TETRAMETHRIN
Human Health Effects:
Human Toxicity Excerpts:
In a semi-closed patch test, an aqueous emulsion containing 1.0% tetramethrin
was applied to the skin of 200 human volunteers (aged 15-80, both male and female), using
cotton gauze, for 4 days. After 2 weeks, an additional application was made in a same
manner. Dermatological examination showed that tetramethrin
is neither a primary irritant nor a human skin sensitizer.
The induction of unscheduled DNA synthesis in human amnion FL cells by tetramethrin (72% industrial grade of unknown origin)
/was reported/.
Contact allergy from pyrethroids ... has not been observed. /Pyrethroids/
The allergenic properties of pyrethroids /with early pyrethrum preparations/ are marked
in comparison with other pesticides. Many cases of contact dermatitis and respiratory
allergy have been reported. Persons sensitive to ragweed pollen are particularly prone to
such reactions. Preparations containing synthetic pyrethroids are less likely to cause
allergic reactions than are the preparations made from pyrethrum powder. /Pyrethroids/
Pyrethroids are not cholinesterase inhibitors. /Pyrethroids/
Some pyrethroid (eg, deltamethrin, fenvalerate, cyhalothrin, lambda-cyhalothrin,
flucythrinate, and cypermethrin) may cause a transient itching and/or burning sensation in
exposed human skin. /Synthetic pyrethroids/
Synthetic pyrethroids are neuropoisons acting on the axons in the peripheral and
central nervous systems by interacting with sodium channels in mammals and/or insects. A
single dose produces toxic signs in mammals, such as tremors, hyperexcitability,
salivation, choreoathetosis, and paralysis. ... At near-lethal dose levels, synthetic
pyrethroids cause transient changes in the nervous system, such as axonal swelling and/or
breaks and myelin degeneration in sciatic nerves. They are not considered to cause delayed
neurotoxicity of the kind induced by some organophosphorus compounds. /Synthetic
prethroids/
The clinical manifestations of inhalation exposure to pyrethrins can be local or
systemic. Localized reactors confined to the upper respiratory tract include rhinitis,
sneezing, scratchy throat, oral mucosal edema, and even laryngeal mucosal edema. Localized
reaction of the lower respiratory tract include cough, shortness of breath, wheezing, and
chest pain. An asthmalike reaction occurs with acute exposures in sensitized patients.
Hypersensitivity pneumonitis characterized by chest pain, cough, dyspnea, &
bronchospasm may occur in an individual chronically exposed. /Pyrethrum and synthetic
pyrethroids/
The low toxicity of pyrethroids in mammals is due largely to their rapid
biotransformation by ester hydrolysis and/or hydroxylation. /Pyrethroids/
Skin, Eye and Respiratory Irritations:
Immediately irritating to the eye. /Pyrethrins/
The chief effect from exposure ... is skin rash particularly on moist areas of the
skin. ... May irritate the eyes. /Pyrethroids/
Medical Surveillance:
Initial medical screening: Employees should be screened for history of certain medical
conditions ... which might place the employee at increased risk from /pyrethroid/
exposure. Chronic respiratory disease: In persons with chronic respiratory disease,
especially asthma, the inhalation of /pyrethroids/ might cause exacerbation of symptoms
due to its sensitizing properities. Skin disease: /Pyrethroids/ can cause dermatitis which
may be allergic in nature. Persons with pre-existing skin disorders may be more
susceptible to the effects of this agent. Any employee developing the above-listed
conditions should be referred for further medical examination. /Pyrethrum/
Probable Routes of Human Exposure:
NIOSH (NOES Survey 1981-1983) has statistically estimated that 9,244 workers (1,759 of
these are female) are potentially exposed to tetramethrin
in the US(1). The NOES Survey does not include farm workers. Occupational exposure to tetramethrin may occur through inhalation of dust
particles and dermal contact with this compound at workplaces where tetramethrin
is produced or used(SRC).
Emergency Medical Treatment:
Emergency Medical Treatment:
| EMT Copyright Disclaimer: |
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reference. THE COMPLETE POISINDEX(R) DATABASE, AVAILABLE FROM MICROMEDEX, SHOULD BE
CONSULTED FOR ASSISTANCE IN THE DIAGNOSIS OR TREATMENT OF SPECIFIC CASES. Copyright
1974-1998 Micromedex, Inc. Denver, Colorado. All Rights Reserved. Any duplication,
replication or redistribution of all or part of the POISINDEX(R) database is a violation
of Micromedex' copyrights and is strictly prohibited. The following Overview, *** PYRETHRINS ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted.
|
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o The mammalian toxicity of natural pyrethrins is
generally low. Very young children are perhaps more
susceptible to poisoning because they may not hydrolyze
the pyrethrum esters efficiently. In humans, allergic
reactions are the main toxic manifestations of
pyrethrin exposure.
1. Pyrethrum and the pyrethrins produce typical type I
motor symptoms in mammals. Severe type I poisoning
may include the following signs in humans:
Severe fine tremor
Marked reflex hyperexcitability
Sympathetic activation
Paresthesia (dermal exposure)
o DERMAL - These compounds are not primary irritants.
The chief effect, however, from exposure is dermatitis.
The usual lesion is a mild erythematous dermatitis with
vesicles, papules in moist areas, and intense pruritus;
a bulbous dermatitis may also occur. Pyrethrins can
cause allergic dermatitis and systemic allergic
reactions.
o INHALATION is the major route of exposure, with airway
irritation as the primary toxic effect. Following
inhalation, a stuffy, runny nose and scratchy throat
are common. Hypersensitivity reactions including
wheezing, sneezing, shortness of breath and
bronchospasm may be noted.
o OCULAR - Eye exposures may result in mild to severe
corneal damage that generally resolves with
conservative care.
o Piperonyl butoxide and other compounds are often added
to pyrethrin insecticides as synergists and may
contribute to toxicity.
o Synthetic pyrethroids, which are related to pyrethrins,
are covered in a separate management.
HEENT
0.2.4.1 ACUTE EXPOSURE
o A stuffy, runny nose and scratchy throat following
inhalational exposure may be noted.
o Eye exposures may result in mild to severe corneal
damage, decreased visual acuity and periorbital edema.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Hypotension and tachycardia, associated with
anaphylaxis, may occur.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Hypersensitivity reactions characterized by
pneumonitis, cough, dyspnea, wheezing, chest pain, and
bronchospasm may occur. Rare cases of respiratory
failure and cardiopulmonary arrest have been reported.
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Paresthesias, headaches, and dizziness are common.
Massive exposure may result in hyperexcitability and
seizures, but this is rare.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Nausea, vomiting and abdominal pain commonly occur and
develop within 10 to 60 minutes following ingestion.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Irritant and contact dermatitis may develop. Erythema
which mimics sunburn has also been noted after
prolonged repeated exposure.
ENDOCRINE
0.2.16.1 ACUTE EXPOSURE
o Type I motor symptoms following severe poisoning may
result in sympathetic activation.
IMMUNOLOGIC
0.2.19.1 ACUTE EXPOSURE
o Sudden bronchospasm, swelling of oral and laryngeal
mucous membranes, and anaphylactoid reactions have been
reported after pyrethrum inhalation. Hypersensitivity
pneumonitis characterized by cough, shortness of
breath, chest pain, and bronchospasm may be noted.
GENOTOXICITY
o Pyrethrum is not mutagenic in bacterial reversion tests
(Ray, 1991).
|
| Laboratory: |
o Pyrethrin plasma levels are not clinically useful or
readily available.
o Monitor for allergic responses such as asthma or contact
dermatitis.
|
| Treatment Overview: |
ORAL EXPOSURE
o There is no specific antidote for pyrethrin poisoning.
Treatment is symptomatic and supportive and includes
monitoring for the development of hypersensitivity
reactions with respiratory distress. Provide adequate
airway management when needed. Gastric decontamination
is usually not required unless the pyrethrin product is
combined with a hydrocarbon.
o ALLERGIC REACTION: MILD: antihistamines with or
without epinephrine. SEVERE: oxygen, aggressive
airway management, antihistamines, epinephrine (ADULT:
0.3 to 0.5 mL of a 1:1000 solution subcutaneously;
CHILD: 0.01 mL/kg; may repeat in 20 to 30 min),
corticosteroids, ECG monitoring, and IV fluids.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
EYE EXPOSURE
o DECONTAMINATION: Irrigate exposed eyes with copious
amounts of tepid water for at least 15 minutes. If
irritation, pain, swelling, lacrimation, or photophobia
persist, the patient should be seen in a health care
facility.
DERMAL EXPOSURE
o DECONTAMINATION: Remove contaminated clothing and wash
exposed area thoroughly with soap and water. A
physician may need to examine the area if irritation or
pain persists.
o Vitamin E topical application is highly effective in
relieving paresthesias.
|
| Range of Toxicity: |
o The minimal lethal dose of pyrethrum is not established,
but is probably in the range of 10 to 100 grams.
o Hypersensitivity reactions may be noted, especially
following a chronic dermal or inhalation exposure.
Patients with underlying asthma may be predisposed to
severe bronchospastic reactions after exposure.
|
Antidote and Emergency Treatment:
Treatment is supportive, and most casual exposures require only decontamination.
