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Parent
chemical/related chemical concept
 The
Logic Behind Grouping Chemicals
Types
of Chemical Groups
How
Can You Tell if a Compound is Toxicologically Similar to Its Parent?
Groups
Likely to Be Toxicologically Similar
Groups
Where Toxicological Similarity May Be Difficult to Assess
The
Logic Behind Grouping Chemicals
There are
~6,400 chemicals in the PAN Chemical database--active ingredients,
transformation products, adjuvants, and solvents. Many of these
compounds are chemically similar to each other; however, typically
only one of a group of similar compounds has been evaluated for
its toxicological properties. We call this compound the "parent."
In many cases, chemicals that are chemically similar (related chemicals)
will have similar toxicological effects and/or similar chemical
reactivity. We wanted to formally group similar compounds to make
it possible for the user to:
- Know which
compounds are chemically similar
- View the
toxicological properties of the parent compound when evaluating
a related compound
The Chemical
Classification (organophosphorus compounds, chlorophenoxy acids
or esters, etc.) is one way of broadly categorizing chemicals. By
creating Parent/Related Chemical rollup categories, we have taken
this classification scheme to a finer level of detail (see below
for two examples). Not all chemicals can easily be placed into a
chemical class; in this case, the Parent/Related Chemical rollup
makes it easier to find similar chemicals.
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Types
of Chemical Groups All
chemicals in a group are related to the parent in one or more ways.
The "Reasons" for combining chemicals into rollup groups
are defined below.
- Parent:
Compounds labeled with a "P" are the parent compound
of the group. The parent chemical was chosen on the basis of available
toxicity information, where chemicals with the maximum amount
of toxicity information assigned to parent status. Where no toxicity
information was available for any member of a group, we assigned
parent status to the least derivatized member of the group for
organic compounds (e.g., benzoic acid would be the parent instead
of methyl benzoate), the sodium salt (for compounds with a common
anion), or the chloride salt (for compounds with a common cation).
These are general guidelines and not hard and fast rules, because
the groups are rarely so easy to categorize. For some groups with
no obvious parent, assignment of parent status was arbitrary.
- Group 1:
Salts, esters and/or complexes of the parent chemical, e.g., glyphosate
and glyphosate, isopropylamine salt; 2,4-D and 2,4-D, butoxyethyl
ester. Alternatively, the parent compound itself is an ester or
salt, and related compounds are other esters or salts.
- Group 2:
Derivatives of the parent chemical, other than esters,
made by substitution of a functional group or groups.
- Group 3:
Compounds or complexes of the same highly toxic metal
as the parent compound. There are distinct groupings for different
types of arsenic, mercury, cadmium, tin, lead, selenium, antimony
and hexavalent chromium compounds.
- Group 4:
Compounds or complexes of the same less-toxic metals
or non-metallic elements as the parent compound. There are distinct
groupings for copper, zinc, iron, silver, iodine and other inorganic
compounds.
- Group 5a:
Transformation or breakdown product of the parent chemical, e.g.
DDE is the transformation product of DDT. This category is also
used for cases where the parent chemical is the transformation
product and the related chemical is a precursor to it. For example,
carbon disulfide is the transformation product of sodium tetrathiocarbonate
and is listed as the parent chemical.
- Group 5b:
Oxygen analogs of a phosphorothioate parent chemical. These compounds
are a special sub-category of parent chemicals and their transformation
products. Metabolism of the phosphorothioates results in the formation
of the oxygen analogs, which are more toxic than the parent phosphorothioates
themselves.
- Group 6:
Optical, geometric, or structural isomer of the parent chemical.
- Group 7:
Inorganic strong acids, weak acids, strong bases, weak bases,
and their salts.
- Group 8:
California Department of Pesticide Regulation's (DPR) "other
related" chemicals. For example, "DDVP" and "DDVP,
other related".
- Group 9:
Bacteria and viruses used as microbial pesticides that are either
a) the same genus and species as the parent, b) the same genus
and the same mechanism of action as the parent, or c) the same
mechanism of action as the parent.
- Group 10:
Different forms of the same chemical element or mineral, for example
graphite vs. diamond or crystalline silica vs. amorphous silica.
- Group 11:
Natural materials and related compounds derived from these natural
materials, including vegetable based compounds such as soybean
oil, olive oil, canola oil, etc.; natural products and their essential
oils such as oil of lemongrass, 3,7-dimethyl-6-octen-1-ol acetate
and citronellol; and inorganic compounds such as clam shells and
oyster shells.
- Group 12:
Unidentified chemicals or mixtures with the same brand name or
use.
