA will permit reasonable variation in the amount of
an ingredient in a product, the Agency expects very few of the
changes in a producer's manufacturing process will necessitate a
revision of certified limits. Finally, even if a registrant must
amend his registration to certify slightly different limits for a
product produced by a new process, the Agency will probably approve
the amendment without delay. Thus, the Agency thinks that the
requirements in the product chemistry guidelines will only inhibit
registrants from making changes that would lead to major differences
in the composition of the product. The Agency does not expect that
registrants will be prevented or even significantly discouraged
from making minor changes.
C. Certified Limits.
EPA proposed in § 163.61-6 that applicants declare and certify
ingredient limits for their products. For each active and
intentionally-added inert ingredient, both upper and lower limits
would be required, and for each identifiable impurity, reaction
product, or degradate, an upper limit. For each limit, the applicant
would explain how the limit was established, and show how much of
each ingredient was in the product.
Comments - Comments on this proposal ranged from questioning
the legality of the proposal to suggesting several alternative ways
to obtain certified limits through modification of some of the
aspects in the requirements. One comment stated that EPA lacked the
legal authority to require applicants to establish certified upper
and lower limits for pesticide ingredients unless there is a specific
need for certified limits for these on a given product to protect
human health or the environment. Others felt that the requirement
for certified limits for every ingredient which might be "reasonably
identifiable" was inappropriate for many products, especially since
the amounts of many minor ingredients are exceedingly difficult to
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control. Therefore, a number of suggestions were offered as
alternatives to the requirement for certified limits in proposed
§ 163.61-6:
- (a) Require certified limits only for biologically-
active ingredients present in toxicologically-
significant amounts;
- (b) Require certified limits only for ingredients identi-
fied by the Occupational Safety and Health Administration
(or some other government body) as constituting "potential
safety hazards";
- (c) Require certified limits only for "major active ingre-
dients," i.e., the technical chemicals intentionally
added to a pesticide product from which a specific pesti-
cidal response is expected;
- (d) Require certified limits only for active ingredients,
intentionally-added inert ingredients, and impurities
appearing in the technical grade of the active ingredient;
- (e) Require upper and lower certified limits of active ingre-
dients, but only upper certified limits for inert ingre-
dients;
- (f) Require certified limits for inert ingredients only when
variations in the amount of the inert ingredient would
affect the efficacy of the product or the hazard to man
or the environment; or
- (g) Require certified limits for impurities only if they are
present in quantities greater"than 0.1 percent of the
product.
Additional commenters stated that it was impossible to control
the amount of ingredients within the narrow certified limits required
by proposed § 163.61-6. They felt EPA should allow an applicant to
set the certified limits at a broad range, such as three times the
standard deviation from the mean value of the amount of impurity
determined to be present m several batches of a product. Also,
a broad range between upper and lower limits was considered
particularly important when "overformulation" of rapidly-deteriorat-
mg active ingredients, like sodium hypochlorite, is necessary.
Responses - [The Agency refers the reader to part I.A. of the
Discussion on Subdivision A for a more thorough explanation of
legal authority.] As to legal authority, the Agency considers that
it has the legal authority to require information which is necessary
to carry out the purposes of the Act. Judged by that standard, EPA
thinks that its requirements for certified limits are legal. EPA
considers the requirement for certified limits not only to be
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reasonable, but to be essential to its regulatory program. A
"certified limit" is a statement of the maximum or minimum amount
(usually expressed as a percentage of the product by weight) of an
ingredient that will appear in a pesticide product. It is also a
promise that any sample of the pesticide distributed in commerce
will not exceed the maximum limits or fall below the minimum limits
(if any) established for ingredients in the product. EPA intends
to use this information when enforcing FIFRA sec. 12(a)(1)(C) which
makes it unlawful to distribute a pesticide
the composition of which differs at the time of its
distribution or sale from its composition as described in
the statement required in connection with its registration
under Section 3.
Without "certified limits" or their equivalent, EPA would be unable
to assure that the pesticides to which humans and the environment
are actually exposed are safe. Hence, EPA believes that it is both
reasonable and legal to require applicants to establish certified
limits.
With regard to the suggestion that EPA must show a "specific
need" for certified limits for "a given product" before it can
require an applicant to establish limits, apparently the commenter
anticipated that the Agency must demonstrate that a particular
product contains an ingredient which would be hazardous, if the
quantity of the ingredient were not regulated. This approach is
totally inconsistent with the statutory scheme. To require EPA to
make a finding about the risk of specific ingredients would, in
effect, relieve applicants of the burden of proving that their
pesticides were safe. The intent of Congress and the FIFRA which
it enacted was to place this burden entirely upon applicants for
registration.
As to the interpretation of ingredients which might be "reason-
ably identifiable" in proposed § 163.61-6, EPA agrees that this
language was vague and would require applicants to establish certi-
fied limits for numerous ingredients which are unlikely to be
present in a product in amounts that would be important for EPA to
evaluate. The Agency recognizes, in addition, that a requirement
to set a certified limit for each potential ingredient regardless
of its quantity, such as for some of the minor ingredients in
pine oil, could be quite burdensome, and probably would not provide
particularly useful information to the Agency. Accordingly, the
Agency has revised the requirements for certified limits. The
universe of pesticide products was divided into two major groups for
purposes of the requirements for certified limits. The first group
consists of manufacturing-use products and those end-use products
produced by an integrated formulation system. All other end-use
products comprise the second group. Basically, a person seeking to
register any kind of a pesticide product must establish an upper
and lower certified limit for each active ingredient and each
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intentionally-added inert ingredient. In addition, if the applicant's
product is in the first group, an upper certified limit is required
for each impurity associated with an active ingredient which was
found (or theorized) to be present in quantities greater than 0.1
percent of the product by weight. [See § 62-2(b) and (c) in the
current guidelines.] The reasons for this approach are explained
below.
The Agency requires an upper certified limit for each active
ingredient primarily to assess the upper bound of toxicity of the
pesticide product. The Agency requires a lower certified limit for
active ingredients for two reasons. First, the amount of an active
ingredient in a product usually has a significant influence on the
efficacy of a product. Thus, the Agency needs to know the lowest
amount of the active ingredient that will be present in the pesti-
cide product for which the producer believes the product will be
efficacious.
The second reason for requiring a lower certified limit for
active ingredients is that the Agency is concerned that a single
pesticide product not have widely different toxicity based on
differences in amount of active ingredient in the product. Large
variations in the toxicity of different packages of a pesticide
product would tend to undermine public confidence in the labeling
of pesticide products/ For example, assume that, when a product
contained an amount of an active ingredient equal to the upper
certified limit, it might cause severe skin burns, but when it
contained an amount of active ingredient at the lower limit, it
might be only mildly irritating to the skin. A warning appropriate
for a package of the product containing the maximum amount of active
ingredient would be inappropriate for a package of the product
containing the minimum amount. A person who happened to purchase,
use, and become exposed to the less dangerous product might thereafter
ignore the warning when using other more dangerous packages of the
product or when using different pesticide products with similar
warnings. Thus, establishing the certified limits for an active
ingredient assists the Agency in its review of precautionary label
statements in relation to product content.
Upper and lower certified limits for intentionally-added inert
ingredients are required for basically the same reasons. The
presence of inert ingredients affects the toxicity, environmental
fate, and efficacy of the product, and in order to evaluate these
characteristics, the Agency needs to know how much of each inten-
tionally-added inert ingredient will be present in a product.
Upper certified limits are required for impurities associated with
an active ingredient and present in quantities greater than 0.1 percent
of the product. Since impurities normally are not included to lower the
toxicity or to alter the environmental fate or efficacy of the entire
mixture, registrants would not need to assure the presence of a minimum
amount of impurity m the product. Thus, only an upper certified limit
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is required. EPA established the 0.1 percent cutoff on the assumption
that impurities present in greater amounts are more likely to present
risks to humans and the environment than impurities present in lesser
amounts. Moreover, impurities which constitute at least 0.1 percent
of the product will generally be easier to identify than those
present in smaller amounts.
Finally, in addition to imposing a quantitative cutoff level
below vAiich routine analysis is not required for impurities, the
Agency has limited the requirements for certified limits to those
impurities associated with an active ingredient. [See the definition
of this term in § 60—2 (d) - ] The two reasons for treating those
impurities differently from impurities associated with an mtentionally-
added inert ingredient have been discussed earlier in this Discussion
under Part II.A. 1. They cure:
- Most impurities of concern are associated with the active
ingredient; and
- Chemically-similar substances often produce similar biological
ef fects.
For these reasons, the requirement for impurity certification
extends only to those impurities associated with an active ingredient.
EPA has considered the several alternatives suggested by the
different commenters. The requirement in the current guidelines
is, generally, a combination of alternatives (d) and (g). Alterna-
tives (a) and (c) were considered inadequate because they ignored
the fact that ingredients viiich are not biologically active may
nonetheless affect the toxicity, efficacy, or environmental behavior
of other ingredients. In addition, alternative (a) is based on
circular logic; EPA cannot tell whether an ingredient will be
present in a toxicologically-significant amount (the criterion that
would necessitate a certified limit) unless it knows how much of
the ingredient is present (i.e., unless a certified limit has been
es tablished).
Alternative (b) suffers from the problems that would afflict
reliance on any list. First, the list would diange. Thus, current
registrants viho had provided product chemistry information when
their products were initially registered would face the constant
possibility that EPA would ask them to certify limits for substances
newly added to the list. This would be burdensome for both
registrants and EPA. Second, it would be difficult to assure that
most ingredients vfriich would be of concern to EPA were listed,
since the potential risks of any ingredient depend not only upon
its inherent toxicity but also on the presence or absence of other
ingredients and on the amount of the ingredient in the product.