Topical vitamin E may ameliorate the paresthesias that accompany contact with synthetic
pyrethroids containing an alpha-cyano group (e.g., fenvalerate, cypermethrin,
flucythrinate). /Synthetic pyrethroids/
The additives (e.g. petroleum distillate), when present, represent a greater toxic
threat to the patient than the active ingredient itself. ... Emesis should not be induced
when petroleum distillate additives are present. ... The alert person with an intact gag
reflex & a sublethal pyrethrum ingestion without other toxic constituents may have
emesis induced by ipecac, followed by a saline cathartic & slurry of activated
charcoal. ... Pulmonary & allergic sequelae are treated symptomatically with airway
maintenance, oxygen, & ventilatory assistance as required. Standard drugs and
management protocols may be used for treatment of bronchospasm & anaphylaxis. Seizures
are treated with diazepam. /Pyrethrum and synthetic pyrethroids/
Basic treatment: . Establish a patent airway. Suction if necessary. Watch for signs of
respiratory insufficiency and assist ventilations if necessary. Administer oxygen by
nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary... . For
eye contamination, flush eyes immediately with water. Irrigate each eye continuously with
normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and
administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a
strong gag reflex, and does not drool. Administer activated charcoal ... . /Pyrethrins,
pyrethroids, and related compounds/
Advanced treatment: Consider orotracheal or nasotracheal intubation for air way control
in the patient who is unconscious. Monitor cardiac rhythm and treat arrhythmias if
necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/.
Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid
overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride
to assist eye irrigation ... . /Pyrethrins, pyrethroids, and related compounds/
Skin decontamination. Wash skin promptly with soap and water ... . If irritant or
paresthetic effects occur, obtain treatment by a physician. Because volatilization of
pyrethroids apparently accounts for paresthesia affecting the face, strenuous measures
should be taken (ventilation, protective face mask and hood) to avoid vapor contact with
the face and eyes. Vitamin E oil preparations (dL-alpha tocopheryl acetate) are uniquely
effective in preventing and stopping the paresthetic reaction. They are safe for
application to the skin under field conditions. Corn oil is somewhat effective, but
possible side effects with continuing use make it less suitable. Vaseline is less
effective than corn oil. Zinc oxide actually worsens the reaction. /Pyrethroids/
Eye contamination. Some pyrethroid compounds can be very corrosive to the eyes.
Extraordinary measures should be taken to avoid eye contamination. the eye should be
treated immediately by prolonged flushing of the eye with copious amounts of clean water
or saline. If irritation persists, obtain professional ophthalmologic care. /Pyrethroids/
Other treatments. Several drugs are effective in relieving the pyrethroid neurotoxic
manifestations observed in deliberately poisoned laboratory animals, but none has been
tested in human poisonings. Therefore, neither efficacy nor safety under these
circumstances is known. Furthermore, moderate neurotoxic symptoms and signs are likely to
resolve spontaneously if they do occur. /Pyrethroids/
Animal Toxicity Studies:
Non-Human Toxicity Excerpts:
Rats fed up to 2000 ppm in food for 3 months showed no toxic symptoms.
When tetramethrin (technical product) was
orally administered at dose levels of 0, 50, 150, or 500 mg/kg body weight per day to
pregnant Japanese white rabbits, (10 per group) on days 8-18 of pregnancy, a slight
transient decline in the body weight of the dams was noted in the middle of the treatment
period at 500 mg/kg. No adverse effects such as embryo lethality, inhibition of fetal
growth, or teratogenic action were observed at any dose level. The NOEL for teratogenicity
in rabbits was considered to be >500 mg/kg body weight per day.
Tetramethrin (technical product) was orally
administered (dose levels of 0, 100, 300, and 1000 mg/kg body weight per day) to Slc: SD
rats (SPF, 20 per group) from day 17 of gestation to day 21 of lactation (perinatal and
postnatal period). In dams, a liver weight increase was noted at 300 and 1000 mg/kg but
there were no abnormalities at delivery or during lactation. Tetramethrin
had no detectable effects on the survival rate of pups, growth and development, sensory
function, motor function, learning ability, or reproductive ability. The NOEL was
considered to be 100 mg/kg body weight per day for dams and >1000 mg/kg body weight per
day for pups.
The induction of unscheduled DNA synthesis in human amnion FL cells by tetramethrin (72% industrial grade of unknown origin)
/was reported/. The same product gave weakly positive results in an Ames test with
Salmonella typhimurium TA 97. It is not clear if the effect was caused by tetramethrin itself or by the unidentified (28%)
portion of the industrial grade material.
Tetramethrin (techanical product) was orally
administered (dose levels of 0, 100, 300, and 1000 mg/kg body weight per day) to 6 wk old
male Slc:SD rats (SPF, 20 per group) for not less than 9 weeks and to 9-week-old females
(20 per group) for 2 weeks of the non-pregnant period and up to day 7 of pregnancy. The
effects of the material on the mating ability of male and female animals and on the
fetuses were investigated. In males, the liver weight increased at all dose levels and a
kidney weight increased was noted at 1000 mg/kg. Salivation and a slower body weight
increase were observed during the latter half of the administration period at 300 and 1000
mg/kg. However, no effects on the reproductive ability of males were noted. In females, no
changes were observed in the rate of pregnancy, but there were effects on the sexual cycle
and an ovulation-inhibiting effect at 1000 mg/kg. In fetuses, growth inhibition was
suspected at 1000 mg/kg. However, all these changes were slight. The NOEL was considered
to be 300 mg/kg body weight per day for reproductive ability of parents and growth of
fetuses.
When tetramethrin (technical product, 93.3%
purity) was fed daily to B6C3F1 mice (dose levels of 0, 12, 60, 300, or 1500 mg/kg diet)
for 104 weeks, there were no significant dose-related changes in survival, clinical signs,
mean body weight, or food consumption. However, the mortality of male mice at 300 mg/kg
was significantly lower than that of control males. The absolute and relative weight of
pituitary and thyroid/parathyroid glands was decreased for males fed 60 mg/kg diet or
more. Absolute spleen weights were also decreased for males fed 300 mg/kg diet or more.
However, gross and microscopic examination of these tissues did not reveal any
treatment-related histomorphological changes. There were no other histopathological
findings attributable to tetramethrin
administration. The NOEL was considered to be 12 mg/kg diet.
When tetramethrin (technical grade) was
administered to Sprague-Dawley CRCDR rats (50 of each sex per group, F1A weanlings from
parental animals pre-treated with the compound at dose levels of 1000, 3000, and 6000
mg/kg diet) at dose levels of 0, 1000, or 5000 mg/kg diet for weeks, no compound- related
effects were detected in investigations of appearance, behavior, survival, hematology,
blood chemistry, urinalysis, eye examination, and organ weight at up to 5000 mg/kg diet.
However, the body weight gain of male and female rats fed 3000 mg/kg or more was
significantly lower than that of controls. The incidence for testicular cell tumors was
increased at dose levels of 3000 mg/kg or more.
Tetramethrin (technical grade, 90.0/93.6%
purity) was tested for long-term toxic effects and tumorigenic potential in Sprague-Dawley
CRCDR and Long-Evans hooded rats by in utero exposure and 104-week chronic exposure at
dose levels of 0, 200, 1000, and 5000 mg/kg diet. No distinct compound-related effects
were observed in either strain with regard to fertility rate, mortality, clinical signs,
and clinical laboratory data. However, body weight gains were significantly lower in both
strains at 5000 mg/kg diet, and absolute and relative liver weights were increased in both
strains at 5000 mg/kg diet. The incidence of interstitial cell tumors in both strains at
5000 mg/kg diet was above the level in the concurrent control groups.
Hartley male guinea pigs, 0.5 ml [1R,cis/trans]-tetramethrin
(technical product, 95.6% purity) in 0.5 ml acetone was applied topically by lint patch to
the back of animals ten times (three times per week). The animals were challenged in the
same manner 2 weeks after the last sensitizing treatment, but no allergic reactions were
observed 24 hr later.
When 0.5 ml [1R,cis/trans]-tetramethrin
(technical grade, 95.6% purity) was applied on a lint patch (2.5 x 2.5 cm) to abraded or
intact skin on the back of rabbits, again no irritating reactions such as erythema and
edema were observed.
Half gram of the technical product (91.3% purity) was applied on a lint patch (3.8 x
3.8 cm) to the abraded or intact skin of six rabbits. The skin was assessed for severity
of erythema and edema 4, 24, 48, 72 hr and 7, 14, and 21 days after application but no
particular changes were noted.
In a skin-sensitization study of tetramethrin
in guinea-pigs, Hartley male guinea pigs (seven per group) were /treated/ ten times at
intervals of one or two days by intracutaneous injections (first injection: 0.05 ml,
subsequent ones: 0.1 ml) of a 1% solution of the technical product (91.3% purity) in corn
oil. The /treated/ animals were then challenged against the same concentration in the same
manner (0.5 ml injection) 14 days later, but no skin sensitization reaction was noted.
