2.2.1 Absorption route: No published data available but d-phenothrin
may be absorbed from the skin, gastrointestinal tract or from the
lungs.
3.8 RESIDUES IN FOOD
Maximum residue limits have been established by the FAO/WHO
Joint Meeting on Pesticide Residues. There are eight Codex
Committees MRLs. The Joint FAO/WHO Meeting on Pesticide Residues
has estimated the Acceptable Daily Intake (ADI) to be 0.07 mg/kg
body weight.
Persons under medication with neuroactive drugs should avoid
contact with d-phenothrin.
5.1.2 Symptoms and signs: No published information
available on the acute toxic effects of d-phenothrin in
humans.
Accompanying chemicals in the formulation may elicit symptoms
before
those observed from d-phenothrin exposure. Early symptoms may
include headache, nausea and vomiting.
5.1.3 Laboratory: There are no simple methods for
determining d-phenothrin in body fluids. The metabolism is
rapid and
there are numerous excretory products. The proportion of each
metabolite may not be constant in all types of exposure and
cannot
therefore be used as a quantitative measure of exposure. Some
urinary metabolites may not be specific to d-phenothrin.
5.1.4 Treatment: Treatment is symptomatic. Wash
contaminated skin with soap and water. Wash contaminated eyes
with
copious amounts of water. Ingestion of a small amount
(< 5 mg/kg b.w.) of d-phenothrin should be treated with a
large dose
of activated charcoal followed by sodium or magnesium sulfate
(0.25 g/kg b.w.) in water.
d-Phenothrin (talc powder formulation with Span
80 as a stabilizer) was applied to the head hair and pudendal hair
of eight male human volunteers (three times at intervals of 3 days)
at a dose of 32 mg/man per administration (0.44 to 0.67 mg/kg body
weight per day). d-Phenothrin powder was washed off
1 hr after application. There were no significant abnormalities due
to d-phenothrin in terms of dermal irritation,
clinical signs, or blood biochemical and hematological parameters.
The blood levels of d-phenothrin were below the
detection limit ... .
One hundred and one subjects with head louse infestation were
entered into two separate studies, in which a phenothrin
aqueous/alcoholic lotion was compared to a carbaryl lotion and a
malathion lotion. Fifty subjects were treated with a single
application of the phenothrin lotion, 28 with the
carbaryl lotion and 23 with the malathion lotion. In the comparative
study of the phenothrin and malathion lotions an
inspection on the day following treatment showed no live lice
remained, but that six of the subjects treated with malathion lotion
still had evidence of viable eggs (p < 0.05). In one subject viable
eggs were still evident at two weeks post-treatment. There were no
cases, however, of live lice or viable eggs at four weeks
post-treatment. Mild cutaneous side-effects were reported in five
subjects, the incidence of which was not significantly different by
treatment group. One subject in the phenothrin and
carbaryl lotion comparative study had evidence of live lice at one
week post-treatment with phenothrin lotion. This
subject received no further treatment and was clear of both live
lice and viable eggs at subsequent visits. A separate case of live
lice infestation was found at two weeks post-treatment in a subject
treated with phenothrin lotion and at four weeks
post-treatment in two subjects treated with carbaryl lotion. As
these subjects were free of live lice infestation at previous
follow-up visits it was highly probable that these were cases of
re-infestation from another source.
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/
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/
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/
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.
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/
Populations at Special Risk:
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. ... /Pyrethroids/
Probable Routes of Human Exposure:
Occupational exposure to phenothrin may occur
through inhalation and dermal contact with this compound at
workplaces where phenothrin is produced or used.
The general population may be exposed to phenothrin
via inhalation and dermal contact with insecticides containing
phenothrin. (SRC)
Emergency Medical Treatment:
Emergency Medical Treatment:
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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:
0.2.1 SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
A) 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:
1. Severe fine tremor
2. Marked reflex hyperexcitability
3. Sympathetic activation
4. Paresthesia (dermal exposure)
B) 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.
C) 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.
D) OCULAR - Eye exposures may result in mild to severe
corneal damage that generally resolves with
conservative care.
E) Piperonyl butoxide and other compounds are often added
to pyrethrin insecticides as synergists and may
contribute to toxicity.
0.2.3 VITAL SIGNS
0.2.4 HEENT
0.2.4.1 ACUTE EXPOSURE
A) A stuffy, runny nose and scratchy throat following
inhalational exposure may be noted.
B) Eye exposures may result in mild to severe corneal
damage, decreased visual acuity and periorbital edema.
0.2.5 CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
A) Hypotension and tachycardia, associated with
anaphylaxis, may occur.
0.2.6 RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
A) 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.
0.2.7 NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
A) Paresthesias, headaches, and dizziness are common.