Alternative (e) not only fails to address impurities, but it would
not require a lower certified limit for intentionally-added inert
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ingredients. In other words, this suggestion assumes that the amount
of any intentionally-added inert ingredient could vary from its upper
limit (e.g., 90 percent of the product) to 0.0 percent. This varia-
tion would would make it exceedingly difficult to assess the toxicity
and other characteristics of the product. Thus, the Agency needs
lower limits for each intentionally-added inert ingredient. (See
also the discussion at part II.G. of this Discussion.)
Alternative (f) ignores both active ingredients and impurities.
More importantly, the Agency knows of virtually no intentionally-
added inert ingredients (except some coloring and odor agents) that
do not affect efficacy, toxicity, or environmental fate of a product.
The Agency thinks a more sensible approach is to routinely require
certified limits for all inert ingredients, and to handle exceptional
cases by waivers.
Alternatives (d) and (g), together, correspond to the Agency's
position in the current guidelines and to the requirement for
certified limits which are specified by 40 CFR § 158.110. Note
that the upper limit set for an impurity may include, when
appropriate, structurally similar impurities. The Agency concludes
that this section of the guidelines now requires applicants to
submit only the information which is needed to evaluate the safety
of their products, and does not impose unreasonable burdens.
D. Requirement for Analytical Methods.
Proposed § 163.61-7 would have required that the application
for registration of a manufacturing-use product or an end-use
product produced by an integrated formulation system contain certain
analytical information. In particular, the application would have
been required to contain an analytical method capable of measuring
"each identifiable impurity that is present in the product in
quantities of 0.01 percent (of the weight of the product) or more."
A similar requirement would have been imposed on end-use products
not produced by an integrated formulation system, except that the
requirement extended only to impurities associated with the manu-
facture of the technical chemical. The following comments and
responses concern these two requirements.
Comments - A number of ccmmenters expressed major concerns
about the requirement to analyze each manufacturing-use product for
impurities present in quantities greater than 0.01 percent of the
product. Their objections fell into three major categories. First,
it is impossible to analyze products at such low levels. Second,
even if such analysis were possible, EPA's requirements are completely
unreasonable since they would do nothing to prevent unreasonable
adverse effects on the environment. Finally, the cost of performing
the required analysis is excessive in view of the small benefits
which would result from having such information.
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Some ccmmenters described in detail the various procedures which
are available for analyzing mixtures of different chemical substances.
Descriptions of these procedures included discussion of the levels of
sensitivity of such procedures, as well as the specific kinds of
ingredients which could be detected using the procedures, with
reference to these procedures, a number of registrants and other
members of the public stated that current analytical methods are
inadequate for analyzing complex mixtures like pesticide products
with the level of sensitivity required by the proposed guidelines,
and some stated flatly that such analyses are not reproducible.
They noted that small changes in the manufacturing or formulating
process could have a major impact on the number and level of impuri-
ties present at or near the 0.01 percent level. Commenters also
noted that analysis to 0.01 percent would reveal many innocuous sub-
stances and might miss some important hazardous chemicals such as
dioxins or nitrosammes that might be present in quantities less
than 0.01 percent.
By far the majority of objections to the requirement for analy-
sis at the 0.01 percent level were based on economic considerations.
The ccmmenters believed the proposal would impose extremely expen-
sive requirements on people seeking to register pesticide products.
Although the various cost estimates proffered by ccmmenters varied
significantly, all exceeded the costs estimated by the Agency's staff
on economic impact of the proposal.
A wide range of alternatives to the requirement were suggested,
including:
- (a) EPA should require applicants to retain samples of the
products they produce and market. EPA could then demand
that the applicant or registrant submit the samples for
analysis whenever EPA desired information on the composi-
tion of pesticides actually being distributed in commerce.
- (b) EPA should require routine analysis only for ingredients
present in a product at levels greater than 1.0 percent
of the product.
- (c) EPA should require routine analysis of pesticides only
for active ingredients present in quantities greater
than 0.1 percent of the product.
- (d) Routine analysis should be required only for organic
ingredients constituting more than 0.1 percent of a
product.
- (e) EPA should require routine analysis to the 0.1 percent
level for all ingredients.
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38
- (f) EPA should require analysis of ingredients present at
some level between 0.1 and 0.01 percent.
- (g) The requirements to analyze for ingredients present in
quantities at or near 0.01 percent should be imposed
only when the ingredient is known to cause toxicity
problems.
- (h) EPA should require routine analysis for active ingre-
dients, "major" inert ingredients, and other biologically-
significant ingredients.
- (i) EPA should require analysis of the composition of pesti-
cide products for ingredients which are expected to be
"biologically active" or for ingredients which are
demonstrated to be of concern.
- (3) EPA should require analysis of ingredients which have been
identified as potentially significant by toxicity testing.
Responses - For many of the reasons stated in these comments,
EPA revised its requirements concerning analytical methods. Basic-
ally, the final guidelines require that each applicant must submit
a description of an analytical method capable of verifying the
certified limits for the active ingredients and certain impurities
(but not intentionally-added inert ingredients) in his pesticide
product. (See § 62-3 of the current guidelines.) Since the require-
ments for analytical methods are based on the requirements for certi-
fied limits, it is useful to review those requirements. Every per-
son who seeks to register a pesticide must certify upper and lower
limits for all active ingredients and intentionally-added inert
ingredients in a pesticide product. In addition, if the product
is a manufacturing-use product or an end-use product produced by
an integrated formulation system, the person must establish an
upper certified limit for each impurity associated with an active
ingredient which constitutes more than 0.1 percent of the product.
(See § 62-2 of the current guidelines.) Thus, an analytical method
is required for each active ingredient and, on a case-by-case basis,
the impurities associated with an active ingredient that are present
in quantities greater than 0.1 percent. Section 62-3 of the current
guidelines contains a provision specifically waiving the requirement
for an analytical method for any impurity which is on the Food and
Drug Administration's GRAS (Generally Recognized As Safe) list or
on EPA's list of ingredients exempt from the requirement for a
tolerance (see 40 CFR 180.1001).
The current guidelines reflect a significant reduction m the
requirements concerning analytical methods; such methods would not
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39
be required for impurities present in quantities between 0.1 and
0.01 percent of a product. This change was recommended by numerous
commenters, many of whom said that routine analysis to the 0.1
percent level was both feasible and reasonable. [See, generally,
alternatives (c), (d), (e), and (f).]
The Agency has considered and rejected the other alternatives
suggested. Alternative (a) is an unworkable approach because it
fails to provide EPA with the information it needs to verify certi-
fied limits: a description of an analytical method. Moreover, there
is a possible problem with limiting analysis only to samples which
were retained by the producer; the sample might be highly unrepre-
sentative of the product as distributed in commerce. The producer's
samples, for instance, are unlikely to have been stored under the
full range of conditions which might occur during commercial distri-
bution of a pesticide, and thus they may have different amounts of
degradation products compared to the commercially-marketed product.
EPA rejects alternative (b) because it would ignore a poten-
tially significant group of impurities (those between 0.1 and 1.0
percent of a product), even though it would be comparatively inex-
pensive to obtain information about these substances. This alterna-
tive is also overly broad since it routinely includes intentionally-
added inert ingredients.
Alternative (c) implicitly recognizes that analysis to 0.1
percent is feasible, but this alternative is unacceptable because
it is limited to active ingredients. Active ingredients and their
associated impurities are more likely to be hazardous^ than other
substances in the product and, therefore, the Agency thinks it
appropriate to require applicants to describe methods capable of
identifying and measuring the the quantity of those substances.
Alternative (d), too, recognizes the reasonableness of a 0.1
percent cutoff, but it also is too restrictive in its scope. EPA
thinks that some inorganic impurities (e.g., lead or mercury) can
be as toxic as many organic impurities.
Of the suggestions received in public comments, alternative
(e) is the closest to the Agency's current guidelines. This alter-
native, however, goes beyond the current guidelines by suggesting
that applicants submit analytical methods for all ingredients,
including, apparently, intentionally-added inert ingredients.
These substances are relatively much less toxic, as a group, than
active ingredients, and their amounts in pesticide products can be
easily controlled in the manufacturing or formulating process.
Moreover, developing analytical methods to detect and quantify
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40
inert ingredients would be an extremely expensive effort, costing
the pesticide industry billions of dollars. EPA believes that
routinely requiring analytical methods for intentionally-added
inert ingredients would not be worth the cost.
Alternative (f) suffers from the same problems as alternative
(e), and raised the added difficulty that no specific cutoff level
is defined.
Alternatives (g), (h), (i), and (j) all contain the idea
that EPA should require an applicant to describe an analytical
method only for those ingredients and impurities in a product
which are potentially toxic to humans or "biologically active."
The Agency sees merit in these suggestions. Eventually, EPA
intends, as genotoxicity tests become more reliable, to require
testing of all products (or, in some cases, all beginning materials
used to formulate end-use products) in a battery of genotoxicity
screening studies. Such studies are inexpensive, quick, sensitive,
and moderately accurate predictors of the biological activity of
chemical substances. Under these requirements, an applicant would
be required to identify and quantify any product component which
caused positive results in one-half of or more of the tests compris-
ing the battery. While a positive test for such a battery would
not be sufficient evidence to confirm a product component as a
clear risk to humans, it would indicate whether a product contained
a biologically-active component which the Agency should further
evaluate.
Although other factors, such as the presence or absence of
other ingredients, may affect the hazards posed by a product compo-
nent, EPA needs to know its amount and its toxicity. Currently,
EPA does not routinely obtain such information about ingredients
other than for the active ingredients. Accordingly, it is difficult
to develop any meaningful list of potentially-hazardous product
impurities on the basis of the currently submitted data.
Currently, EPA only specifies criteria that will aid in identi-
fying those product canponents and impurities which are likely to
be of greatest concern. The requirement for certified limits
reflect these criteria. The two criteria routinely used are:
(a) A component must be present in quantities equal to or greater
than 0.1 percent; and
(b) An impurity must be associated with an active ingredient.