0.1 Ml [1R,cis/trans]-tetramethrin (technical
grade, 95.6% purity) was applied to one eye of Japanese albino rabbits. The treated eye
was subsequently washed in five rabbits but not in three other rabbits. The material did
not produce any lesions in the cornea or iris of the treated eyes that were not washed,
but slight hyperemia and/or chemosis of the conjunctiva was observed 1 hr after
application In the washed eyes, slight hyperemia of the conjunctiva was observed in all
animals 1 hr after treatment. These changes, however, had disappeared by 48 h after
application in the unwashed eyes and 24 hr in the washed eyes. The irritating potency of
the material was judged to be minimal in the unwashed eyes and negative in the washed
eyes.
In a study 50 mg of the technical product (91.3% purity) was instilled in one eye of
Japanese albino male rabbits. The treated eye was washed with distilled water 5 min (group
I) or 24 hr (group II) thereafter. The conjunctiva, cornea, and pupil were examined, 1,
24, 72 hr and 7, 14, and 21 days after application. No particular changes were noted
except that a very slight erythema and edema of the conjunctiva was transiently observed
in the rabbits in group II.
The toxic symptoms observed following [1R,cis/trans]-tetramethrin
administration were hyperexcitability, muscle twitching, tremor, ataxia, irregular
respiration, and depression. Mice were invariably more susceptible than rats. No
differences in susceptibility were observed between male and female animals.
Neither tetramethrin nor its 1R,cis/trans
isomers were mutagenic in a variety of in vivo and in vitro test systems, which
investigated gene mutations, DNA damage, DNA repair, and chromosomal effects.
The no-observed-effect level in a 26-week study in dogs was 1250 mg/kg diet.
When rats were fed tetramethrin at dietary
levels of up to 5000 mg/kg diet for 91 days, reduced body weight gain was observed at 5000
mg/kg diet. The results from 3 or 6 month feeding studies using the 1R, cis/trans isomer
in rats at dietary levels ranging from 25 mg/kg diet to 3000 mg/kg diet indicated that the
no-observed-effect level was 200 mg/kg diet for males and 300 mg/kg diet for females
(observations included decreases in the body weight gain and in final body weight, and
effect on the kidney and liver). The effects on the liver were thought to be an adaptive
response to the feeding of the corn oil vehicle.
When mice and rats were exposed to aerosolized tetramethrin
by inhalation at a concentration of 200 mg/cu m for 3-4 h/day for up to 4 weeks, no
significant compound related changes were observed. An additional inhalation study, in
which rats were exposed to a mist (1.2-1.5 um diameter droplets) of 1R,cis/trans isomer in
deodorized kerosene at concentrations up to 87 mg/cu m, 3 hr/day, 7 days/week for 28 days,
indicated a no-observed-effect level of 49 mg/cu m. Toxic signs were noted only during the
exposure period.
In 13 wk feeding trials, dogs receiving 5000 mg/kg diet showed no ill effects. In 6 mo
feeding trials, no-effect level for rats was 1500 mg/kg diet.
Non-irritant to skin.
The type I pyrethroids /including tetramethrin/
produce the simplest poisoning syndrome & produce sodium tail currents with relatively
short time constants. Poisoning closely resembles that produced by DDT & involves a
progressive development of fine whole-body tremor, exaggerated startle response,
incoordinated twitching of the dorsal muscles, hyperexcitability, & death. The tremor
is associated with a large incr in metabolic rate & leads to hyperthermia, which, with
metabolic exhaustion, is the usual cause of death. Respiration & blood pressure are
well sustained but plasma noradrenaline, lactate, & to a lesser extent adrenaline are
greatly increased.
Tetramethrin (technical grade) was
administered to Sprague-Dawley rats at dose levels of 0, 1000, 3000, and 6000 mg/kg diet
for 9 weeks through weaning of the F1A generation. Body weight reduction occurred at 6000
mg/kg diet in the parent rats. The lactation index was depressed for the F1A generation at
6000 mg/kg diet, and the weaning body weights for both sexes of the F1A generation were
reduced at doses of 3000 mg/kg diet or more. There were no other compound-related adverse
effects. The NOEL was considered to be 1000 mg/kg diet.
(1R,cis/trans)-tetramethrin (technical
product, 93.4% purity) was administered at dose levels of 0, 100, 500, and 3000 mg/kg diet
to two successive generations of Sprague-Dawley CDR albino rats to determine the effects
on growth and reproductive performance. The body weights of parental females were
significantly lower during the pre-mating growth, gestation, lactation, and post-weaning
periods, and the body weight of offspring of both generations decreased during lactation
at 3000 mg/kg diet. Slight bile duct hyperplasia was noted in F1 females sacrificed after
a 30 day feeding period following weaning of the F2 offspring at 3000 mg/kg diet. This
was, however, a commonly observed change in old rats. Thus, tetramethrin
did not affect the reproductive performance of male and female rats in two successive
generations at up to 500 mg/kg diet.
Groups of 10-15 pregnant New Zealand white rabbits received tetramethrin
orally on days 6-18 of gestation at doses of 0, 30, or 90 mg/kg per day. Fetuses were
obtained by caesarean section prior to parturition and were examined for external and
skeletal abnormalties. Seven extra pregnant animals were allowed to give birth naturally
and the pups were examined for several weeks to check their growth and development. No
significant adverse effects were observed.
Non-systemic insecticide with contact action. Gives rapid knockdown.
Synthetic pyrethroids have been shown to be toxic for fish, aquatic arthropods, and
honeybees in laboratory tests. But, in practical usage, no serious adverse effects have
been noticed because of the low rates of application and lack of persistence in the
environment. The toxicity of synthetic pyrethroids in birds and domestic animals is low.
/Synthetic pyrethroids/
The in vitro effects of pyrethroids on the mitogenic responsiveness of murine splenic
lymphocytes to concanavalin A and lipopolysaccharide were determined. Allethrin was the
most potent inhibitor, with effective concn in the range of 1X10-6 to 1.5X10-5 M. The
results support the possibility of immune suppression by pyrethroid exposure.
/Pyrethroids/
The Type I poisoning syndrome or "T syndrome" is produced by esters lacking
the alpha-cyano substituent and is characterized by restlessness, incoordination,
prostration, and paralysis in the cockroach, ascompared to the rat, which exhibits such
signs as sparring and aggressive behavior, enhanced startle response, whole body tremor,
and prostration. /Pyrethroid esters lacking the alpha-cyano substituent/
Non-Human Toxicity Values:
LD50 Mouse oral >20,000 mg/kg
LD50 Mouse dermal >15,000 mg/kg
LD50 Rat oral >20 g/kg
LD50 Mouse (male) sc 2020 mg/kg /1R,cis/trans)-/
LD50 Mouse (female) sc 1950 mg/kg /(1R,cis/trans)-/
LD50 Mouse (male) ip 631 mg/kg /(1R,cis/trans)-/
LD50 Mouse (female) ip 527 mg/kg /(1R,cis/trans)-/
LD50 Rat oral 4600 mg/kg /Racemic/
LD50 Rat dermal >10,000 mg/kg /Racemic/
LD50 Mouse (male) oral (animals not fasted, corn oil vehicle) 1920 mg/kg /Racemic/
LD50 Mouse (female) oral (animals not fasted, corn oil vehicle) 2000 mg/kg /Racemic/
LD50 Rat sc >5000 mg/kg /(1R,cis/trans)-/
LD50 Rat (male) ip 770 mg/kg /(1R,cis/trans)-/
LD50 Rat (female) ip 548 mg/kg /(1R,cis/trans)-/
LD50 Mouse (male) oral (animals not fasted) 1060 mg/kg /(1R,cis/trans)-/
LD50 Mouse (female) oral (animals not fasted) 1040 mg/kg /(1R,cis/trans)-/
LD50 Rat oral >20 gm/kg
LD50 Mouse oral 5200 mg/kg
LD50 Albino rat male oral >4640 mg/kg
LD50 Rat percutaneous >5000 mg/kg
LC50 Rat inhalation >2.74 mg/l air/3 hr
Ecotoxicity Values:
LD50 Bobwhite quail oral >1000 mg/kg
LD50 Mallard duck oral >1000 mg/kg
LC50 Bluegill sunfish 0.021 mg/l/96 hr /Conditions of bioassay not specified/
LC50 Oryzias latipes (killifish) adult (static system @ 25 deg C) 0.2 mg/l/48 hr.
/Technical/
LC50 Oryzias latipes (killifish) adult 0.2 mg/l/48 hr at 25 deg C static bioassay
/(+)-trans/
LC50 Oryzias latipes (killifish) adult 0.5 mg/l/48 hr at 25 deg C static bioassay
/(+)-Cis/
LC50 Lepomis macrochirur (Bluegill sunfish) 0.019 mg/l/96 hr /Conditions of bioassay
not specified/
LC50 Salmo gairdneri (Rainbout trout) 0.021 mg/l/96 hr /Conditions of bioassay not
specified/
LC50 Dapnia pulex (static system @ 25 deg C) >50 mg/l/3 hr /Technical/
LC50 Dapnia pulex (static system @ 25 deg C) > 50 mg/l/3 hr /(+)-trans/
LC50 Dapnia pulex (static system @ 25 deg C) > 50 mg/l/3 hr /(+)-cis/
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
In mammals, the principal metabolite is 3-hydroxycyclohexan-1,2-dicarboximide
Acetone powder preparations of milkweed bugs, cockroaches, houseflies, cabbage loopers
(Trichoplusia ni Hubner) and yellow mealworms (Tenebrio molitor L.) hydrolyzed both
(+)-trans- and (+)-cis-isomers of tetramethrin.