Massive exposure may result in hyperexcitability and
seizures, but this is rare.
0.2.8 GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
A) Nausea, vomiting and abdominal pain commonly occur and
develop within 10 to 60 minutes following ingestion.
0.2.14 DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
A) Irritant and contact dermatitis may develop. Erythema
which mimics sunburn has also been noted after
prolonged repeated exposure.
0.2.16 ENDOCRINE
0.2.16.1 ACUTE EXPOSURE
A) Type I motor symptoms following severe poisoning may
result in sympathetic activation.
0.2.19 IMMUNOLOGIC
0.2.19.1 ACUTE EXPOSURE
A) 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.
0.2.20 REPRODUCTIVE HAZARDS
A) At the time of this review, no reproductive studies were
found for pyrethrum in humans.
0.2.21 CARCINOGENICITY
0.2.21.1 IARC CATEGORY
A) IARC Carcinogenicity Ratings for CAS8003-34-7 (IARC,
2004):
1) Not Listed
0.2.21.2 HUMAN OVERVIEW
A) At the time of this review, no studies were found on
the potential carcinogenic activity of pyrethrum in
humans.
0.2.21.3 ANIMAL OVERVIEW
A) One review mentioned that pyrethrum has caused tumors
in laboratory animals; however, no original studies
were found to confirm these assertions at the time of
this review.
0.2.22 GENOTOXICITY
A) Pyrethrum is not mutagenic in bacterial reversion tests
(Ray, 1991).
Laboratory:
A) Pyrethrin plasma levels are not clinically useful or
readily available.
B) Monitor for allergic responses such as asthma or contact
dermatitis.
Treatment Overview:
0.4.2 ORAL EXPOSURE
A) 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.
B) ALLERGIC REACTION: MILD/MODERATE: antihistamines with or
without inhaled beta agonists, corticosteroids or
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, 0.5 ml max; may repeat in 20 to 30 min),
corticosteroids, ECG monitoring, and IV fluids.
0.4.3 INHALATION EXPOSURE
A) 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 inhaled
beta2 agonist and oral or parenteral corticosteroids.
0.4.4 EYE EXPOSURE
A) DECONTAMINATION: Irrigate exposed eyes with copious
amounts of room temperature water for at least 15
minutes. If irritation, pain, swelling, lacrimation, or
photophobia persist, the patient should be seen in a
health care facility.
0.4.5 DERMAL EXPOSURE
A) OVERVIEW
1) 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.
2) Vitamin E topical application is highly effective in
relieving paresthesias.
Range of Toxicity:
A) The minimal lethal dose of pyrethrum is not established,
but is probably in the range of 10 to 100 grams.
B) 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 (eg, 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/
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:
SYNTHETIC PYRETHROIDS (INCL PHENOTHRIN)
INCREASED FREQUENCY OF SPONTANEOUS DISCHARGES IN ABDOMINAL NERVE
CORD EXCISED FROM CRAYFISH, PROCAMBARUS CLARKI. THE INCREASE IN
FREQUENCY IS RELATED TO THEIR EFFECTS TO DEPOLARIZE THE RESTING
AXONIC MEMBRANE &, POSSIBLY, TO SUPPRESS RELEASE OF INHIBITORY
TRANSMITTERS FROM SYNAPTIC NERVE ENDING.
Rats fed 6000 ppm for 2 years showed only a small reduction in
weight gain.
In a standard 3-generation (2 liters per generation) reproduction
study groups of rats (8 male and 16 female Charles River albino rats
per group) were fed racemic phenothrin at dose
levels of 0, 200, 600, or 2000 mg/kg diet. Various reproductive
indices (i.e. mating index, fecundity index, male fertility index,
female fertility index and incidence of parturition) were measured.
The adult rats showed no significant mortality or complications
during the study, and the reproductive parameters revealed no
significant dose-related adverse effects attributable to
phenothrin. Gross and microscopic findings indicated no
adverse effect resulting from dietary phenothrin.
It was concluded that phenothrin had no effect on
reproduction.
d-Phenothrin was fed to Charles River CD rats
(30 of each sex per group) at dose levels of 0, 300, 1000, or 3000
mg/kg diet throughout two successive generations and up to the
maturation of a third generaton. At 300 and 1000 mg/kg, there was no
adverse effect upon mortality, somatic growth, development, or
reproductive performance. At 3000 mg/kg, mortality, body weight, and
reproductive performance showed no significant response to
treatment, and selected F2 animals reared to maturity were in
respects comparable with control rats. However, F0 and F1 females
and selected F2B male and female weanlings showed a slight but
consistent increase in the relative liver weight. The NOEL in this
study was 1000 mg/kg diet.