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41
E« Accuracy and Precision of Methods.
Proposed § 163.61-7 required that analytical methods submitted
for detecting and measuring product ingredients or impurities should
include "qualitative confirmatory methods" and "validation data",
and that the applicant "must supply his assessment of the sensiti-
vity or limit of detection" in each of the methods.
Comments - A number of comments were received concerning the
accuracy and precision of the analytical methods which would be
used to satisfy the requirements of proposed § 163.61-7. The
following statements reflect these comments:
- Less than 25 percent error of method may be difficult to
obtain.
- An accuracy level of i 25 percent and a precision level of
i 5 percent might be achieved for analysis of impurities
present at the 0.01 percent level inmost pesticides.
- Normal best practice analytical variation of * 1 percent
precludes defining the active ingredient content to better
than + 0.8 percent.
- An instrumental analysis, meticulously conducted, might
characteristically yield a value for the major components
that is within i 0.5 percent of the true value.
- At the present time, a precision level of i 0.05 percent
is considered excellent.
Responses - EPA has added a new paragraph specifying the recom-
mended relative standard deviation for analytical methods required
by the guidelines. Section 62-3(b)(3)(iii) of the current guidelines
provides:
The Agency will evaluate the acceptability of an analy-
tical method on the basis of the precision of the results
obtained by the registration applicant on a homogeneous
sample of the product. The following guide indicates
the recanmended levels of precision:
-------
Ingredient measured Precision:
in sample 100 x (standard deviation r arithmetic mean)
More
than 10.0%
Not
greater
than
2%
1.0%
up to 10.0%
Not
greater
than
5%
0.1%
up to 1.0%
Not
greater
than
10%
Less
than 0.1%
Not
greater
than
20%
F. Deferred Submittal of Data.
Proposed § 163.61-2(c) stated that data to meet the requirements of
product chemistry be submitted at the time of registration, to the extent
possible. However, for those data that could not be supplied at the time
of registration, the data would have to be submitted within six months
after commercial production had ccmmenced. At the time of registration,
a schedule would have to be submitted for those data that would be supplied
later.
Comments - Many ccmmenters misinterpreted this requirement, as-
suming that the late data would have to be submitted within six
months after registration rather than six months after commercial
production began. Ccmmenters felt that these requirements should be
revised to allow for more time before submittal. They supplied a
number of reasons for allowing a registrant more than six months
after registration to submit the required data. First, to the extent
that data must be derived from testing a ccmmercially-produced pesti-
cide, they felt it was not possible to fulfill a data requirement
until commercial production begins. They stated that a company will
often not begin to build a commercial pesticide manufacturing plant
until after EPA approves a registration. Construction could easily
last longer than six months. Second, some products are only manufac-
tured during certain times of the year (e.g., to meet seasonal demands)
and that time might next occur more than six months after registra-
tion. Third, if the required data included determination of degra-
dation products in the pesticide or development of analytical
techniques for particular ingredients, the time needed to develop
these data would last longer than six months, since both are time-
consuming efforts. Last, the ingredients used in the process of
manufacturing a pesticide change slightly during the year (e.g.,
seasonal variation in supply, adjustment of process to compensate
for temperature differences). In order to obtain representative
samples, a registrant may need to wait more than six months.
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43
Because of the reasons discussed above, cammenters recommended
that EPA should modify the proposal concerning deferred submittal
of data. The following alternatives were suggested:
- (a) Submittal within 12 months after registration.
- (b) Submittal "as soon as possible" or "as soon as practical"
after registration.
- (c) Submittal "within a reasonable time, preferably six months
after registration."
- (d) Submittal in accordance with a schedule determined on a
case-by-case basis.
Responses - In spite of the fact that the basis for some of the
comments was not sound, EPA has reconsidered the provisions of the
proposal, and has removed the requirements for submitting data on
the commercial product within six months after commercial production
of the product. Instead, EPA has chosen to determine the schedule
for submitting data based on testing with the commercially-produced
pesticide on a case-by-case basis, using its authority under FIFRA
sec. 3(c)(2)(B).
Alternative (a) is inappropriate for the same reasons as the
original proposed 6-month requirement. Alternative (b) is unaccept-
able since it fails to establish a specific deadline for submitting
the required data. Alternative (c) suffers from the combined dif-
ficulties of alternatives (a) and (b). Thus, EPA has chosen alter-
native (d) and will establish submission of the required data on a
case-by-case basis.
G. Multiple Formulations.
It has long been the policy of the Agency to accept, under a
single registration, multiple or alternate formulas for the same
product. Typically, these alternate formulas show variation either
in the percentage of composition or in trade names of inert ingre-
dients such as surfactants, solvents, and similar product components.
However, if directions for use or precautionary statements were
different, separate registrations would be required. Obviously,
if there were already separate registrations for variant formulas
for a typical product, the registration applicant(s) would have
been required to submit Product Chemistry data or information on
each separate individual formula. Therefore, for the purposes of
this Discussion, the Agency is proposing the same standard for
multiple formulations under the same registration: each variant
alternate formula beyond the basic formula would be subject to the
applicable requirements in following sections of Subdivision D:
-------
§ 60-3;
§§ 61-1 through -3 ;
§§ 62-1 through -3;
§§ 63-1 through -21;
§ 64-1.
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45
SUBDIVISION D - GUIDELINES FOR PRODUCT CHEMISTRY
Series 60: GENERAL INFORMATION
§ 60-1 Overview
(a) Scope and purpose (1) This subdivision describes the
data and other information concerning product chemistry which the
Agency requires [see 40 CFR §§ 158.110 and 158.120] in support of
registration of pesticide products. Product chemistry data and
information are used by the Agency primarily to establish the
composition of each pesticide product; basic information which is
needed to assess toxicity to humans and hazards to the environment
resulting from use of the product. Product composition is reported
in the Confidential Statement of Formula which identifies and
gives the amounts of the active ingredients, intentionally-added
inert ingredients and, in some cases, the impurities contained in
each product. Product chemistry data and information are also
needed to assess the physical and chemical hazards of products,
such as corrosiveness, explosiveness, and flammability.
(2) Each applicant submits data which explain and support
the information reported in the Confidential Statement of Formula
submitted for each product. These data include information on the
beginning materials used in manufacture of the product, a descrip-
tion of the manufacturing process, a theoretical discussion of the
formation of impurities, the results of analysis of manufacturing-
use products and integrated formulation system products, and assur-
ance through certified limits that the composition will not vary
from that described at registration. The Agency also requires an
analytical methodology appropriate for use in verifying certified
limits for the active ingredients and certain other ingredients.
Registrants of most end-use products can obtain analytical methods
from the basic manufacturer of the active ingredient.
(3) Information on a number of physical and chemical proper-
ties is required to characterize active ingredients in their tech-
nical or purer form, and to characterize manufacturing-use products
and end-use products. Determination of other physical and chemical
properties is required to assess hazards posed by products to man
and the environment and to determine appropriate labeling cautions
for such products.
(b) List of requirements. The Product Chemistry data
requirements can be found in 40 CFR Part 158. The guidelines
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46
sections describing the information and data required for
manufacturing-use and end-use formulated products are as follows:
(c) Application status and compliance. The requirements im-
posed by 40 CFR Part 158 apply to products already registered as
well as those being proposed for registration.
(1) When supporting data are not adequate the Agency will
notify registrants of products already registered, either (occa-
sionally) through the data call-in program, or (routinely) upon
development of a registration standard as to vdiat additional product
chemistry data must be submitted. Current product registrations
will remain valid so long as registrants comply with the terms
of the subsequent Agency notification.
(2) For purposes of conditionally registering a new product
under FIFRA section 3(c)(7)(A) or (B) ("Me-Too" registration or
registration of additional uses) applicants must submit the product
chemistry data and information required by 40 CFR § 162.18-2 (c) (1)
or (d)(1). These requirements and those for conditional registra-
tions under FIFRA section 3(c)(7)(c) (Experimental-use permits)
are listed in more detail in 40 CFR § 158. 120. These data require-
ments (which are quoted below) correspond to the following sections
of the product chemistry guidelines:
Conditional registration - Corresponding section(s) of
Product chemistry data requirements product chemistry guidelines
Product identity
Confidential Statement of Formula and
§ 61-l(a)
information on ingredients
Manufacturing process
Discussion of the formation of impurities
Preliminary Analysis of product samples
Certification of ingredient limits
Analytical methods for certified limits
Physical and chemical characteristics
Submittal of samples
§ 61-1(b)
§ 61-2
§ 61-3
§ 62-1
§ 62-2
§ 62-3
§§ 63-1 through -21
§ 64-1
I. Manufacturing-use Products
§ 162.18-2
(c) (1) (l): "Product identity and dis-
closure of ingredients, including im-
purities "
§ 61-1, Product Identity and
Disclosure of Ingredients
(c) (1) (ii) : "A description of the
manufacturing process, including
composition and purity of starting
and intermediate materials"
§ 61-2, Description of
Beginning Materials and
Manufacturing Process
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47
(c)(1)(iii): "Analytical methods and
sample assays for the impurities"
(c)(1)(iv): "Physical and chemical
properties"
§ 162.18-2
(d)(1){1): "Product identity
and disclosure of ingredients"
(d)(1)(ii): "If requested by
the Agency, a sample of the
product proposed for regis-
tration"
(d)(1)(iii): "If any active
ingredient of the formulated
(end-use) product is derived
from any substance other than
a registered product, data
required by paragraph (c) of
this section"
§ 62-1, Preliminary Analysis
of Product Samples
§§ 63-1 and 63-2 through 63-13
(part of) Physical and
Chemical Characteristics
64-1, Submittal of Samples
§ 61-1, Product Identity and
Disclosure of Ingredients
§ 64-1, Submittal of Samples
§§ 61-1, -2; 62-1; 63-1 through
-21; and 64-1 (see items
above for titles)
(c)(1)(v): "If requested by the Agency, §
a sample of the technical product"
II. End-use Products
Prior to granting a conditional registration, the Agency may, on a
case-by-case basis, require additional product chemistry data or
information. In addition, applicants for conditional registration
under FIFRA sec. 3(c)(7)(A) or (B) must satisfy the other data
requirements in this subdivision by the same date as that set for
similar products already registered.