Of these two isomers, the (+)- trans-isomer was cleaved more rapidly.
When phthalthrin was applied topically to
houseflies, chromatography of extracts indicated the presence of chrysanthemic acid and
N-hydroxymethyltetrahydrophthalimide. Three other compounds were not identified.
When alcohol- or acid-labelled [1RS,trans]-tetramethrin
(1 mmol/litre) was incubated for 1 h at 37 deg C with 30 mg protein of a rat liver
subcellular fraction (i.e. nuclei plus mitochondria, microsomes, and soluble fraction),
the microsomes and nuclei plus mitochondria fractions were active in degrading tetramethrin. Rat microsomal fraction degraded
[1R,trans]-tetramethrin to crysanthemic acid,
N-(hydroxymethyl)-3,4,5,6-tetrahydrophthalimide, and 3,4,5,6-tetrahydrophthalimide in the
absence of NADPH. In the presence of NADPH, tetramethrin
was more rapidly degraded to yield oxidized tetramethrin
(wt-alc-, wt-ald-, and wt-acid-tetramethrin),
oxidized chrysanthemic acid (wt-alc-, wt-ald-, and wt-acid-chyrsanthemic acid),
3,4,5,6-tetrahydrophthalimide, and unidentified metabolites in larger amounts. The major
metabolite 3,4,5,6-tetrahydrophthalimide was shown to be produced non-enzymatically from
N-(hydroxymethyl)-3,4,5,6-tetrahydrophthalimide. The degradation rate of tetramethrin
was greatly reduced by the inhibition of ester hydrolysis with paraoxon.
Although both cis to trans and trans to cis isomerizations of tetramethrin
were observed, cis to trans conversion seemed to be predominant. On the other hand, the
detected metabolites from the alcohol moiety were 3,4,5,6-tetrahydrophthalimide,
cyclohexane-1,2-dicharboximide, 3-hydroxy-3,4,5,6-tetrahydrophthalimide,
3,4,5,6-tetrahydrophthalic acid amide, 2-hydroxy-cyclohexane-1,2-dicarboximide,
3-hydroxy-cyclohexane-1,2-dicarboximide, and 4-hydroxy-cyclohexane-1,2-dicarboximide. Of
these metabolites, 2-hydroxy- cyclohexane-1,2-dicarboximide was found in relatively large
amounts.
Following a single oral or subcutaneous administration to Sprague-Dawley rats of
[1R,trans]- or [1R,cis]-tetramethrin, labelled
with (14)C in the acid or alcohol moieties at concentrations of 3.2-5.3 mg/kg, ... the
major metabolic reactions of both [1R,trans]- and [1R,cis]-tetramethrin
were ester cleavage, loss of the hydroxymethyl group from the alcohol moiety, reduction of
the 1-2 bound of the alcohol moiety, and oxidation at the isobutenyl group of the acid
moiety and at the 2-, 3-, and 4-positions of the alcohol moiety. The metabolites produced
via these reactions were in part conjugated with glucuronic acid. None of the trans isomer
remained unmetabolized, whereas 0.3-1.2% of the cis isomer was found unchanged in the
feces. The major metabolites from the acid moiety of both isomers were chrysanthemic acid
and its derivatives oxidized at the trans-methyl of the isobutenyl group.
3-(2'-E-Carboxy-1'-propenyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid, (wt-acid-t,c-CA)
accounted for 17-27% and 7-9% of the dose of the trans and cis isomers, respectively.
Other significant metabolites were
3-(2'-E-hydroxymethyl-1'-propenyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid
(wt,alc-t,c-CA), 3-(2'-Z-carboxy-1'-propenyl)-2,2-dimethyl-1- cyclopropanecarboxylic acid
(wc-acid-t,c,-CA), and 3-(2'-Z-hydroxymethyl-1'-
propenyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid (wc-alc-t,c-CA).
3,4,5,6-Tetrahydrophthalimide readily underwent the Micheal addition with thiols. The tetramethrin-glutathione conjugate was formed under
physiological conditions in the presence of mouse liver homogenate fractions, probably by
a non-enzymatic reaction. The soluble thiol level of mouse liver was decreased by
intraperitoneal administration of 3,4,5,6-tetrahydrophthalimide. However, mercapturic acid
and GSH conjugates of tetramethrin were not
detected in the bile or urine of rats or mice treated intraperitoneally with tetramethrin.
The relative resistance of mammals to the pyrethroids is almost wholly attributable to
their ability to hydrolyze the pyrethroids rapidly to their inactive acid & alcohol
components, since direct injection into the mammalian CNS leads to a susceptibility
similar to that seen in insects. Some additional resistance of homeothermic organisms can
also be attributed to the negative temperature coefficient of action of the pyrethroids,
which are thus less toxic at mammalian body temperatures, but the major effect is
metabolic. Metabolic disposal of the pyrethroids is very rapid, which means that toxicity
is high by the iv route, moderate by slower oral absorption, & often unmeasureably low
by dermal absorption. /Pyrethroids/
FASTEST BREAKDOWN IS SEEN WITH PRIMARY ALCOHOL ESTERS OF TRANS-SUBSTITUTED ACIDS SINCE
THEY UNDERGO RAPID HYDROLYTIC & OXIDATIVE ATTACK. FOR ALL SECONDARY ALCOHOL ESTERS
& FOR PRIMARY ALCOHOL CIS-SUBSTITUTED CYCLOPROPANECARBOXYLATES, OXIDATIVE ATTACK IS
PREDOMINANT. /PYRETHROIDS/
Synthetic pyrethroids are generally metabolized in mammals through ester hydrolysis,
oxidation, and conjugation, and there is no tendency to accumulate in tissues. In the
environment, synthetic pyrethroids are fairly rapidly degraded in soil and in plants.
Ester hydrolysis and oxidation at various sites on the molecule are the major degradation
processes. /Synthetic pyrethroids/
Absorption, Distribution & Excretion:
Following a single oral or subcutaneous admin to Sprague-Dawley rats of [1R,trans]- or
[1R,cis]-tetramethrin, labelled with (14)C in
the acid or alcohol moieties at concn of 3.2-5.3 mg/kg, the radiocarbon was rapidly &
almost completely eliminated from the rat body. The total recoveries 7 days after admin
were 93-97% for the trans isomer & 90-101% for the cis isomer (approx equal amounts
being eliminated in urine & feces). In the cases of the oral dose of acid-labelled tetramethrin, 1-3% of the radiolabel was excreted as
(14)CO2, whereas in other cases (14)CO2 accounted for <1% of the dose. The tissue
residue 7 days after admin was very low. The trans isomer yielded somewhat more complete
radiolabel recovery & lower tissue residues than the cis isomer. In addtn, acid
labelling resulted in slightly lower tissue residues than did alcohol labelling. However,
there were no significant differences, according to sex or admin route, in the total
radiocarbon recoveries & tissue residue levels.
Tetramethrin is readily absorbed &
excreted by rats. Following a single oral admin of [1RS,trans]-tetramethrin,
labelled with (14)C at the carbonyl group of the alcohol moiety, to male Wistar rats at a
concn of 500 mg/kg, 47% & 42% of the radiolabel were excreted into the urine &
feces, respectively, during the subsequent 2 days & 95% was recovered during the 5 day
period that followed dosing. The tissue levels during the first 2 days after admin were
very low & the tetramethrin content in
tissues was <0.01% of the dosed radioactivity. Unmetabolized trans-tetramethrin
was not excreted into the urine, & the major metabolite was
3-hydroxy-cyclohexane-1,2-dicarboximide in free & glucuronide forms.
N-(Hydroxymethyl)-3,4,5,6-tetrahydrophthalimide, & cyclohexane-1,2-dicarboximide were
identified as minor urinary & fecal metabolites.
1. The toxicokinetics of cis- & trans-tetramethrin
isomers were investigated using the isolated perfused rat liver preparation. 2. The concn
of cis- & trans-tetramethrin decr rapidly in
the plasma perfusate & was initially replaced by
N-(hydroxymethyl)3,4,5,6-tetrahydrophthalimide & then by
3,4,5,6-tetrahydrophthalimide. Plasma perfusate concn of the intact cis-isomer were higher
than those of the trans-isomer. Concn of N-(hydroxymethyl)3,4,5,6-tetrahydrophthalimide
& 3,4,5,6-tetrahydrophthalimide were higher in livers treated with the trans-isomer.
3. Tetramethrin & its metabolites were
rapidly excreted in the bile. Bile from livers perfused with trans-isomer contained higher
concn of parent isomer & metabolites N-(hydroxymethyl)3,4,5,6-tetrahydrophthalimide
& 3,4,5,6-tetrahydrophthalimide, than did bile from livers treated with the
cis-isomer.