- Group 13:
Mixture of compounds with one compound in the mixture being the
parent compound. For example, benfuracarb is a mixture of two
similar, but slightly different chemicals. Alternatively, the
parent is a mixture and the group members are compounds in that
mixture.
- Group 14:
Pheromones and derivatives with the same carbon chain length.
- Group 15:
Parent is a mixture of compounds. Related substances are also
mixtures with structures similar to the parent mixture.
- Group 16:
Polymer of parent compound.
- Group 17:
An analytical method or a device for dispensing a chemical.
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How
Can You Tell if A Compound is Toxicologically Similar to Its Parent?
In short, you
cannot be absolutely sure of the toxicological properties of a particular
compound unless that compound has been through the full battery
of toxicological tests. However, you can make reasonable estimates
of toxicity by knowing something about what happens to the compound
after it enters the environment or the human body. If the related
compound is transformed into the parent compound through some physiological
or environmental process, it is likely to have similar toxicological
properties to the parent. However,
toxicological similarity doesn't require the compound to
be transformed to its parent. It may simply be that the toxicologically
significant portion of the parent molecule is identical or nearly
so in the related compounds. In any case, specific characteristics
of the related compound may accentuate or attenuate the toxicity.
The U.S. EPA
uses this knowledge of toxicological similarity when it registers
a group of chemicals, such as "2,4-D and derivatives,"
"maleic hydrazide and salts," "2,4,5-T/Silvex,"
"pentachlorophenol, salts and esters," and others (1).
Groups
Likely To Be Toxicologically Similar
Group 1:
Parent chemical and its salts and esters
Sodium, potassium, and ammonium salts of organic
compounds will typically act like the parent acid because these
ions are rapidly replaced by hydrogen ions in an aqueous environment
to form the parent compound. Other salts (amine or alkanolamine
salts) may behave differently because of the solubility properties
of the counterion, particularly when the counterion contains a hydrophobic
hydrocarbon component. A change in solubility will change the rate
of uptake into the body or the environment. Examples are: pentachlorophenol
and its sodium salt, glyphosate and its isopropylamine salt.
Esters can
hydrolyze to form the parent compound; however, the time frame of
this reaction may be slow relative to excretion. For esters to be
toxicologically similar to their parent acid, either the hydrolysis
to form the parent must be rapid or the toxicologically significant
part of the molecule must not depend on the acid functionality.
Esters of 2,4-D, 2,4,5-T/silvex, 2,4-DP, and 2,4-DB are toxicologically
similar to their parent compound, as indicated by the fact that
the U.S. EPA registers these compounds as a group with the parent
acid (1).
Group
2: Parent chemical and derivatives (not esters)
Many pesticides are created by taking
a compound that is known to be toxic to a particular target pest
and derivatizing it--exchanging methyl groups for hydrogen atoms,
fluorine atoms for chlorine atoms, or various other substitutions,
limited only by the imagination of the synthetic chemist. Not all
of these compounds have the same toxicological activity, although
it is frequently quite similar to the parent compound. While most
groupings in this category can be described as chemical
classes, others are sub-categories of chemical classes, or are
used when a compound cannot readily be assigned to a chemical class.
Examples are: the coumarins, a family of rat poisons that differ
in the identity of substituents placed on a double ring system (see
sample structure); or
cyanuric acid and its chlorinated derivatives.
Groups
3 and 4: Metal-containing compounds
Metals are elements and do not break down in
the environment like organic compounds. As a result, they always
maintain their potential for biological activity. However, the form
of the compound (i.e., whether it is a metal sulfide, hydroxide,
chloride or an organometallic compound) plays a role in its bioavailability
and hence its toxicity. For example, mercury sulfide is extremely
insoluble in water. If this compound is ingested, very little of
the toxic mercury ion will be absorbed by the body and little if
any toxicity will result. In contrast, if the same amount of water-soluble
mercury chloride is ingested, most of the mercury will be absorbed
by the body, resulting in acute poisoning.
The oxidation
state of the metal is also important. For example, chromium (III)
is not particularly toxic, while chromium (VI) is extremely toxic.
For some metals, one oxidation state predominates under normal physiologic
conditions and the metal is not readily transformed into a different
oxidation state. For other metals (Hg, As), oxidation states are
changing continuously under normal physiologic conditions, which
means that any form of the metal could be transformed into
a toxic and/or bioavailable form.
