Methoxychlor
Presentation
By Dave Lewis
Structure and Properties
Methoxychlor [1,1,1-trichloro-2,2-di(4methoxyphenyl)ethane] is a bicycle aromatic DDT
analog
Structure Compared to DDT
Methoxychlor
DDT
Physical & Chemical Properties
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Molecular Wt.
Color
Physical State
Boiling Pt.
Solubility in Water
Partition Coefficients
Log Kow
Log Koc
345.65
Light Yellow
Crystalline Solid
Decomposes
Very slightly soluble 0.045 Mg./L
Lipophilic 4.7-5.1
4.9
Uses and Application, Production
History etc
This DDT analog was very heavily used after cancellation of DDT
in the 1970s, although usage has declined more recently. In the
early ‘90s about 300 to 500 thousand pounds of methoxychlor
was used per year in the US (ATSDR, 1994).
Compared to DDT, methoxychlor is rapidly metabolized both in
the environment and in living organisms, so it does not produce
the long-lasting toxicity and bioaccumulation, which led to the
cancellation of DDT.
Uses and Application, Production
History etc
First synthesized by Elbs (1893), its insecticidal properties were described by
Lauger et al. (1944) together with DDT, and it has been commercial
insecticide for about 60 years.
It has been used against houseflies, mosquitoes, cockroaches, chiggers,
various arthropods found on field crops, and insect pests in stored grain
or seed for planting. It has been registered for use on more than 85 crops,
including fruits, vegetables, soybeans, nuts, and alfalfa. It is also approved
for use on forests, ornamental plants, and for insect control around
houses, barns, and other agricultural premises (ATSDR, 1994). It has
often been formulated with other pesticide products, such as captan,
diazinon, and malathion. It has been available in many forms, including
technical-grade concentrate, wettable powders, dusts, granules,
emulsifiable concentrates, and pressurized sprays for home use. It’s use
was suspended in California in 1995 and use limited to stocks on hand. In
2000, the EPA did not reregister it for continued use.
Mode of Entry in Aquatic
Environment
Methoxychlor binds tightly to soils, but is not usually detectable in
soil except in areas where it has been applied as a pesticide. Wind
and rain can erode contaminated soils, resulting in the migration
of methoxychlor-containing particulates. Some methoxychlor
can persist in soils for more than a year after its application.
However, most of it is degraded to dechlorinated,
dehydrochlorinated, and demethylated products. These
metabolites are more polar than methoxychlor and bind less
tightly to soils which can contribute to wider dispersion.
Methoxychlor can be released directly to surface waters on farms
when used to control larvae of insects. Methoxychlor had prior
approval for use on cranberries (EPA 1988b), which are grown
in bogs, and therefore methoxychlor could be released directly to
surface waters where cranberries are grown. Methoxychlor may
be released to water from agricultural runoff from soil
containing methoxychlor where it can be adsorbed onto
suspended soil particles.
Chemical reactivity with water
Methoxychlor undergoes a spontaneous elimination reaction
in water to yield dehydrochlorinated products. The half-life
is one year through this process.
Methoxychlor can also undergo direct photolysis (half-life
4.5 months) or indirect "sensitized" photolysis (half-life <5
hours) depending upon the presence of photosensitizers
Half-life of Methoxychlor in
Sediments.
Anaerobic >28 days
Aerobic >100 days
Methoxychlor is very toxic to aquatic
life.
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Reported 96 hour LC50 values are 20 ug/L for cutthroat trout, Atlantic
salmon, brook trout, lake trout, northern pike and largemouth bass
(Johnson and Finley 1980).
Reported 96 hour LC50 values are between 20 and 65 ug/L in rainbow
trout, goldfish, fathead minnow, channel catfish, bluegill, and yellow
perch (Johnson and Finley 1980).
Aquatic invertebrates with 96- or 48-hour LC50, values of less than 0.1
mg/L include Daphnia, scuds, sideswimmers, and stoneflies (Johnson and
Finley 1980
In comparison to mammals, rat oral 96 hour LC50 values
were >6000 mg per kg –much less sensitive.
Molecular mode of toxic interaction
Acute:
At the sodium gates of the
axon, DDT exerts its toxic
action by preventing the
deactivation or closing of
that gate after activation
and membrane
depolarization. The result is
a lingering leakage of Na+
ions through the nerve
membrane, creating a
destabilizing negative
afterpotential. The
hyperexcitability of the
nerve results in trains of
repetitive discharges in the
neuron after a single
stimulus and/or occur
spontaneously
Molecular mode of toxic interaction
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There are at least ten
separate binding sites for
ligands on the sodium
channel
The binding sites are accessible to the lipid
bilayer and therefore to lipid-soluble
insecticides. The binding of insecticides
and formation of binding contacts
across different channel elements could
stabilize the channel when in the open
state
There are at least ten
separate binding sites for
ligands on the sodium
channel
Molecular mode of toxic interaction
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There are at least ten
separate binding sites for
ligands on the sodium
channel
The Methoxychlor binding site is thought
to lie in a cavity formed between the D2
and D3 domains.