Bile collected from rats treated by iv injection with (14)C labeled isomers of the
pyrethroid insecticide tetramethrin /was
analyzed/. For both the cis & trans isomers, the excretion of radioactivity into the
bile was rapid; 25% of the admin radioactivity was excreted within 1 hr of dosing. Within
an 8 hr period, approximately 41% of the admin dose of either isomer was excreted in the
bile. Tetramethrin isomers & their
metabolites were also rapidly excreted in bile in isolated perfused rat liver studies ...
& accounted for approximately 18% of the admin radioactivity with 15 min. 3 hr after
admin of the tetramethrin isomer to the
reservoir of the isolated perfused rat liver system, 41% of the admin radioactivity was
excreted in bile.
In rats, following oral admin, around 95% of tetramethrin
(metabolized) is eliminated in the urine and feces within 5 days.
/PYRETHROIDS/ READILY PENETRATE INSECT CUTICLE AS SHOWN BY TOPICAL LD50 TO PERIPLANETA
(COCKROACH) ... /PYRETHROIDS/
WHEN RADIOACTIVE PYRETHROID IS ADMIN ORALLY TO MAMMALS, IT IS ABSORBED FROM INTESTINAL
TRACT OF THE ANIMALS & DISTRIBUTED IN EVERY TISSUE EXAMINED. EXCRETION OF
RADIOACTIVITY IN RATS ADMIN TRANS-ISOMER: DOSAGE: 500 MG/KG; INTERVAL 20 DAYS; URINE 36%;
FECES 64%; TOTAL 100%. /PYRETHROIDS/
Rats /were/ treated by iv injection with C-labeled isomers of the pyrethroid
insecticide tetramethrin. For both the cis &
trans isomers, the excretion of radioactivity into the bile was rapid; 25% of the admin
radioactivity was excreted with in 1 hr of dosing. Within an 8 hr period, approx 41% of
the admin dose of either isomer was excreted in the bile. Tetramethrin
isomers & their metabolites were also rapidly excrete in bile in isolated perfused rat
liver studies & accounted for approx 18% of the admin radioactivity with 15 min. Three
hr after admin of the tetramethrin isomer to the
reservoir of the isolated perfused rat liver system, 41% of the admin radioactivity was
excreted in bile.
Although limited absorption may account for the low toxicity of some pyrethroids, rapid
biodegradation by mammalian liver enzymes (ester hydrolysis and oxidation) is probably the
major factor responsible. Most pyrethroid metabolites are promptly excreted, at least in
part, by the kidney. /Pyrethroids/
Mechanism of Action:
Tetramethrin greatly prolongs the sodium
current during step depolarization and the sodium tail current associated with step
repolarization of the squid axon membrane. Non-linear current-voltage relationships for
the sodium tail current were analyzed to assess the open sodium channel properties, which
included the permeation of various cations, calcium block, and cation selectivity. Tetramethrin had no effect on any of these properties.
It was concluded that tetramethrin modifies the
sodium channel gating mechanism without affecting the pore properties.
1R,trans-Tetramethrin markedly prolongs the
open time of single sodium channels recorded by the gigaohmseal voltage clamp technique in
a membrane patch excised from the N1E-115 neuroblastoma cell. Single channel conductance
is not altered by tetramethrin. The modification
by tetramethrin occurs in an all or nothing
manner in a population of sodium channels. The observed tetramethrin-induced
modification of single sodium channels is compatible with previous sodium current data
from axons.
Analysis of the dose dependence of the two kinetic phases of tail current development
suggests that the apparent dissociation constant for 1R,trans-tetramethrin
depends on the conformational state of the channel. Thus, it can be concluded that tetramethrin binds to sodium channels and modifies the
state of the channel in the resting, open, or inactivated state.
In electrophysiological studies, tetramethrin
produced repetitive discharges in housefly muscle and uncoupling in motor units and caused
repetitive firing in cockroach cercal sensory nerves at a concentration of 3 x 10-13
mol/litre.
The effects of tetramethrin on the sodium
channel gating mechanism were studied using the squid giant axons under voltage clamp
conditions. Tetramethrin prolonged the falling
phase of sodium current during depolarization and increased and prolonged the tail current
associated with repolarization. The prolongation of the sodium current was due to the
channel remaining open. The channel returned slowly to the resting state upon
repolarization.
The synthetic pyrethroids delay closure of the sodium channel, resulting in a sodium
tail current that is characterized by a slow influx of sodium during the end of
depolarization. Apparently the pyrethroid molecule holds the activation gate in the open
position. Pyrethroids with an alpha-cyano group (e.g., fenvalerate) produce more prolonged
sodium tail currents than do other pyrethroids (e.g., permethrin, bioresmethrin). The
former group of pyrethroids causes more cutaneous sensations than the latter. /Synthetic
pyrethroids/
Interaction with sodium channels is not the only mechanism of action proposed for the
pyrethroids. Their effects on the CNS have led various workers to suggest actions via
antagonism of gamma-aminobutyric acid (GABA)-mediated inhibition, modulation of nicotinic
cholinergic transmission, enhancement of noradrenaline release, or actions on calcium
ions. Since neurotransmitter specific pharmacological agents offer only poor or partical
protection against poisoning, it is unlikely that one of these effects represents the
primary mechanism of action of the pyrethroids, & most neurotransmitter release is
secondary to incr sodium entry. /Pyrethroids/
The interaction of a series of pyrethroid insecticides with the sodium channels in
myelinated nerve fibers of the clawed frog, Xenopus laevis, was investigated using the
voltage clamp technique. Of 11 pyrethroids, 9 insecticidally active cmpd induced a slowly
decaying sodium tail current on termination of a step depolarization, whereas the sodium
current during depolarization was hardly affected. /Pyrethroids/
Mode of action of pyrethrum & related cmpd has been studied more in insects &
in other invertebrates than in mammals. This action involves ion transport through the
membrane of nerve axons &, at least in invertebrates & lower vertebrates, it
exhibits a negative temperature coefficient. In both of these important ways & in many
details, the mode of action of pyrethrin & pyrethroids resembles that of DDT.
Esterases & mixed-function oxidase system differ in their relative importance for
metabolizing different synthetic pyrethroids. The same may be true of the constituents of
pyrethrum, depending on strain, species, & other factors. /Pyrethrins and pyrethroids/
The primary target site of pyrethroid insecticides in the vertebrate nervous system is
the sodium channel in the nerve membrane. Pyrethroids without an alpha-cyano group
(allethrin, d-phenothrin, permethrin, and cismethrin) cause a moderate prolongation of the
transient increase in sodium permeability of the nerve membrane during excitation. This
results in relatively short trains of repetitive nerve impulses in sense organs, sensory
(afferent) nerve fibers, and, in effect, nerve terminals. On the other hand the
alpha-cyano pyrethroids cause a long lasting prolongation of the transient increase in
sodium permeability of the nerve membrane during excitation. This results in long-lasting
trains of repetitive impulses in sense organs and a frequency-dependent depression of the
nerve impulse in nerve fibers. The difference in effects between permethrin and
cypermethrin, which have identical molecular structures except for the presence of an
alpha-cyano group on the phenoxybenzyl alcohol, indicates that it is this alpha-cyano
group that is responsible for the long-lasting prolongation of the sodium permeability.
Since the mechanisms responsible for nerve impulse generation and conduction are basically
the same throughout the entire nervous system, pyrethroids may also induce repetitive
activity in various parts of the brain. The difference in symptoms of poisoning by
alpha-cyano pyrethroids, compared with the classical pyrethroids, is not necessarily due
to an exclusive central site of action. It may be related to the long-lasting repetitive
activity in sense organs and possibly in other parts of the nervous system, which, in a
more advance state of poisoning, may be accompanied by a frequency-dependent depression of
the nervous impulse. /Synthetic pyrethroids/
Pyrethroids also cause pronounced repetitive activity and a prolongation of the
transient increase in sodium permeability of the nerve membrane in insects and other
invertebrates. Available information indicates that the sodium channel in the nerve
membrane is also the most important target site of pyrethroids in the invertebrate nervous
system. /Synthetic pyrethroids/
Type I Pyrethroid esters /lacking the alpha-cyano substituents/ affect sodium channels
in nerve membranes, causing repetitive (sensory, motor) neuronal discharge and a prolonged
negative afterpotential, the effects being quite similar to those produced by DDT.
/Pyrethroid esters lacking the alpha-cyano substituent/
Interactions:
/Pyrethroid/ detoxification ... important in flies, may be delayed by the addition of
synergists ... organophosphates or carbamates ... to guarantee a lethal effect. ...
/Pyrethroid/
Piperonyl butoxide potentiates /insecticidal activity/ of pyrethrins by inhibiting the
hydrolytic enzymes responsible for pyrethrins' metabolism in arthropods. When piperonyl
butoxide is combined with pyrethrins, the insecticidal activity of the latter drug is
increased 2-12 times /Pyrethrins/
Pharmacology:
Therapeutic Uses:
Pyrethrins with piperonyl butoxide are used for topical treatment of pediculosis (lice
infestations). Combinations of pyrethrins with piperonyl butoxide are not effective for
treatment of scabies (mite infestations). Although there are no well-controlled
comparative studies, many clinicians consider 1% lindane to be pediculicide of choice.