Pregnant New Zealand White rabbits (17 per group) were
administered racemic phenothrin orally at dose
levels of 0, 3, 10, or 30 mg/kg body weight on days 6 to 18 of
gestation. They were sacrificed on day 29 and the the young obtained
by caesarian section were examined. At 30 mg/kg, the body weight of
females decreased during gestation, and there was a slight decrease
in the number of live young and a slight reduction in fetal weight.
Racemic phenothrin had no apparent teratogenic
effect, as shown by a lack of gross internal or external somatic
abnormalities and by normal fetal skeletal development following
prenatal exposure.
Sprague Dawley rats exposed to d-phenothrin by
inhalation at concentrations of up to 3760 mg/cu m for 4 h showed no
toxic signs as a result of exposure. Histopathologically, there were
no compound-related alterations in the sciatic nerve.
When d-phenothrin was given to Sprague Dawley
rats orally for 5 consecutive days (5 g/kg body weight per day), one
out of ten female rats died after four doses and signs of poisoning
(piloerections and urinary incontinence) were noted in several of
the animals. However, these signs disappeared rapidly at the end of
the treatment and there were no other signs of poisoning such as leg
weakness or ataxia. All pathological examination of the sciatic
nerve revealed minute changes in axon and myelin, characterized by
very slight axonal swelling, axonal disintegration, and/or
demyelination. Since there were similar changes in the control
animals, it was suggested that they were not due to the d-phenothrin.
It was considered that the oral administration of very high doses of
d-phenothrin does not lead to the neurotoxic
effects observed with several other pyrethroid esters.
d-Phenothrin /was examined/ for its ability to
induce chromosomal aberrations in vivo using bone marrow cells. ICR
mice were treated intraperitoneally with single doses of 2500, 5000,
or 10,000 mg/kg body weight and sacrificed 6, 24, or 48 hr after
treatment. No chromosomal aberrations as a result of d-phenothrin
treatment were detected.
A mutagenicity test with Escherichia coli (WP2 uvr) and
Salmonella typhimurium (TA 1535, TA 1537, TA 1538, TA 98, and TA
100) using d-phenothrin at dose levels of up to 5
mg/plate with and without metabolizing enzyme system (S9 mix)
yielded negative results, whereas a positive control gave a
significant number of mutants.
The ability of d-phenothrin to induce
sister-chromatid exchanges (SCEs) was tested in cultured mouse
embryonic cells in vitro. At doses of 1X10-5, 1X10-4, and 1X10-3
mol/l (with and without S9 mix), d-phenothrin did
not induce any increase in the frequency SCEs.
In a DNA-repair test with Bacillus subtilis (M45 rec- and H17
wild type strains) using dose levels of up to 5 mg/disk per plate,
d-phenothrin did not inhibit the growth of any
strain at any dose level, whereas the positive control, mitomycin C,
showed a clear effect. The negative control gave a result similar to
that of d-phenothrin.
In a host-mediated assay using Salmonella typhimurium G46
(indicator bacteria), d-phenothrin in corn oil was
given orally (twice with a 24-hr interval) to groups of six male ICR
mice at dose levels of 2500 or 5000 mg/kg body weight. Soon after
the last administration, each mouse was injected intraperitoneally
with the indicator cells. Three hours later, the bacterial mutation
frequency in d-phenothrin-treated mice was no
greater than that in the control group.
B6C3F1 Hybrid mice (90 of each sex per group) were fed d-phenothrin
in the diet at dose levels of 0, 300, 1000, or 3000 mg/kg. Fifty of
each sex per group were allocated to a standard oncogenicity study
lasting 104 weeks. The remaining mice were assigned to a chronic
toxicity study, where 10 of each sex per group were sacrificed for
interim study after 26 or 53 weeks and the remaining animals were
examined after 78 weeks of treatment. There were no compound-related
effects on clinical signs, mortality, ophthalmology, blood
biochemistry, hematology, or urinalysis. However, body weight gains
for males fed d-phenothin at 3000 mg/kg were reduced and relative
liver weights were increased in both sexes fed 3000 mg/kg and in
males receiving 1000 mg/kg. Microscopic examination revealed that
the incidence of periacinar hepatocyte hypertrophy with cytoplasmic
eosinophilia was higher in males fed 3000 mg/kg. The incidence of
liver tumors appeared higher in phenothrin-treated
female mice than in control females, but the difference was not
statistically significant. It was concluded, therefore, that
administration of d-phenothrin to mice for 2 years
at dietary levels of up to 3000 mg/kg diet did not significantly
disturb the tumor burden or tumor profile of B6C3F1 hybrid mice. The
NOEL in this study was 300 mg/kg diet for males (40 mg/kg body
weight per day) and 1000 mg/kg diet for females (164 mg/kg body
weight per day).