(3) The product chemistry data requirements for applicants for
conditional registration under FIFRA sec. 3(c)(7)(C) will be deter-
mined on a case-by-case basis.
(4) For products being proposed for full registration under
FIFRA sec. 3(c)(5), applicants must satisfy all of the data require-
ments of 40 CFR Part 158 prior to full registration.
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48
§ 60-2 Definitions.
Terms used in this subdivision shall have the meanings set
forth in sec. 2 of FIFRA, in 40 CFR § 162.3, and in 40 CFR Part 158.
In addition:
(a) The term "beginning material" means any substance which
constitutes or contains any of the product's active or intentionally-
added inert ingredients or which constitutes or contains a chemical
precursor of any ingredient used in making the product.
(b) The term "end-use product" means a pesticide product in-
tended to be labeled with instructions for direct use or application
for pesticidal purposes.
(c) The term "impurity" means any substance in a pesticide
product other than an active ingredient or an intentionally-added
inert ingredient; the term includes beginning materials, side-
reaction products, contaminants, and degradation products.
(d) The term "impurity associated with an active ingredient"
means:
(1) Any impurity present in the technical grade of the active
ingredient (e.g., a substance carried over from a beginning material,
or from an intermediate, and impurities formed through side-reactions
or by degradation of the active ingredient); and
(2) Those impurities which form in a pesticide product through
reactions between the active ingredient and other substances in the
product, or in the packaging of the product.
(e) The term "integrated formulation system" means a process
for producing an end-use product through the use of any substance
vhich contains an active ingredient and which:
(1) Is not a registered manufacturing-use product; or
(2) Was produced or acquired in a manner that does not permit
its inspection by the Administrator under sec. 9(a) of FIFRA, prior
to its use in the process.
(f) The term "intentionally-added inert ingredient" means any
ingredient of a product (other than an active ingredient) which is
intentionally made a part of the product to serve some useful
function.
(g) The term "manufacturing-use product" means any pesticide
product other than an end-use product. Usually, these products
contain only the technical grade of the active ingredient or a high
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49
concentration of the active ingredient with small amounts of inert
ingredients such as stabilizers and similar substances.
(h) The term "nominal concentration" means the amount of an
ingredient which is expected to be present in a typical sample of a
pesticide product.
(i) The term "technical grade of an active ingredient" (which
is synonymous with the term "technical chemical") means a material:
(1) Which contains an active ingredient;
(2) Which is produced on a commercial or pilot-plant scale
(though it may never be held for sale); and
(3) To which no ingredient has been deliberately added for
any purpose other than synthesis or purification of the active
ingredient.
§ 60-3 General provisions.
(a) Data on the pesticide product. Except as noted by
paragraph (c) of this section, the data and information described in
§§ 61-1 through 64-1 shall be based on the product as commercially
produced. Thus, for example, data specified by §§ 63-1 through -21
(physical and chemical characteristics) must be derived from studies
conducted with a test substance representative of the commercial
product, and the information specified by § 61-2 (Description of
beginning materials and.manufacturing process) must describe the
commercial production process.
(b) Omitting certain of the required data. (1) Some of the
information specified by §§ 61-1 through 63-21 might prove to be
extremely difficult to develop, especially with respect to certain
highly complex organic or inorganic substances (e.g., corn cobs,
clay, and synthetic polymers). In some cases the applicant may
know of no way even to attempt to develop such data, and in other
cases he may find that one or more plausible means to develop the
data are in fact incapable of producing the data. In either case,
the applicant may omit such data, but he shall describe all attempts
made to obtain the information or data. If some appropriate means
to meet the requirement has not been undertaken, the Agency will
specify for the applicant what additional efforts must be undertaken.
If these efforts are not undertaken, the Agency may refuse to
register the product.
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50
(2) Applicants may omit data and information on grounds other
than those specified m paragraph (b)(1) of this section. The
Agency will consider these requests on a case-by-case basis.
(c) Timing of data submissions. Except as provided in para-
graphs (c)(1), (2), and (3) of this section, each applicant for
registration of a new product shall supply the data and information
required by 40 CFR Part 158 at the time the application for regis-
tration is made. For products already registered, registrants
shall submit the required data at the time indicated in a notice
issued pursuant to FIFRA sec. 3(c)(2)(B). See also § 60-1(c).
(1) Deferral of data submission for products not in commer-
cial production. Some applicants may consider it impractical to
construct facilities to produce their products in commercial quan-
tities prior to receiving registration for their products. Thus,
they may not be able to provide data, as required by this subdivi-
sion, from studies which use a test substance representative of
the commercially-produced product. Upon request, the Agency will
consider deferring the requirement to submit such data until
after the registration of the product is approved. (Note: a deci-
sion to allow deferment of data does not necessarily mean that the
Agency will approve the registration of the product for which
deferred submission of the data is allowed.)
(2) Contents of a deferral request. A request for deferral
must contain:
(i) A statement that the applicant has no facilities for
producing the product in commercial quantities and does not intend
to construct such facilities until the product is registered;
(n) Based on material produced on a pilot scale, the data
required by 40 CFR §§ 158.110 and 158.120.
(iii) A description of the commercial manufacturing process
(see § 61-2), a discussion of the formation of impurities in the
commercially-produced product (see § 61-3), and a discussion of
changes in the certified limits for the product which might result
from differences between the pilot-scale and commercial production
processes; and
(iv) A schedule for submitting the other data required by
40 CFR Part 158 based on the commercially-produced material.
(3) Notification for submittal of deferred data. If the
Agency approves a request for deferred submission of data on
commercially-produced material, and if the product: is otherwise
acceptable for registration, the product will be registered and the
registrant at the same time will be furnished a notice under FIFRA
sec. 3(c)(2)(B) requiring submission of the deferred data as soon
as possible after the commercial production facilities are completed.
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51
(d) Confidential treatment of product chemistry information.
Information submitted by applicants or registrants concerning
product chemistry will be afforded confidential treatment only to
the extent required by FIFRA sec. 10. A person submitting infor-
mation entitled to confidential treatment under sec. 10 should
comply with the procedures in 40 CFR § 2.203.
Series 61: PRODUCT IDENTITY AND COMPOSITION
§ 61-1 Product identity and disclosure of ingredients.
In accordance with 40 CFR § 158.120, each product's registration
must be supported by the following:
(a) Information on product identity. This information includes
(1) The product name;
(2) The trade name(s) (if different); and
(3) The company code number(s) (optional).
(b) Statement of Formula. Each product's registration shall
be supported by a statement describing the product's composition.
A request for an amended registration other than for amending the
statement of composition may state that an accurate and current
description of the product's composition is already on file with
the Agency's Registration Division, if that is the case. The
statement of ccmposition should contain:
(1) The name, nominal concentration, and certified limits for
each active ingredient and each intentionally-added inert ingre-
dient; and
(2) The name and upper certified limit for each impurity
or each group of impurities for which a certified limit is required
(see § 62-2);
(3) The purpose of each active ingredient and each
intentionally-added inert ingredient;
(4) For each ingredient required to be listed by paragraph
(b)(1) of this section, the chemical name from the Chemical Abstracts
Index of Nomenclature or other well-defined name, and the Chemical
Abstracts Service (CAS) Registry Number; and
(5) For each active ingredient: the product name, trade name,
and common name (if established); the molecular, structural, and
MaterifAs Belong To.
OPPTLifcTMy „
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52
empirical formulas; the molecular weight or weight range; and any
experimental or internal code number the company has assigned.
§ 61-2 Description of beginning materials and manufacturing
process.
(a) Beginning materials. Each product's registration must be
supported by the following information on each beginning material:
(1) If the beginning material is a registered manufacturing-
use pesticide product, the registration number of the product.
(2) For each other beginning material:
(i) The name and address of the manufacturer or producer of
the beginning material or, if that information is not known by the
applicant, the name and address of the supplier of the beginning
material;
(li) Each brand name, trade name, or similar commercial
designation of the beginning material used by the manufacturer,
producer, or supplier of the beginning material;
(iii) A copy of all available technical specifications, data
sheets, and other documents by which the manufacturer, producer, or
supplier of the beginning material describes its composition,
properties, or toxicity; and
(iv) All other information which the pesticide product's
producer has concerning the qualitative and quantitative composition
of the beginning material.
(b) Manufacturing process. Each product's registration must
be supported by an accurate and current description of the process
used to manufacture or formulate the product. The description will
normally contain the following information:
(1) A statement of whether the process is a batch or continuous
process;
(2) The relative amounts of beginning materials and the order
in which they are added;
(3) A description of the equipment used to produce the product
which may influence the product's composition;
(4) A description of the physical conditions (e.g, temperature,
pressure, humidity) which are controlled during each step of the
process in order to influence the product's composition, and the
parameters that are maintained;
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53
(5) A statement of whether the process for producing the
product involves intended chemical reactions (that is, combination
of beginning materials which are expected to react with each other
to produce an active ingredient or intentionally-added inert
ingredient);
(6) A flow chart with chemical equations of each intended
chemical reaction occurring at each step of the process;
(7) The duration of each step of the process;
(8) A description of any purification procedures, including
procedures to recover or recycle starting materials, intermediates,
or the final product; and
(9) A description of measures taken to assure the quality of
the final product, including procedures involving the equipment
used for blending product components and for filling and packaging.
(c) Changes in beginning materials or manufacturing process.