However, some clinicians recommend use of pyrethrins with piperonyl butoxide, esp in
infants, young children, & pregnant or lactating women ... . If used correctly, 1-3
treatments ... are usually 100% effective ... Oil based (eg, petroleum distillate)
combinations ... produce the quickest results. ... For treatment of pediculosis, enough
gel, shampoo, or solution ... should be applied to cover affected hair & adjacent
areas ... After 10 min, hair is ... washed thoroughly ... treatment should be repeated
after 7-10 days to kill any newly hatched lice. /Pyrethrins/
Interactions:
/Pyrethroid/ detoxification ... important in flies, may be delayed by the addition of
synergists ... organophosphates or carbamates ... to guarantee a lethal effect. ...
/Pyrethroid/
Piperonyl butoxide potentiates /insecticidal activity/ of pyrethrins by inhibiting the
hydrolytic enzymes responsible for pyrethrins' metabolism in arthropods. When piperonyl
butoxide is combined with pyrethrins, the insecticidal activity of the latter drug is
increased 2-12 times /Pyrethrins/
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Tetramethrin's production and use as an
insecticide will result in its release to the environment. If released to air, a vapor
pressure of 7.1X10-6 mm Hg at 30 deg C indicates tetramethrin
will exist in both the vapor and particulate phase in the ambient atmosphere. Vapor-phase tetramethrin will be degraded in the atmosphere by
reaction with photochemically-produced hydroxyl radicals and ozone molecules. The
half-life for the reaction in air with hydroxyl radicals is estimated to be 3 hours. The
half-life for the reaction in air with ozone is estimated to be 30 minutes. Direct
photolysis may also be an important fate process for this compound based on a
photodegradation half-life of approximately 1 hour for tetramethrin
on glass films irradiated with a sunlamp. Particulate-phase tetramethrin
will be removed from the atmosphere by wet and dry deposition. If released to soil, tetramethrin is expected to have no mobility based
upon an estimated Koc of 8,900. Volatilization from moist soil surfaces may be an
important fate process based upon an estimated Henry's Law constant of 1.7X10-6 atm-cu
m/mole. However, adsorption to soil is expected to attenuate volatilization. Tetramethrin is not expected to volatilize from dry
soil surfaces based upon its vapor pressure. Although biodegradation data for tetramethrin are not available, the pyrethroid class
of insecticides is degraded readily by environmental microorganisms and based upon its
structure, tetramethrin is also expected to
degrade readily. If released into water, tetramethrin
is expected to adsorb to suspended solids and sediment based upon its estimated Koc.
Volatilization from water surfaces may be an important fate process based upon this
compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model
river and model lake are 26 and 290 days, respectively. However, volatilization from water
surfaces is expected to be attenuated by adsorption to suspended solids and sediment in
the water column. The volatilization half-life from a model pond is about 36 years when
adsorption is considered. An estimated BCF of 20 suggests the potential for
bioconcentration in aquatic organisms is low. Estimated hydrolysis half-lives are 2.5
years and 90 days at a pH of 7 and 8, respectively. Occupational exposure to tetramethrin may occur through inhalation of dust
particles and dermal contact with this compound at workplaces where tetramethrin
is produced or used. (SRC)
Probable Routes of Human Exposure:
NIOSH (NOES Survey 1981-1983) has statistically estimated that 9,244 workers (1,759 of
these are female) are potentially exposed to tetramethrin
in the US(1). The NOES Survey does not include farm workers. Occupational exposure to tetramethrin may occur through inhalation of dust
particles and dermal contact with this compound at workplaces where tetramethrin
is produced or used(SRC).
Artificial Pollution Sources:
Tetramethrin's production and use as an
insecticide(1) is expected to result in its release to the environment(SRC).
Environmental Fate:
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of
8,900(SRC), determined from a measured log Kow of 4.73(2) and a regression-derived
equation(3), indicates that tetramethrin is
expected to be immobile in soil(SRC). Volatilization of tetramethrin
from moist soil surfaces may be an important fate process(SRC) given an estimated Henry's
Law constant of 1.7X10-6 atm-cu m/mole(SRC), determined from its vapor pressure, 7.1X10-6
mm Hg at 30 deg C(4), and water solubility, 1.83 mg/l at 25 deg C(4). However, adsorption
to soil is expected to attenuate volatilization(SRC). Tetramethrin
is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of
7.1X10-6 mm Hg(4). Direct photolysis on soil surfaces may be an important fate process
based on a photolysis half-life of approximately 1 hour(7). Although biodegradation data
for tetramethrin are not available, the
pyrethroid class of insecticides is degraded readily by environmental microorganisms(5,6)
and based upon its structure, tetramethrin is
also expected to biodegrade readily(5,6).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of
8,900(SRC), determined from a measured log Kow of 4.73(2) and a regression-derived
equation(3), indicates that tetramethrin is
expected to adsorb to suspended solids and sediment(SRC). Volatilization from water
surfaces may be expected(3) based upon an estimated Henry's Law constant of 1.7X10-6
atm-cu m/mole(SRC), determined from its vapor pressure, 7.1X10-6 mm Hg at 30 deg C(4), and
water solubility, 1.83 mg/l at 25 deg C(4). Using this Henry's Law constant and an
estimation method(3), volatilization half-lives for a model river and model lake are 26
and 290 days, respectively(SRC). However, volatilization from water surfaces is expected
to be attenuated by adsorption to suspended solids and sediment in the water column.
Direct photolysis may be an important fate process in surface waters based on a photolysis
half-life of approximately 1 hour(5). According to a classification scheme(6), an
estimated BCF of 20(SRC), from its log Kow of 4.73(2) and a regression-derived
equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC).
Although biodegradation data for tetramethrin
are not available, the pyrethroid class of insecticides is degraded readily by
environmental microorganisms(8,9) and based upon its structure, tetramethrin
is also expected to biodegrade readily(8,9).
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile
organic compounds in the atmosphere(1), tetramethrin,
which has a vapor pressure of 7.1X10-6 mm Hg at 30 deg C(2), will exist in both the vapor
and particulate phases in the ambient atmosphere. Vapor-phase tetramethrin
is degraded in the atmosphere by reaction with photochemically-produced hydroxyl
radicals(SRC) and ozone molecules. The half-life for the reaction in air with hydroxyl
radicals is estimated to be 3 hours(SRC), calculated from its rate constant of 1.3X10-10
cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). The
half-life for the reaction in air with ozone molecules is estimated to be 30 minutes(SRC),
calculated from its rate constant of 5.0X10-16 cu cm/molecule-sec at 25 deg C(SRC)
determined using a structure estimation method. Direct photolysis is also expected to be
an important fate process based on a photolysis half-life of approximately 1 hour for tetramethrin on glass films irradiated with a
sunlamp(4). Particulate-phase tetramethrin may
be removed from the air by wet and dry deposition(SRC).
Environmental Biodegradation:
Although environmental biodegradation data specific to tetramethrin
are not available, the pyrethroid class of insecticides is degraded readily by
environmental microorganisms(1,2); based upon its structure, tetramethrin
is also expected to biodegrade readily(1,2).
Environmental Abiotic Degradation:
The rate constant for the vapor-phase reaction of tetramethrin
with photochemically-produced hydroxyl radicals has been estimated as 1.3X10-10 cu
cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds
to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5
hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of tetramethrin with ozone molecules has been estimated
as 5.0X10-16 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1).
This corresponds to an atmospheric half-life of about 30 minutes at an atmospheric
concentration of 7X10+11 ozone molecules per cu cm(2). A base-catalyzed second-order
hydrolysis rate constant of 0.088 L/mole-sec(SRC) was estimated using a structure
estimation method(3); this corresponds to half-lives of 2.5 years and 90 days at pH values
of 7 and 8, respectively(3). The photodegradation half-life of tetramethrin
on glass films exposed to a sunlamp was approximately 1 hour, with nearly 100%
photodecomposition observed after 15 hours of illumination(4). However, trifluralin was
found to stabilize tetramethrin to
photodecomposition; only 2% of applied tetramethrin
was photodecomposed from a silica gel plate after 18 hours of irradiation when trifluralin
was used(5).
Environmental Bioconcentration:
An estimated BCF of 20 was calculated for tetramethrin(SRC),
using a log Kow of 4.73(1) and a regression-derived equation(2). According to a
classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic
organisms is low(SRC).
Soil Adsorption/Mobility:
The Koc of tetramethrin is estimated as
8,900(SRC), using a measured log Kow of 4.73(1) and a regression-derived equation(2).
According to a classification scheme(3), this estimated Koc value suggests that tetramethrin is expected to be immobile in soil.
Volatilization from Water/Soil:
The Henry's Law constant for tetramethrin is
estimated as 1.7X10-6 atm-cu m/mole(SRC) based upon its vapor pressure, 7.1X10-6 mm Hg at
30 deg C(1), and water solubility, 1.83 mg/l at 25 deg C(1). This Henry's Law constant
indicates that tetramethrin may volatilize from
water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a
model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 26
days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec,
wind velocity of 0.5 m/sec)(2) is estimated as 290 days(SRC). However, volatilization from
water surfaces is expected to be attenuated by adsorption to suspended solids and sediment
in the water column. The estimated volatilation half-life from a model pond is 36 years if
adsorption is considered(3). Tetramethrin's
estimated Henry's Law constant indicates that volatilization from moist soil surfaces may
occur(SRC). Tetramethrin is not expected to
volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1).