Group
5b: Phosphorothioates and their oxygen analogs
Phosphorothioates are organophosphorus
compounds containing a P=S bond, for example, malathion. This
bond hydrolyzes in aqueous solution (or is metabolized in the liver)
to form malaoxon, an analogous compound where the P=S bond has been
replaced by a P=O bond. The cholinesterase-inhibiting
effects of the parent compound are largely caused by the oxygen
analog (the P=O bonded compound) because it is more physiologically
active than the parent.
Group 11:
Natural materials and related compounds derived from these
natural materials
Because compounds extracted from natural materials are
contained in the pure form of the natural material, their toxicity
properties are likely to be similar. However, an extract of a natural
material typically concentrates a specific substance in the natural
material (like an extract of peppermint oil from the peppermint
plant), which may accentuate any toxicity.
Group 13:
Mixture of compounds with one compound in the mixture being
the parent compound
Because the parent compound is contained in the mixture, the toxicity
of the mixture is likely to be similar to that of the parent.
Groups
Where Toxicological Similarity May Be Difficult to Assess
Group 5a:
Parent chemical and its transformation products
In some
cases, transformation products still possess the functional group
of the molecule that causes toxicity and can even be more toxic
than the parent compound. In other cases, the molecule has been
transformed to a compound that is no longer toxic.
Group 6:
Optical, geometric, and structural isomers of compounds
Isomeric
compounds often do not have the same biological activity. Compounds
in this category include most pheromones, pyrethroids, polychlorinated
phenols, and some others.
Optical isomers
are chiral (i.e., they exist as left and right-handed molecules)
and physiological activity is often specific to one isomer.
Geometric (cis/trans)
isomers, where the geometry about a C=C double bond is different,
may or may not have similar biological activity. For example, the
Z-isomer of the pheromone 11-tetradecen-l-yl acetate acts as a mating
disruptor for leafrollers, while the E-isomer acts as a mating disruptor
for the apple bud moth.
Structural
isomers differ by the arrangement of atoms within the molecule and
may or may not be toxicologically similar (e.g., 2,4,5-trichlorophenol
and 2,4,6-trichlorophenol).
Group 7:
Acids and Bases
Strong
and weak inorganic acids and bases are grouped together based on
chemical properties only. They will have similar corrosive effects,
but not necessarily the same systemic toxicity.
Group 8:
California Department of Pesticide Regulation's "other related"
compounds
It is not
clear on which properties DPR bases its classification or indeed
what the exact identity of these "other related" compounds
is, so it is impossible to judge the toxicological similarity of
the parent and related compound. However, "other related"
compounds are generally contained in the same products as the parent
compound.
Group 9: Bacteria and viruses used as
microbial pesticides
Microbes that attack plants, insects, and/or fungi have not (so
far) been observed to show extensive toxicity from systemic effects
(although they may be lung irritants if a dust or spray containing
the compound is inhaled).
Group 10: Different forms of the same
chemical element or mineral
Different forms of the same chemical element may have very different
toxicities because of differences in solubility or differences in
chemical structure that change the physical or chemical properties.
For example, crystalline silica is very irritating to the lungs,
while amorphous silica is much less so.
Group 12: Unidentified chemicals or mixtures
with the same brand name or use
Because chemicals in this group are not identified, it
is impossible
to judge the toxicological similarity of the parent and related
compound. Our favorite in this group is: "Secret formula
#1," and "Secret formula #2".
Group
14: Pheromones and derivatives with the same carbon
chain length
Most pheromones have not (so far) been observed to be especially
toxic to humans. This may be because amounts used are very small
and exposure is very low. Pheremones of the same carbon chain length
often (but not always) have similar attractive effects on insects.
Group 15: Parent and related compounds
are both mixtures of similar compounds
Chemicals in this group may or may not be toxicologically similar.
Although a mixture may contain similar chemicals, the ratio of different
components will be different, a factor that will affect toxicity.
An example would be gasoline and kerosene, both of which are mixtures
of hydrocarbons in different proportions.
Group 16: Polymer of parent compound
The parent chemical
from which a polymer is formed (called the monomer) typically has
a much greater toxicity than the polymer itself. However, polymers
usually contain unreacted monomer (the parent), so it is possible
to observe some toxicity from the polymer due to escape of the monomer
into water, food, and air (that "new car" smell is just
such a phenomenon).
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Reference:
- Status
of Pesticides in Registration, Reregistration, and Special Review
(Rainbow Report), U.S. EPA, Spring 1998 (download,
982K). See, for example, 2,4-D and derivatives on pp. 69-73, maleic
hydrazide and salts on page 128, pentachlorophenol, salts and
esters on p. 197, 2,4,5-T/Silvex on p. 44. Viewed on September
22, 2003.
Last
updated
September 22, 2003
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