Under FIFRA sec. 6(a)(2) registrants are required to inform the
Agency of changes made in beginning materials or in the manufacturing
process when such change alters substantially the product's composi-
tion; other changes need not be reported. In such instances, if
the change effects the certified limits established in accordance
with § 62-2, the provisions of § 62-2(a)(7) apply (i.e., a revised
statement of certified limits must be submitted). Note that formu-
lators are also expected to provide current information on the
identity of their suppliers.
§ 61-3 Discussion of the formation of impurities.
(a) General requirements. In accordance with 40 CFR § 158.120
each product's registration must also be supported by a discussion
of the impurities that may be present in the product, and why they
may be present. The discussion should be based on established
chemical theory and the information submitted under § 61-2 concern-
ing the beginning materials and manufacturing processes used to
make the product. The types of impurities which must be discussed
are specified in paragraphs (b) and (c) of this section.
(b) Manufacturing-use products and those end-use products
produced by an integrated formulation system. In the discussion
referred to by paragraph (a) of this section, an applicant for
registration of a manufacturing-use product or of an end-use
product produced by an integrated fonnuulation system should
discuss:
(1) Each impurity which he believes may be present in his
product as marketed at a level equal to or greater than 0.1% (1000
ppm) , based on his knowledge of:
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54
(1) The composition (or composition range) of each beginning
material which he uses to produce any active ingredient of his
product;
(11) The composition (or composition range) of each begin-
ning material containing an active ingredient vfriich he purchases
(or otherwise obtains from another) and uses to produce his prod-
uct;
(ni) The canposition (or composition range) of each
intentionally-added inert ingredient of his product;
(iv) The impurities which he knows are present, or believes
are likely to be present, m the materials mentioned in paragraphs
(b)(1)(1), (11), and (111) of this section, and the known or pre-
sumed level (or range of levels) of those impurities;
(v) The substances which result from the intended (main)
reactions and side reactions which occur in the manufacturing and
formulation of his product, and the relative amount of each such
substance produced;
(vi) Degradation of any of the product's active ingredients
after production of the product but prior to its use, and post-
production reactions between any of the product's active ingredients
or intention ally-added inert ingredients and any other components of
the product or its packaging;
(vn) Migration of components of packaging materials into the
product;
(vni) Contaminants resulting from earlier use of production
equipment to produce other products or substances; and
(ix) The process control, purification, and quality control
measures he uses; and
(2) Each other impurity which was found to be present in any
analysis of the product he has conducted.
(c) End-use products not produced by an integrated formula-
tion system. (1) In the discussion required by paragraph (a) of
this section, an applicant for registration of an end-use product
vdiich is not produced by an integrated formulation system should
discuss each impurity vhich may be present m his product as mar-
keted at a level equal to or greater than 0.1 percent (1000 ppm),
based on his knowledge of:
(i) The carry-over of impurities present in any registered
product serves as the source of any of his product's active
ingredients. (As explained in preamble, the " f o rmula to rs ' exemption"
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55
[see also the FIFRR Sec. 3(c)(2)(D)] applies to the requirement to
develop quantitative data concerning the impurities present in
registered products.)
(ii) The carry-over of impurities present in the intentionally-
added inert ingredients of his product;
(in) Reactions occurring during the production of his product
between any of the product's active ingredients, between the active
ingredients and intentionally-added inert ingredients, or between
the active ingredients and the production equipment;
(iv) Post-production reactions between any of the product's
active ingredients and any other component of the product or its
packaging ;
(v) Migration of packaging materials into the product;
(vi) Contaminants resulting from earlier use of production
equipment to produce other products or substances.
(2) On a case-by-case basis, the Agency may require further
discussion of possible chemical reactions involving other ingre-
dients.
Series 62: ANALYSIS AND CERTIFICATION OF PRODUCT INGREDIENTS
§ 62-1 Preliminary analysis of product samples.
(a) When required. In accordance with 40 CFR § 158.120,
composition data based on a preliminary analysis of the product
will be required to support the registration of each manufacturing-
use product and those end-use products produced by an integrated
formulation system. If the technical chemical has not been used
as a formulating ingredient in registered products, the preliminary
analysis will include analyses of both the product and the technical
chemical (TGAI). In the analysis of such technical chemicals the
degree of accountability (or closure) is to be indicated (and
typically >_ ca 98%). Preliminary analysis of end-use products not
produced by an integrated formulation system will be required only
on a case-by-case basis.
(b) Requirements for performing sample analyses. (1) Selection
of samples. (l) Five or more representative samples should be se-
lected for the preliminary analysis.
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56
(n) If the product is produced by a batch process, each
sample should be taken from a different batch of the product.
(iii) If the product is produced by a continuous process,
samples should be taken at intervals sufficiently spaced to provide
representative aliquots.
(iv) On a case-by-case basis, the Agency may require the
analysis of additional samples.
(2) What ingredients to look for. If the product is a
manufacturing-use product or an end-use product produced by an
integrated formulation system, each sample should be analyzed for
each of the following ingredients:
(i) Each active ingredient; and
(ii) Each impurity for which a certified limit is required.
[See § 62-2(b)(2).]
(3) Selection of analytical methods. For the analyses indi-
cated by paragraph (b)(2) of this section, the applicant may use
any appropriate analytical methods.
(4) Additional requirements. On a case-by-case basis, the
Agency may require the analysis of samples for additional ingre-
dients, including intentionally-added inert ingredients, or analysis
using more sensitive or more accurate analytical methods.
(c) Description of analytical methods and reporting of sam-
ple analysis results. (1) Description of analytical methods. The
report on the results of analysis of product samples indicated by
this section should contain a description of (or reference to) each
analytical method used to detect the presence of, or to quantify
the amount of, each ingredient in each sample. The description of
each method should include:
(1) A complete, detailed description of each step in the
analytical method; and
(n) A statement of the precision and accuracy of the analy-
tical method.
(2) Reporting of sample analysis results. The report on the
results of analysis of product samples indicated by this section
should contain the results from each analysis conducted on each
sample.
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(i) The results should include the identity of each ingredient
for which the analysis was conducted, the quantity (if any) detected,
and the mean and relative standard deviation of reported analytical
results•
{ii) The results should be reported to at least the first deci-
mal place (e.g., 97.1%, 2.4%); or if the measured quantity of an
active ingredient is less than 1.0%, the results should be reported
to the first significant figure (e.g., 0.9%, 0.05%, 0.001%).
(d) Identifying spectral data. If requested by the Agency,
identifying spectral data shall be submitted for the product or
any substance listed in its statement of composition. The spectral
data which may be requested include infrared, nuclear magnetic
resonance, ultraviolet, and mass spectra.
(e) References. For guidance in conducting the analysis of
samples as requested by this section, the applicant is referred to
the following publications:
(1) Bontoyan, W.R. , ed. 1976. Manual of chemical methods
for pesticides and devices. U.S. Environmental Protection Agency.
Published and distributed by the Association of Official Analytical
Chemists, Arlington, Virginia.
(2) Horwitz, W., ed. 1980. Official Methods of Analysis of
the Association of Official Analytical Chemists. Association of
Official Analytical Chemists, Arlington, Virginia.
(3) CIPAC Handbook, Vol. 1. (1970) and Vol. 1A. 1980.
Collaborative Handbook. International Pesticides Analytical
Council Limited, Plant Pathology Laboratory, Hatching Green,
Harpenden, Hertfordshire, England.
(4) Zweig, G., and J. Sherma, eds. 1963-1978. Analytical
methods for pesticides and plant growth regulators. Continuing
series. Academic Press, New York, N.Y.
§ 62-2 Certification of ingredient limits.
(a) General. (1) Requirement and considerations. (l) In
accordance with 40 CFR § 158.110, eadi registration must be support-
ed by a certification that each upper and lower limit established in
accordance with paragraph (b), (c) , or (d) of this section will be
maintained for all quantities of the product sold or distributed
in commerce. Certified limits are used m two ways. First, the
Agency will consider the certified limits in making the registration
determination required by sees. 3(c)(5), 3(c)(7), and 3(d) of the
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58
Act and in making other regulatory decisions required by the Act.
Second, the Agency will collect and analyze commercial samples of
the registered products. When, upon analysis, the composition of
such samples is found to differ from that certified, the results may
be used by the Agency in regulatory actions under sec. 12(a)(1)(C)
and other pertinent sections of FIFRA. [See paragraph (a)(6) of
this section.]
(ii) In certifying a limit for a rapidly degrading ingredient,
the applicant or registrant should consider carefully the maximum
quantity needed to assure the declared strength of the product for
its stated life. [See paragraph (a)(5) of this section.] The
applicant should note the possibility that increasing the amount of
active ingredient in a product may place the product in a higher
category of toxicity or result in residues exceeding an established
tolerance.
(2) Submittal of explanations. The applicant or registrant
should submit an explanation of how each certified limit was estab-
lished (e.g., by sample analysis, quantitative estimate based on
amounts of ingredients used, etc.) and what is known about the
accuracy and precision of the procedures used to establish the
limit.
(3) Expression of limits. The limits certified for ingredients
should be stated as percentages of the total product, calculated by
weight.
(i) For each ingredient present in quantities equal to or
greater than 1.0 percent, limits should be expressed to the first
decimal place.
(ii) For each ingredient which may be present in quantities
less than 1.0 percent, limits should be expressed to the first
significant figure.
(4) Setting appropriate certified limits. The Agency suggests
that the range between the upper and lower certified limit for
each active ingredient and each intentionally-added inert ingredient
be based on a consideration of the variability of each of these
ingredients when normal quality assurance procedures are utilized
in the production process. To be acceptable for the purposes
specified in § 158.22 (a), the limits stated for each intentional
ingredient should not greatly exceed its actual variability in the
product.
Unless a lower level is specifically requested by the Agency, the
applicant is expected to set upper levels for impurities at levels
exceeding levels normal to the product by a reasonable amount and
which would not be expensive or difficult for a manufacturer to
certify.