Environmental Standards & Regulations:
FIFRA Requirements:
As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of
older pesticides to consider their health and environmental effects and make decisions
about their future use. Under this pesticide reregistration program, EPA examines health
and safety data for pesticide active ingredients initially registered before November 1,
1984, and determines whether they are eligible for reregistration. In addition, all
pesticides must meet the new safety standard of the Food Quality Protection Act of 1996.
Pesticides for which EPA had not issued Registration Standards prior to the effective date
of FIFRA, as amended in 1988, were divided into three lists based upon their potential for
human exposure and other factors, with List B containing pesticides of greater concern and
List D pesticides of less concern. Tetramethrin
is found on List B. Case No: 2660; Pesticide type: Insecticide; Case Status: OPP is
reviewing data from the pesticide's producers regarding its human health and/or
environmental effects, or OPP is determining the pesticide's eligibility for
reregistration and developing the Reregistration Eligibility Decision (RED) document.;
Active ingredient (AI): (1-Cyclohexene-1,2-dicarboximido)methyl
2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylate; Data Call-in (DCI) Date(s):
06/10/91, 10/13/95; AI Status: The producers of the pesticide has made commitments to
conduct the studies and pay the fees required for reregistration, and are meeting those
commitments in a timely manner.
Chemical/Physical Properties:
Molecular Formula:
C19-H25-N-O4
Molecular Weight:
331.41
Color/Form:
White crystalline solid
Colorless crystals
Odor:
Slight pyrethrum-like odor
Boiling Point:
180-190 deg C at 0.1 mm Hg
Melting Point:
68-70 deg C
Corrosivity:
Non-corrosive
Density/Specific Gravity:
1.108 @ 20 deg C/20 deg C
Octanol/Water Partition Coefficient:
log Kow = 4.73
Solubilities:
Methanol (53 g/kg), hexane (20 g/kg), xylene (1 g/kg), acetone, toluene.
In acetone, ethanol, methanol, hexane, n-octanol all >2 g/100 ml.
In water, 1.83 mg/l @ 25 deg C.
Spectral Properties:
Index of refraction: 1.5175 at 21.5 deg C/D
Intense mass spectral peaks: 79 m/z, 107 m/z, 123 m/z, 164 m/z.
Vapor Pressure:
7.1X10-6 mm Hg @ 30 deg C
Other Chemical/Physical Properties:
MP: 60-80 deg C /Technical/
Chemical Safety & Handling:
Skin, Eye and Respiratory Irritations:
Immediately irritating to the eye. /Pyrethrins/
The chief effect from exposure ... is skin rash particularly on moist areas of the
skin. ... May irritate the eyes. /Pyrethroids/
Fire Fighting Procedures:
Use carbon dioxide, foam, or dry chemical /on fires involving pyrethroids/. /Pyrethrum/
Fire-fighting: Self-contained breathing apparatus with a full facepiece operated in
pressure-demand or other positive-pressure mode. /Pyrethrum/
Hazardous Reactivities & Incompatibilities:
Incompatible with mineral carriers such as kieselguhr, acidic clays and kaolin.
Incompatibility: Strong oxidizers. /Pyrethrins/
... Incompatible with lime & ordinary soaps because acids & alkalies speed up
processes of hydrolysis. /Pyrethrins/
Hazardous Decomposition:
When heated to decomp it emits toxic fumes of /nitrogen oxides/.
Protective Equipment & Clothing:
Employees should be provided with and required to use dust- and splash-proof safety
goggles where /pyrethroids/ ... may contact the eyes. /Pyrethroids/
Employees should be provided with and be required to use impervious clothing, gloves,
and face shields (eight-inch minimum). /Pyrethroids/
Wear appropriate equipment to prevent: Repeated or prolonged skin contact. /Pyrethrum
and pyrethrins/
Wear eye protection to prevent: Reasonable probability of eye contact. /Pyrethrins/
Recommendations for respirator selection. Max concn for use: 50 mg/cu m: Respirator
Classes: Any chemical cartridge respirator with organic vapor cartridge(s) in combination
with a dust, mist, and fume filter. May require eye protection. Any supplied-air
respirator. May require eye protection. Any self-contained breathing apparatus. May
require eye protection. /Pyrethrins/
Recommendations for respirator selection. Max concn for use: 125 mg/cu m: Respirator
Classes: Any supplied-air respirator operated in a continuous flow mode. May require eye
protection. Any powered, air-purifying respirator with organic vapor cartridge(s) in
combination with a dust, mist, and fume filter. May require eye protection. /Pyrethrins/
Recommendations for respirator selection. Max concn for use: 250 mg/cu m: Respirator
Classes: Any chemical cartridge respirator with a full facepiece and organic vapor
cartridge(s) in combination with a high-efficiency particulate filter. Any self-contained
breathing apparatus with a full facepiece. Any supplied-air respirator with a full
facepiece. Any powered, air-purifying respirator with a tight-fitting facepiece and
organic vapor cartridge(s) in combination with a high-efficiency particulate filter. May
require eye protection. /Pyrethrins/
Recommendations for respirator selection. Max concn for use: 5,000 mg/cu m: Respirator
Class: Any supplied-air respirator with a full facepiece and operated in a pressure-demand
or other positive pressure mode. /Pyrethrins/
Recommendations for respirator selection. Condition: Emergency or planned entry into
unknown concn or IDLH conditions: Respirator Classes: Any self-contained breathing
apparatus that has a full facepiece and is operated in a pressure-demand or other positive
pressure mode. Any supplied-air respirator with a full face piece and operated in
pressure-demand or other positive pressure mode in combination with an auxiliary
self-contained breathing apparatus operated in pressure-demand or other positive pressure
mode. /Pyrethrins/
Recommendations for respirator selection. Condition: Escape from suddenly occurring
respiratory hazards: Respirator Classes: Any air-purifying, full-facepiece respirator (gas
mask) with a chin-style, front- or back-mounted organic vapor canister having a
high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing
apparatus. /Pyrethrins/
Preventive Measures:
Skin that becomes contaminated with /pyrethrum/ should be promptly washed or showered
with soap or mild detergent and water. /Pyrethrum/
Clothing contaminated with /pyrethrum/ should be placed in closed containers for
storage until provision is made for the removal of /pyrethrum/ from the clothing.
/Pyrethrum/
Respirators may be used when engineering and work practice controls are not technically
feasible, when such controls are in the process of being installed, or when they fail or
need to be supplemented. Respirators may also be used for operations which require entry
into tanks or closed vessels, and in emergency situations. /Pyrethrum/
Employees who handle /pyrethrum/ ... should wash their hands thoroughly with soap or
mild detergent and water before eating, smoking, or using toilet facilities. /Pyrethrum/
Avoid contact with skin. Keep out of any body of water. Do not contaminate water by
cleaning of equipment or disposal of waste. Do not reuse empty container. Destroy it by
perforating or crushing. /Pyrethrum/
Contact lenses should not be worn when working with this chemical. /Pyrethrins/
Workers should wash: Promptly when skin becomes contaminated. /Pyrethrins/
Work clothing should be changed daily: If it is reasonably probable that the clothing
may be contaminated. /Pyrethrins/
Remove clothing: Promptly if it is non-impervious clothing that becomes contaminated.
/Pyrethrins/
SRP: The scientific literature for the use of contact lenses in industry is
conflicting. The benefit or detrimental effects of wearing contact lenses depend not only
upon the substance, but also on factors including the form of the substance,
characteristics and duration of the exposure, the uses of other eye protection equipment,
and the hygiene of the lenses. However, there may be individual substances whose
irritating or corrosive properties are such that the wearing of contact lenses would be
harmful to the eye. In those specific cases, contact lenses should not be worn. In any
event, the usual eye protection equipment should be worn even when contact lenses are in
place.
Stability/Shelf Life:
Stable under normal storage and use.
Sensitive to alkalis and strong acids. Stable on storage up to ca 50 deg C. Stable in
ketones, chloroform, xylene, common aerosol propellant. Variable stability with inorganic
carriers.
Pyrethrins ... /are/ stable for long periods in water-based aerosols where ...
emulsifiers give neutral water systems. /Pyrethrins/
Storage Conditions:
Ventilate well. Store in closed drum in a cool, dry place.
Pyrethrins with piperonyl butoxide topical preparations should be stored in well-closed
containers at a temperature less than 40 deg C, preferably between 15-30 deg C.
/Pyrethrins/
Cleanup Methods:
Spillages of pesticides at any stage of their storage or handling should be treated
with great care. Liquid formulations may be reduced to solid phase by evaporation. Dry
sweeping of solids is always hazardous: these should be removed by vacuum cleaning, or by
dissolving them in water, or other solvent in the factory environment. /Pesticides/
Disposal Methods:
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill)
disposal practices are subject to significant revision. Prior to implementing land
disposal of waste residue (including waste sludge), consult with environmental regulatory
agencies for guidance on acceptable disposal practices.