Flat topography of the
Na+ channel
Toxic Effects
(Endocrine Disruption)
Activation of Methoxychlor to Estrogenic Metabolites. The
rapid demethylation of methoxychlor decreases its neurotoxicity
and leads to a rapid elimination from the body (Lehman 1952),
making it significantly less toxic than its structural analogue,
DDT. However, this detoxification pathway also is thought to act
as an activation pathway for reproductive and developmental
effects. Data from in vitro and in vivo studies indicate that the
phenolic metabolites of methoxychlor resulting from
demethylation (and contaminants in technical grade and
laboratory grade methoxychlor) are responsible for most of the
estrogenic activity rather than methoxychlor itself.
Toxic Effects
(Endocrine Disruption)
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Methoxychlor has been shown to bind the androgen
receptor and competitively displace testosterone from
the receptor in goldfish testis (Antagonistic effect)
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Methoxychlor treatment in channel catfish (Ictalurus punctatus) increased
serum estradiol and vitellogenin (egg yolk protein) levels, demonstrating
estrogenic activity. (Agonistic effect)
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To determine the estrogenic capacity of MXC, adult zebrafish were exposed
to 0, 0.5, 5, and 50 µg MXC/L for 14 d. Induction of vitellogenin ([VTG]
measured with protein electrophoresis and Western blot) in males was
detected at 5 and 50 µg MXC/L (Agonistic effect)
Developmental Effects
Normal
Environmental estrogens may interfere
with hormone signaling during
development.
Xenopus laevis embryo treated with 1
μM methoxychlor developed a
thin, poorly developed dorsal fin
devoid of melanocytes, spotty
melanocytes atop the spinal cord,
crooked spine, and poorly defined
somites
Methoxychlor
treatment
Mode of entry into organisms
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Methoxychlor is absorbed through dermally,
through gills and consumed in food.
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Some organisms like Daphnia have the potential
to bio-accumulate methoxychlor
Biochemical metabolism and
breakdown
Defense strategies available for
detoxification by organism
Methoxychlor is rapidly metabolized by CYP isoenzymes into less
toxic metabolites which are not generally stored, and rapidly
excreted.
However, during chronic exposure or critical development, these
mechanisms can fail to protect the organism.
Bibliography
ATSDR (1994) Toxicological profile for methoxychlor. U.S. Department of Health and Human
Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. TP-93/11.
Bevan.C, Porter.D , (2003) Environmental Estrogens Alter Early Development in Xenopus laevis.EnvironHealthPerspec
pp. 488-496.
Coats, J.R., (1990) Mechanisms of Toxic Action and Structure-Activity Relationships for Organochiorine and
Synthetic Pyrethroid Insecticides. Environ Health Perspect Vol. 87, pp. 255-262,
Cummings AM. (1997) Methoxychlor as a model for environmental estrogens. Crit Rev Toxicol
Vol.27:4 pp.367-79.
Johnson, W.W., and M.T. Finley. (1980). Handbook of acute toxicity of chemicals to fish and aquatic invertebrates.
U.S. Fish Wildl. Serv. Resour. Publ. 137. pp 98.
Lintelmann, J., Katayama, A.,. Kurihara, N., Shore, L. (2003)
Endocrine Disrupters in The Environment. Pure Appl. Chem., Vol. 75: 5, pp. 631–681,.
Nimrod, A.C. and Benson, W.H. (1997) Xenobiotic Interaction with and Alteration of Channel Catfish Estrogen
Receptor Toxicology and Applied Pharmacology
Vol.147:2 pp. 381-390
O’reilly, A., Khambay ,B., (2006) Modelling insecticide-binding sites in the voltage-gated sodium channel Biochem. J.
Vol. 396, pp. 255–263
Versonnen, B. J., Roose, P., Monteyne, E. M., Janssen, C. R. Estrogenic and toxic effects of methoxychlor on
zebrafish (Danio rerio). Environmental Toxicology and Chemistry Vol. 23: 9 pp. 2194–2201
Wells, K. (1) ; Van Der Kraak. G. (2000) Differential binding of endogenous steroids and chemicals to androgen
receptors in rainbow trout and goldfish Environmental Toxicology and Chemistry Vol.19 pp. 2059–2065,