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(5) Duration of limits. The certified limits become effective
upon Agency approval in connection with registration of the product,
and would apply to all units of the product in channels of trade
until the expiration date specified on the product label or, if no
such date is specified, for as long as the product is available
for sale.
(6) Enforcement of limits. The Agency may use the analytical
methods submitted under § 62-3 or any other scientifically-sound
method to determine whether the composition of a product conforms
to the limits certified under this section. If the Agency deter-
mines that the amount of an ingredient in a product does not fall
within the certified limits, the Agency will regard the product to
be in violation of FIFRA sec. 12(a)(1)(C) or other pertinent sec-
tions of the Act and subject to possible regulatory action.
However, if such a determination is based upon improved methodology
and the violation occurred because both methods submitted under
§ 62-3 and data submitted under § 62-1 were definitely erroneous,
the registrant shall not be subject to regulatory action provided
he makes the necessary corrections in his product within a reasonable
time, vriiich will be specified by the Agency.
(7) Revision of limits. If a registrant desires to amend the
certified limits for his product, he may apply for an amendment to
the registration. Until the amendment has been accepted by the
Agency in connection with registration of the product, the currently
approved limits will apply to the product.
(b) Manufacturing-use products and those end-use products
produced by an integrated formulation system. The statement of
formula for a manufacturing-use product or for an end-use product
produced by an integrated formulation system [see § 61-1(b)] shall
contain, as required by 40 CFR § 158.110, the following certified
limits:
(1) For each active ingredient and each intentionally-added
inert ingredient, an upper and lower limit;
(2) For each impurity (or, if appropriate, for each group of
structurally-similar impurities) associated with an active ingredi-
ent that was indicated in the discussion required by § 153.24 as
being potentially present at a level equal to or greater than 0.1%
by weight, an upper limit; and
(3) For each other impurity (or, if appropriate, for each
group of structurally-similar impurities) associated with an active
ingredient that was found in any sample in quantities equal to or
greater than 0.1 percent by weight, an upper limit.
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60
(c) End-use products not produced by an integrated formula-
tion system. The statement of formula for an end-use product not
produced by an integrated formulation system [see § 61-1(b)] shall
contain, as required by 40 CFR § 158.110, upper and lower certified
limits for each active ingredient and each intentionally-added
inert ingredient.
(d) Certified limits for additional ingredients and impurities.
The Agency may require, on a case-by-case basis:
(1) More precise limits;
(2) Certified limits for additional ingredients;
(3) More thorough explanation of how the certified limits
were determined;
(4) Certified upper limits for impurities which will be
present at levels lower than 0.1 percent (1,000 ppm) of the product;
or
(5) A narrower range between the upper and lower certified
limits than that proposed by the applicant.
§ 62-3 Analytical methods to verify certified limits.
(a) When required. In accordance with 40 CFR § 158.120,
analytical methods to verify certified limits, as specified by
paragraphs (b) and (c) of this section, are required to support
the registration of each manufacturing-use product and each
end-use product.
(b) Requirements for analytical methods and supporting data.
(1) Substances for which methods are required. (1) If the appli-
cant's product is a manufacturing-use product or an end-use product
produced by an integrated formulation system, an analytical method
is required for:
(A) Each active ingredient; and
(B) Each impurity for which a certified limit is required (see
§ 62-2) unless it is exempt from the requirement to obtain a tolerance
and complies with the provisions of 40 CFR 180.1001, or it is a
substance designated by the Food and Drug Administration as generally
recognized as safe (GRAS) when it is a component of food. (See 2 1
CFR 182, 184, and 186. )
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(ii) If the applicant's product is an end-use product not
produced by an integrated formulation system, an analytical method
meeting the requirements of paragraph (b)(3) of this section is
required for each active ingredient.
(iii) On a case-by-case basis, the Agency may require analytical
methods for additional ingredients.
(2) Analytical methods and supporting data for impurities. For
most product impurities, the analytical methodology and data provided
by the preliminay analysis [see § 62-1 (c)(1)(i) and (ii)] are expected
to be sufficient. However, in some instances, the Agency may require
the applicant to develop better, more precise methodology and provide
more quantitative data. In making such a decision, the Agency will
consider the toxicological and environmental significance of the
impurity.
(3) Precision and accuracy of analytical methods, (i) For
active ingredients (and for those intentionally-added inert ingred-
ients for which the Agency may require methodology), the method must
have sufficient precision and accuracy to determine whether the
amount of such an ingredient found in any sample of the product
is within the limits certified for that ingredient.
(ii) If an analytical method for an impurity is required, the
method must have sufficient precision and accuracy to determine
whether the amount of such impurity found in any sample of the prod-
uct exceeds the upper limit certified for the impurity.
(iii) The Agency will evaluate the acceptability of an analyt-
ical method for an active ingredient or an intentionally-added inert
ingredient (if methodology for the inert is specifically required by
the Agency) on the basis of the precision of the results obtained
by the applicant on a homogeneous sample of the product. The follow-
ing guide indicates the recommended levels of precision:
Ingredient measured Precision:
in sample 100 x (standard deviation t arithmetic mean)
More than 10.0% Not greater than 2%
1.0% up to 10.0% Not greater than 5%
0.1% up to 1.0% Not greater than 10%
Less than 0.1% Not greater than 2 0%
(iv) The analytical methods required by this section should be
as simple, quick, and inexpensive to perform as possible, while
satisfying the requirements of paragraphs (b)(3)(i), (ii), and (iii)
of this section.
(4) Validation studies. Each analytical method shall be vali-
dated by studies of the precision and accuracy of the method (includ-
ing, when appropriate, qualitative confirmatory methods).
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(c) Description of analytical methods. (1) Each analytical
method required by this section shall be described fully. The des-
cription shall identify each step of the analytical method and pro-
vide sufficient information for an analytical chemist to perform
the analysis properly. If the method has been reported in the scien-
tific literature or previously submitted to the Agency in support
of the registration of another product, the applicant may submit an
appropriate reference to the method. In such cases, a reprint or
copy of the method should be included with the submission to help
expedite Agency review.
(2) Validation data shall be provided for each analytical
method required by this section. The applicant shall indicate the
level of precision and accuracy of each method, as demonstrated by
the validation data.
Series 63: PHYSICAL AND CHEMICAL CHARACTERISTICS
§ 63-1 General provisions for physical and chemical characteristics
testing.
(a) Summary of test requirements. (1) Table 1 lists the chem-
ical and physical properties for which tests are required by 40 CFR
§ 158.120. The table also indicates the kind of test substance that
must be used in each test. The reader should consult each individual
section for details, as the table only summarizes some of the basic
test requirements.
(2) The "formulators1 exemption" contained in FIFRA sec. 3(c)
(2)(D) applies to the data requirements of §§ 63-2 through -13 of
this subdivision. This exemption provides that an applicant for
registration of an end-use product who purchases and legally uses a
registered product to formulate his end-use product is not required
to submit or cite any data under this subdivision pertaining to the
safety of such purchased product. However, the purchased product
must be registered and labeled for manufacturing-use or , if is an
end-use product, it must be reformulated by the applicant for the
same use as the purchased product.
(b) Test methods and the "References" paragraphs. (1) Most of
the following sections, §§ 63-2 through -21, contain a paragraph
entitled "Reference" or "References." These paragraphs list refer-
ences to various published testing methodologies appropriate for
making the required determinations. Unless specifically stated
otherwise, the Agency recommends (but does not require) use of the
referenced methodologies. Applicants may use any other scientifical
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63
ly-sound techniques, provided that data are presented to show that
the techniques used produce results comparable to the referenced
methodology.
(2) References that denote "ASU4" refer to standardized
methods published by the American Society for Testing and Materials,
Philadelphia, Pa. References denoting "CIPAC" refer to standardized
methods of the Collaborative International Pesticides Analytical
Council, Ltd., Hatching Green, Harpenden, Hertfordshire, England.
(c] General reporting requirements. (1) Any methods used to
meet the requirements discussed in §§ 63-2 through -21 shall be
referenced or described m the application for registration. If
methods used are listed in the references paragraphs of this section
series, reference to the methods will suffice. If other methods
are used, references may be used only if the instructions are
readily available in texts or periodicals; otherwise, copies of
such methods must be submitted with the application.
(2) The applicant shall submit his own statistical evaluations
of the precision of these measurements (e.g., standard deviations
or confidence intervals) when appropriate.
(d) General references. The Agency considers the following
publications to contain useful information and acceptable proce-
dures for conducting the tests required by this section:
(1) Weissberger, A., ed. 1959-1970. Technique of organic
Chemistry. interScience Publishers, New York, N.Y.
(2) American Society for Testing and Materials. {Continuing
series) Annual Book of ASTM Standards. Amer. Soc. for Testing and
Materials, 1916 Race St., Phila., Pa. 1910 3.
(3) Environmental Protection Agency. 1976. Guidelines for
registering pesticides in the United States. Fed. Reg. 40(123):
26802-26927. (June 25, 1975).
(4) Environmental Protection Agency. 1979. Toxic Substances
Control - Discussion of premanufacture testing policy and technical
issues; Request for ccmment. Fed. Reg. 44(53): 16240-16292. (March
16, 1979).
(5) CIPAC Handbook. Vol. 1. (1970), and CIPAC Handbook. Vol.
1A (1980), Collaborative International Pesticides Analytical Council,
Ltd., Plant Pathology Lab., Hatching Green, Harpenden, Hertfordshire,
England.