Treatment and disposal methods: Open burning. Burn tetramethrin
in a shallow depression well away from any buildings, animals, or susceptible vegetation.
Recommendable methods: Incineration, ... . Peer review: Small amounts: Only well diluted
discharge to sewer. Large amounts: Incinerate in a unit with effluent gas scrubbing. (Peer
review conclusions of an IRPTC expert consultation May 1985).
Incineration would be an effective disposal procedure where permitted. ... /Pyrethrin
products/
Occupational Exposure Standards:
Manufacturing/Use Information:
Major Uses:
For Tetramethrin (USEPA/OPP Pesticide Code:
069003) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but
approved pesticide uses may change periodically and so federal, state and local
authorities must be consulted for currently approved uses./
Insecticide
MEDICATION
Methods of Manufacturing:
N-hydroxymethyl-3,4,5,6-tetrahydrophthalimide + (1RS)-cis/trans-chrysanthemic acid
(esterification)
General Manufacturing Information:
Available commercially as the racemic of (1R)-enriched product.
Synthetic pyrethroid compound developed in Japan.
It is a mixture of four stereoisomers. The cis:trans ratio is reported to be 1:4 and
optical ratio of 1R:1S is 1:1 (racemic). Thus its composition is roughly 4:1:4:1 for the
(1R,trans), (1R,cis), (1S,trans) and (1S,cis) isomers. The (1R,trans])isomer is the most
active biologically of the isomers, followed by the [1R,cis] isomer. Neo-Pynamin Forte is
a mixture of the (1R,cis,) and (1R,trans) isomers in the ratio of 1:4.
Potent synthetic pyrethroid insecticide.
The commercial product is a mixture of isomers.
Normally used in combination with synergists (eg piperonyl butoxide) and other
insecticides.
/Pyrethroids/ are modern synthetic insecticides similar chemically to natural
pyrethrins, but modified to increase stability in the natural environment. /Pyrethroids/
Formulations/Preparations:
USEPA/OPP Pesticide Code 069003; Trade Names: Neopynamin, Phthalthrin,
Evercide intermediate 2265 (069330+109301), ENT-27339.
Aerosol, oil liquid, emulsifiable concentrate.
Technical material 85% active ingredient. ... Oil based and water based sprays as well
as aerosol sprays made up of tetramethrin in
combination with piperonyl butoxide, resmethrin, methylated naphthalenes.
Aerosol dispenser; emulsidiable concentrate; dustable powder; ultra-low volume liquid;
oil; emulsion, oil in water
Mixtures: (tetramethrin +) resmethrin,
fenitrothion; piperonyl butoxide + pyrethrins; piperonyl butoxide + resmethrin;
phenothrin; permethrin; piperonyl butoxide; fenitrothion + lindane; permethrin + piperonyl
butoxide
Tech. is 92% pure
Laboratory Methods:
Analytic Laboratory Methods:
EAD Method 1660. The Determination of Pyrethrins and Pyrethroids in Municipal and
Industrial Wastewater by High-Performance Liquid Chromatography. Detection limit = 2.000
ug/l.
EPA-B Method PMD-TFK. Determination of Tetramethrin
and d-Phenothrin by Internal Standard Gas Chromatography.
FDA Method 212.1. Organochlorine Residues (Nonionic) General Method for Nonfatty Foods
Including Acetonitrile Extraction, Water/Acetonitrile Extraction, Aqueous Acetonitrile to
Petroleum Ether Transfer, and Florisil Column Cleanup.
... Liquid chromatography method has been developed to quantitate pyrethrins in
pesticide formulations. ... Detection was monitored at 240 nm. ... Percent coefficients of
variation ranged from 1.39 to 9.68 with the majority less than 5.00. ... /Pyrethrins/
Pyrethrins were detected in soils by gas chromatography after extraction with hexane.
/Pyrethrins/
Low level pyrethrin formulations are extracted with tetrahydrofuran and determined via
capillary gas chromatography with electron capture detection. ... Analysis of 5
formulations gave an average standard deviation of 3.3%. /Pyrethrins/
Special References:
Special Reports:
Miyamoto J; Environ Health Perspect 14: 15-28 (1976). Degradation, metabolism, and
toxicity of synthetic pyrethroids.
Miyamoto J, et al; Pure Appl Chem 53: 1967-2022 (1981). The chemistry, metabolism, and
residue analysis of synthetic pyrethroids.
Hutson DH; Progress in Drug Metabolism 3: 215-252 (1979). The metabolic fate of
synthetic pyrethroid insecticides in mammals.
Casida JE et al; Ann Rev Pharmacol Toxicol 23: 413-38 (1983). The mechanisms of
selective action of pyrethroid insecticide are discussed.
Papadopoulou-Mourkidou E; Residue Rev 89: 179-208 (1983). A review with many references
on analysis of allethrin & other pyrethroid insecticides.
Synonyms and Identifiers:
Synonyms:
N-(chrysanthemoxymethyl)-1-cyclohexene-1,2-dicarboximide
**PEER REVIEWED**
Cyclohex-1-ene-1,2-dicarboximidomethyl (1RS)-cis,trans-2,2-dimethyl-3-(2-
methylprop-1-enyl)cyclopropanecarboxylate
**PEER REVIEWED**
1-cyclohexene-1,2-dicarboximidomethyl-2,2-dimethyl-3-(2-methylpropenyl) cyclopropane
carboxylate
**PEER REVIEWED**
2,2-Dimethyl-3-(2-methyl-1-propenyl) cyclopropanecarboxylic acid (1,3,4,5,6,7-
hexahydro-1,3-dioxo-2H-isoindol-2-yl)methyl ester
**PEER REVIEWED**
2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylic acid ester with
N-(hydroxymethyl)-1-cyclohexene-1,2-dicarboximide
**PEER REVIEWED**
Pesticide Code 069003
**PEER REVIEWED**
FMC-9260
**PEER REVIEWED**
(1,3,4,5,6,7-hexahydro-1,3-dioxo-2H-isoindol-2-yl) methyl 2,2-dimethyl-3-(2-
methyl-1-propenyl)cyclopropanecarboxylate.
**PEER REVIEWED**
Neopynamin
**PEER REVIEWED**
Phthalthrin
**PEER REVIEWED**
Py-kill
**PEER REVIEWED**
SP 1103
**PEER REVIEWED**
N-(3,4,5,6-tetrahydrophthalimide)methyl-cis, trans-chrysanthemate
**PEER REVIEWED**
3,4,5,6-Tetrahydrophthalimidomethyl (+)-cis,trans-chrysanthemate
**PEER REVIEWED**
Tetramethrine
**PEER REVIEWED**
Weo-Pynamin
**PEER REVIEWED**
Formulations/Preparations:
USEPA/OPP Pesticide Code 069003; Trade Names: Neopynamin, Phthalthrin,
Evercide intermediate 2265 (069330+109301), ENT-27339.
Aerosol, oil liquid, emulsifiable concentrate.
Technical material 85% active ingredient. ... Oil based and water based sprays as well
as aerosol sprays made up of tetramethrin in
combination with piperonyl butoxide, resmethrin, methylated naphthalenes.
Aerosol dispenser; emulsidiable concentrate; dustable powder; ultra-low volume liquid;
oil; emulsion, oil in water
Mixtures: (tetramethrin +) resmethrin,
fenitrothion; piperonyl butoxide + pyrethrins; piperonyl butoxide + resmethrin;
phenothrin; permethrin; piperonyl butoxide; fenitrothion + lindane; permethrin + piperonyl
butoxide
Tech. is 92% pure
Administrative Information:
Hazardous Substances Databank Number: 6738
Last Revision Date: 20011010
Last Review Date: Reviewed by SRP on 5/10/2001
Update History:
Complete Update on 10/10/2001, 50 fields added/edited/deleted.
Field Update on 08/08/2001, 1 field added/edited/deleted.
Field Update on 05/16/2001, 1 field added/edited/deleted.
Complete Update on 09/12/2000, 1 field added/edited/deleted.
Complete Update on 06/12/2000, 1 field added/edited/deleted.
Complete Update on 03/13/2000, 1 field added/edited/deleted.
Complete Update on 02/08/2000, 1 field added/edited/deleted.
Complete Update on 02/02/2000, 1 field added/edited/deleted.
Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 08/27/1999, 1 field added/edited/deleted.
Complete Update on 06/08/1999, 5 fields added/edited/deleted.
Field Update on 06/03/1998, 1 field added/edited/deleted.
Field Update on 11/01/1997, 1 field added/edited/deleted.
Field Update on 05/09/1997, 1 field added/edited/deleted.
Complete Update on 03/17/1997, 1 field added/edited/deleted.
Complete Update on 02/28/1997, 1 field added/edited/deleted.
Complete Update on 10/20/1996, 1 field added/edited/deleted.
Complete Update on 09/06/1996, 1 field added/edited/deleted.
Complete Update on 05/14/1996, 1 field added/edited/deleted.
Complete Update on 02/01/1996, 1 field added/edited/deleted.
Complete Update on 08/21/1995, 1 field added/edited/deleted.
Complete Update on 03/01/1994, 49 fields added/edited/deleted.
Record Length: 118638