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TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES TEST REQUIREMENTS
FROM 40 CFR § 158.120
Test substance
Section and title
63-2 Color
63-3 Physical state
63-4 Odor
63-5 Melting point
63-6 Boiling point
63-7 Density, bulk density,
or specific gravity
63-8 Solubility
63-9 Vapor pressure
63-10 Dissociation constant
63-11 Octanol/water
partition coefficient
Technical grade of Manufacturmg-
active ingredient use product
yes
yes
yes
yes (solids)
yes (liquids)
yes
yes
yes (pure form)
case-by-case
(pure form)
yes, for non-polar
organics (pure form)
yes
yes
yes
no
no
yes
no
no
no
63-12 pH
63-13 Stability
63-14 Oxidizing or reducing
63-15 Flammability - flashpoint:
- flame extension:
63-16 Explodability
63-17 Storage stability
63-18 Viscosity
63-19 Miscibility
63-20 Corrosion
characteristics
yes
yes
no
no
no
no
no
yes
no
yes
End-use
product
yes
yes
yes
no
no
yes
no
no
no
yes
yes
no
yes
yes
(combustible liquids only)
no yes
(aerosols only)
63-2 1 Dielectric
breakdown voltage
no
no
no
no
yes
yes
yes
yes
yes
yes
(liquids only)
yes yes
(emulsiflable liquids only)
yes yes
(when packaged in metal,
plastic, or paper containers)
no yes (If
for use around electrical equipment)
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§ 63-2 Color.
(a) When required. (1) End-use products. A statement of the
color of the end-use product and of the technical grade of each active
ingredient in the product is required by 40 CFR § 158.20 to support
the registration of each end-use product.
(b) Manufacturing-use products. A statement of the color of
the manufacturing-use product and of the technial grade of each
active ingredient in the product is required by 40 CFR § 158.120
to support the registration of each end-use product.
(c) Reporting. A description of the color (or lack of it) of
each substance shall be reported. Any intentional coloration or
discoloration, in accordance with the FIFRA sec. 3 regulations (see
40 CFR § 162.13) shall be reported in terms of the Munsell color
system, together with the name of the coloring or discoloring agent
and the percentage by weight of the product for such agent. The
applicant is referred to paragraph (d) of this section for the source
of information on the Munsell color system.
(d) References.
(1) ASTM D1535-68•
(2) Information on the Munsell color system may be obtained
frcm Munsell Color, MacBeth Color and Photometry, Div. of Kollmorgen
Corp., 2441 N. Calvert St., Baltimore, MD 2 1218.
§ 63-3 Physical state.
(a) When required. (1) End-use products. A description of the
physical state of the end-use product and the technical grade of each
active ingredient in the product is required by 40 CFR § 158.120 to
support the registration of an end-use product.
(2) Manufacturing-use products. A description of the physical
state of the manufacturing-use product and the technical grade of
each active ingredient in the product is required to support the
registration of a manufacturing-use product.
(b) Test method. The description of the physical state of
each substance shall be based on a visual inspection of the substance
at 20°C or 25°C.
(c) Reporting. Conventional terms such as "solid," "granular,"
"semisolid," "mixture of liquid and solid," "volatile liquid,"
"powder," "gas," and similar terms shall be used, as appropriate,
to describe each substance.
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§ 63-4 Odor.
(a) When required. (1) End-use products. A description of
the odor (or lack of it) of each end-use product and the technical
grade of each active ingredient in the product is required by 40 CFR
§ 158.120 to support the registration of an end-use product.
(2) Manufacturing-use products. A description of the odor
(or lack of it) of the manufacturing-use product and the technical
grade of each active ingredient in the product is required to
support the registration of a manufacturing-use product.
(3) Exemption. No information on the odor of a substance is
required if a determination of the odor would involve an inhalation
hazard.
(b) Test method. The determination of odor shall be made at
room temperature.
(c) Reporting. The odor, if any, should be reported in des-
criptive terms such as "garlie-like," "characteristic of sulfur-
containing compounds," or "characteristic of aromatic compounds."
§ 63-5 Melting point.
(a) When required. If the technical grade of an active ingre-
dient in a product is a solid at room temperature, a determination
of the melting point (or melting point range) of each such technical
chemical in the product is required by 40 CFR § 158.120 to support
the registration of a manufacturing-use product and end-use product.
The determination is not required for any substance which sublimes
or decomposes.
(b) Test method. The Agency reccnimends the methods referenced
in paragraph (d) of this section.
(c) Reporting. (1) The melting point will be reported in
degrees centigrade.
(2) Any decomposition observed in the melting point determina-
tion shall be reported along with temperature at which decomposition
occurs.
(d) References.
(1) CIPAC MT 2, 45 Fed. Reg. 7 7341 (Nov. 21, 1980)
(2) OECD Guidelines for Testing Chemicals. May 1981, Section 1,
Number 102. Melting Point/Melting Range.
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67
§ 63-6 Boiling point.
(a) When required. If the technical grade of an active ingre-
dient in a product is a liquid at room temperature, a determination
of the boiling point range of each such technical chemical in the
product is required by 40 CFR § 158.120 to support the registration
of both a manufacturing-use product and an end-use product. No
data on boiling point are required if the determination would be
hazardous.
(b) Test method. The boiling point or boiling point range
shall be determined at 760 mm Hg or at a reduced pressure, when
appropriate, because of the inherent properties of the chemical.
(c) Reporting. (1) The boiling point or boiling point range
shall be reported in °C. The conditions under which the determina-
tion was made should be stated.
(2} Any decanposltion observed in the boiling point determina-
tion shall be reported along with temperature at which decomposition
occurs.
(d) References.
(1) OECD Guidelines for Testing Chemicals. May 1981, Section
1, Number 103. Boiling Point/Boiling Range.
§ 64-7 Density, bulk density, or specific gravity.
(a) When required. (1) End-use products. Measurements of
the density, bulk density, or specific gravity of the end-use
product and of the technical grade of each active ingredient in the
product are required by 40 CFR § 158.120 to support the registration
of each end-use product.
(2) Manufacturing-use products. Measurements of the density,
bulk density, or specific gravity of the manufacturing-use product
and of the technical grade of each active ingredient in the product
are required to support the registration of each manufacturing-use
product.
(3) Limitation. Measurements of density, bulk density, or
specific gravity are required only for substances which are in
solid or liquid state at rocm temperature.
(b) Test method. (1) Measurements shall be made at 20°C or
25°C.
(2) When a substance is a solid in particulate form, a
measurement of bulk density may be substituted for a measurement of
density.
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68
(3) When a substance is a liquid, the specific gravity of the
substance shall be determined with reference to water at 20°C.
(c) Reporting. Density and bulk density shall be reported in
g/ml.
(d) References. (1) The following references have been
published in 45 FR 77338 (Nov. 21, 1980):
(1) CIPAC MT 3.
(li) ASTM D941-55.
(iii) ASTM D 792-66.
(lv) ASTM D1480-62.
(v) ASTM D1481-62.
(vi) ASTM D1217-54.
(2) OECD Guidelines for Testing Chemicals. May 1981, Section
1, Number 109. Density of Liquids and Solids.
§ 63-8 Solubility.
(a) When required. Data on the solubility of the technical
grade of each active ingredient in a product are required by 40 CFR
§ 158. 120 to support the registration of each manufacturing-use
product and end-use product.
(b) Test method. The solubility of each substance in distilled
water and representative polar and non-polar solvents ccmnionly used
for pesticides shall be determined at 20°C or 25°C.
(c) Reporting. Solubility shall be reported in g/100 ml of
solvent. If a substance is sparingly soluble, its solubility may be
reported in other terms such as ppm (mg/kg).
(d) References.
(1) 40 Fed. Reg. 26879 (June 25, 1975).
(2) 44 Fed. Reg. 16253 (Mar. 16, 1979).
(3) OECD Guidelines, May 1981, May, W.E. , S.P. Wasik, and
D.H.Freeman. 1978. Determination of the aqueous solubility of
polynuclear aranatic hydrocarbons by a coupled column liquid
chromatographic technique. Anal. Chem. 50: 175-179.
(4) May, W.E., S.P. Wasik, and D.H. Freeman. 1978. Determina-
tion of the solubility behavior of some polycyclic aromatic hydro-
carbons m water. Anal. Chem. 5 0:997-1000.
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(5) (Reserved for: OECD Guidelines for Testing Chemical.
Section 1, Number 105. Water Solubility.)
§ 63-9 Vapor pressure.
(a) When required. If the boiling point of the pure form of
the active ingredient in a product is equal to or greater than
30°C, then a determination of the vapor pressure of the pure form
of such active ingredient is required by 40 CFR § 158.120 to support
the registration of that product.
(b) Test method. (1) Vapor pressure shall be determined at
25°C.
(2) If the vapor pressure of an active ingredient is less
than 1 x 10~7 torr, information demonstrating that the vapor pressure
is below that level satisfies the data requirements of this section
(unless specifically indicated otherwise by the Agency).
(c) Reporting. The vapor pressure of a substance shall be
reported in mm Hg (torr, or other conventional units).
(d)
References.
(1 )
ASTM D3074-72•
(2)
40 Fed. Reg. 26889 (June 25,
1975).
(3)
OTS Guidelines; Chem Fate CG
1600, Aug. 1982.
(4)
45 Fed. Reg. 77345 (Nov. 21,
1980 ).
(5)
(OECD Guidelines for Testing
Chemicals. Section 1, Number
104. Vapor Pressure Curve.)
§ 63-10 Dissociation constant.
(a) When required. A determination of the dissociation
constant for the pure grade of each active ingredient in a product
is required by 40 CFR § 158.120 on a case-by-case basis to support
the registration of each manufacturing-use product and end-use product.
(b) Test method. The Agency recommends the methods referenced
in paragraph (d) of this section.
(c) Reporting. Report the measurement obtained by the methods
referenced in paragraph (d) of this section.
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(d) References.
(1) OECD Guidelines for Testing Chemicals. May 1981, Section
1, Number 112. Dissociation Constants in Water.
§ 63-11 Octanol/water partition coefficient.
(a) when required. A determination of the octanol/water
partition coefficient for the pure grade of each non-polar organic
active ingredient in a product is required by 40 CFR 158.120
to support the registration of each manufacturing-use product and
end-use product.
(b) Test method. The Agency recommends that the octanol/water
partition coefficient be determined using either of the methods
specified in paragraph (d) of this section. The determination
shall be made at 20°C or 25°C. If the solubility of the test
substance is less than 1 ppm, then the concentrations used shall be
equivalent to its solubility and to one-half its solubility in water.
(c) Reporting. Report the data and calculations as recommended
by any of the methods referenced in paragraph (d) of this section.
(d) References.
(1) OTS Guidelines; CG-1400; August 1982 (2) 45 Fed. Reg.
77350 (Nov. 21, 1980).
(3) [Reserved for: OECD Guidelines for Testing Chemicals.
May 1981, Section 1, Number 107. Partition Coefficient
(M-Octanol/Water).]
§ 63-12 £H.
(a) When required. (1) End-use products. A determination
of the pH of the end-use product and the technical (or purer) grade
of each active ingredient in the product is required by 40 CFR § 158.120
to support the registration of each end-use product.
(2) Manufacturing-use product. A determination of the pH of
the manufacturing-use product and the technical (or purer) grade of
each active ingredient in the product is required to support the
registration of each manufacturing-use product.
(3) Limitation. pH determinations are required only for sub-
stances which can be diluted or dispersed with water.
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(b) Test method. Each substance for which a pH determination
is required shall be diluted or dispersed with distilled water.
The determination shall be made at 20°C or 25°C in accordance with
the method described in paragraph (d) of this section or by any
other method of equivalent reliability.
(c) Reporting. Report the measurements obtained by using any
of the methods provided in the reference given in paragraph (d) of
this section, and in accordance with the test method requirements
of paragraph (b) of this section.
(d) Reference.
(1) ASTM E70-74.
(2) OTS Guidelines; CG-1450 August 1982.
§ 63-13 Stability.
(a) When required. Information on the stability of the
technical grade of each active ingredient in the product is required
by 40 CFR § 158.120 to support the registration of each manufactur-
ing-use product and end-use product.
(b) Test method. The Agency recommends any of the methods
referenced in paragraph (d) of this section.
(c) Reporting. The information on stability shall include
consideration and discussion of the sensitivity of the active
ingredient to metal ions and metal, the stability of the active
ingredient at normal and elevated temperatures, and the sensitivity
of the active ingredient to sunlight.
(d) References.
(1) CIPAC MT 39.
(2) CIPAC MT 41.
(3) CIPAC MT 46.
(4) CIPAC MT 55.
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§ 63-14 Oxidizing or reducing action.
(a) When required. Information on the tendency of a product
to act as an oxidizing or reducing agent is required by 40 CFR
§ 158.120 to support the registration of each manufacturing-use
product and end-use product.
(b) Test method. Information on the oxidation or reduction
potential of a product may be obtained through a knowledge of the
chemistry of the product and by application of the method referred
to in paragraph (d) of this section.
(c) Reporting. Report the data on oxidation or reduction
action by following the instructions in the method referenced in
paragraph (d) of this section.
(d) Reference.
(1) 44 Fed. Reg. 16267 (Mar. 16, 1979).
§ 63-15 Flammability.
(a) When required. A determination of the flash point of a
product is required by 40 CFR § 158.120 to support the registration
of each manufacturing-use product and end-use product which is a
combustible liquid. A flame extension determination for a product
is required to support the registration of each end-use product
which is an aerosol.
(b) Test methods. (1) The flash point shall be determined
by any procedure which is consistent with those listed in paragraph
(d) of this section or which is acceptable to any other Federal
agency that requires this determination. When the product is
intended for packaging under pressure, the flash point is to be
determined with the propellent-free portion of the formulation
before it is packaged.
(2) The flame extension or flame projection of a product
shall be determined by the Standard Method of Test for Flammability
of Aerosol Products (ASTM D3065-72).
(c) Reporting. (1) The flash point shall be reported in °F
and °C.
(2) The flame extension or flame projection shall be reported
to the nearest centimeter or inch.
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(d) References~
(1) CIPAC MT 12.
(2) ASTM D56-70.
(3) ASTM D93-73.
(4) ASTM D3278-73.
§ 63-16 Explodability.
(a) When required. Information on the impact explosion charac-
teristics, if any, of a product is required by 40 CFR § 158.120
to support the registration of each manufacturing-use product
and end-use product that contains an explosive ingredient.
(b) Test method. The Agency recanmends that the impact explod-
ability of a product be determined by a procedure listed in paragraph
(d) of this section.
(c) Reporting. Report the data on explodability by following
the instructions in the method referenced in paragraph (d) of this
section.
(d) Reference. (1) 44 Fed. Reg. 16265 (March 16, 1979).
§ 64-17 Storage stability.
(a) When required. Data concerning the storage stability of
a product are required by 40 CFR § 158.120 to support the registra-
tion of each manufacturing-use product and end-use product.
(b) Test methods. (1) The test shall be conducted with the
product in its commercial package or in smaller packages of the
same construction and materials.
(2) The amount of the active ingredient in the product shall
be determined at the beginning and at the end of the test period.
The applicant shall also determine if any deterioration or degrada-
tion products develop in the product during the test period. At
the end of the test period, the applicant shall examine the product
for physical changes, such as phase separation or "clumping," and,
m particular, any changes which would interfere with the useful-
ness or safe handling of the product if used according to the
label directions.
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(3) The test period shall be at least one year; and
(4) The test shall be conducted under either of the
following conditions:
(1) At 20°C or 25°C, and, if the packaging is permeable, at
a relative humidity of 50%; or
(ii) Under warehouse conditions which reflect the expected
storage conditions of the commercial product.
(c) Reporting. (1) The report shall describe the duration
of the test and the conditions under which the storage stability
test was conducted (e.g., temperature, humidity).
(2) The report shall include quantitative analyses for the
active ingredient it and on identification and any deterioration
or degradation products.
(3) The report shall describe any physical changes m the
product during the test period and also the consequences, if
any, of such changes for safe handling and use of the product.
(d) Reference.
(1) CIPAC MT 22.
(2) (Reserved for: OECD Guidelines for Testing Chemicals.
May 1981, Section 1, Number 114. Viscosity of Liquids.)
§ 63-18 Viscosity.
(a) When required. A determination of the viscosity of a prod-
duct is required by 40 CFR § 158.120 to support the registration
of each manufacturinguse product and end-use product which is a
liquid.
(b) Test methods. (1) The Agency recommends that viscosity
be determined by any of the methods described in paragraph (d) of
this section.
(2) Viscosity shall be determined at 20°C or 25°C.
(c) Reporting. Viscosity shall be reported in terms of poises,
stokes, or other conventional units.
(d) References.
(1) CIPAC MT 22
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75
(2) (Reserved for OECD Guidelines for Testing Chemicals.
Section 1, Number 114, Viscosity of Liquids,)
§ 63-19 Miscibility¦
(a) When required. An evaluation of the miscibility of a
product is required by 40 CFR § 158.20 to support the registration
of each manufacturing-use product and end-use product which is an
emulsifiable liquid, and which also bears directions for dilution
with petroleum solvents.
(b) Test method. (1) The evaluation of miscibility shall be
made at 20°C or 25°C.
(2) The product shall be mixed with petroleum solvents whose
composition reflects those on the label and at the rate specified
on the label. After the mixture has stood for 30 minutes, it shall
be examined for separation.
(c) Reporting. Report the data on miscibility by following
the instructions in the method referenced in paragraph (d) of this
section.
(d) Reference.
(1) CIPAC MT 23.
§ 63-20 Corrosion characteristics.
(a) When required. Information on the corrosion characteris-
tics of a product is required by 40 CFR § 158.120 to support the
registration of each manufacturing-use product and each end-use
product which comes in contact with metal, plastic, or paper con-
tainers or closures when commercially packaged.
(b) Combined testing. A study of the corrosion characteris-
tics of a product may be performed in combination with the storage
stability test described in § 64-16.
(c) Reporting. Report the data on corrosion characteristics
by following the instructions in the method referenced in paragraph
(d) of this section.
(d) Reference•
( 1) ASTM G31-72.
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§ 63-21 Dielectric breakdown voltage.
(a) When required. A measurement of the dielectric breakdown
voltage of an end-use product is required by 40 CFR § 158.20 to sup-
port the registration of each end-use product which is a non-conductant
end-use liquid intended for use in or around electrical equipment.
(b) Test method. The Agency recommends either of the methods
referenced in paragraph (d) of this section.
(c) Reporting. Report the data on dielectric breakdown vol-
tage by following the instructions in either of the methods refer-
enced in paragraph (d) of this section.
(d) References.
(1) ASTM D877-67.
(2) ANSI/ASTM D877-76.
Series 64: OTHER PRODUCT CHEMISTRY REQUIREMENTS.
§ 64-1 Submittal of samples.
(a) A sample of the analytical grade of each active ingredient
in a product, weighing about 5 grams, and a sample of the technical
grade of each active ingredient in a product, weighing about 200
grams, must be submitted (see 40 CFR § 158.120) to support the
registration of each manufacturing-use product and those end-use
products produced by an integrated formulation system.
(b) When specifically requested by the Agency, the applicant
for an end-use product or a manufacturing-use product shall submit
samples that are representative of:
(1) The proposed product (about 200 grams) with a composition
conforming to the limits certified under § 62-2.
(2) Intentionally-added inert ingredient(s), listed in
accordance with § 61—1(b)•
(3) A specific product impurity, for which a certified upper
composition limit, in accordance with §62-2, may be required.
(4) A specific degradation product or metabolite of either
the active ingredient or an intentionally-added inert.
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All samples required by this section shall be sent to:
Chief, Chemical and Biological Investigations Branch,
Benefits and Field Studies Division, OPP/OPTS, U.S.
Environmental Protection Agency, Building 402, ARC-East,
Beltsville, Md. 20705
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