When beagle dogs (six of each sex per group) were fed d-phenothrin
at dose levels of 0, 100, 300, or 1000 mg/kg diet for 26 weeks,
there were no compound-related abnormal findings in mortality,
clinical signs, body weight, food consumption, ophthalmology, gross
or microscopic pathology, hematology, or urinalysis studies.
However, the alkaline phosphatase activity in males fed 300 mg/kg
and males and females fed 1000 mg/kg was noted. The NOEL in this
study was 300 mg/kg.
In a study of unscheduled DNA synthesis, Hela S3 cells were
treated with d-phenothrin at dose levels of 0,
0.25, 0.5, 1.0, 2.0 or 4.0 mg/ml in the presence of (3)H-thymidine
(with and without S9 mix) for 3 hr, and the incorporation of
3H-thymidine into DNA was measured. There was no significant
increase in the radioactivity of DNA from cells treated with d-phenothrin.
In an in vitro chromosomal aberration test, Chinese hamster ovary
cells (CHO-K1) were treated with d-phenothrin (dose
levels: 2 x 10-5 to 2 x 10-4 mol/litre for 24 and 48 hr in the
absence of S9 mix; 5 x 10-5 to 5 x 10-4 mol/litre for 6 hr in the
presence of S9 mix). No significant increase in the number of cells
with chromosomal aberrations was observed.
Beagle dogs (four of each sex per group) were fed d-phenothrin
at dose levels of 0, 100, 300, 1000, or 3000 mg/kg diet for 52
weeks. There were no significant effects on clinical signs, body
weight, food consumption, ophthalmology, or urinalysis. However,
decreases in erythrocyte count, hemoglobin concentration,
hematocrit, and total blood protein were noted in both male and
female dogs fed 3000 mg/kg, whereas mean absolute and relative liver
weights increased. Compound-related histopathological alterations
were noted in the adrenal glands and liver. Focal degeneration of
the adrenal cortex with cytoplasmic deposition of crystalline
material was seen in one male dog fed 1000 mg/kg and four dogs fed
3000 mg/kg. The chemical nature or biological significance of this
crystalline material was not recorded. Hepatocytes appeared to
enlarge slightly in one male dog fed 1000 mg/kg and seven dogs fed
3000 mg/kg. The NOEL in this study was 300 mg/kg diet for males and
1000 mg/kg for females (8.24 and 26.77 mg/kg body weight per day for
males and females, respectively).
When Sprague Dawley rats (50 of each sex per group) were fed a
diet containing racemic phenothrin (0, 200, 600,
2000, and 6000 mg/kg diet) for 2 years, body weight and food
consumption were slightly depressed at 6000 mg/kg in both males and
females. There were no abnormal clinical or behavioral problems
associated with phenothrin administration. The
survival rate of all groups of treated rats was similar to that of
controls. Males fed 6000 mg/kg showed a significant increase in
serum glutamine-pyruvate aminotransferase activity. Ophthalmological
examinations revealed some abnormalities, all of which appeared to
be age related. Histopathological examination revealed no
significant differences between the treated groups and the control
group with respect to severity of lesions. No histopathological
changes suggestive of oncogenicity resulting from phenothrin
treatment were found.
When Swiss White mice (50 of each sex per group) were fed racemic
phenothrin for 18 months at dose levels of 0, 300,
1000, or 3000 mg/kg diet, there were no significant effects on
mortality, clincial signs, hematologic values, clinical chemistry
parameters, or gross pathological findings. Slight body weight
depression occurred in males fed 3000 mg/kg, and increased liver
weight was found at the highest dose level in both males and
females. There was a statistically significant difference (compared
with the controls) in lung amyloidosis in the 1000 and 3000 mg/kg
dose groups, but no significant increase in tumors attributed to
phenothrin ingestion.
(1R,cis)-Phenothrin (d-phenothrin)
was administered to Sprague Dawley rats (20 of each sex per group)
at dose levels of 0, 1, 3, or 10 g/kg diet for 6 months. Ten rats of
each sex per group were sacrificed after 3 months. d-Phenothrin
had no significant effect on mortality, clinical signs,
ophthalmology, urinalysis, or gross and histopathological findings.
The serum albumin level was elevated after 3 months in males fed 10
g/kg and in females fed 3 or 10 g/kg, and after 6 months in males
fed 3 or 10 g/kg. The albumin-blobulin ratio was raised after 3
months in males fed 3 or 10 g/kg and in females fed 10 g/kg, and in
both males and females fed 10 g/kg after 6 months. Absolute and
relative liver weights in both males and females fed 3 or 10 g/kg
were increased. Based on these data, it was concluded that the NOEL
for d-phenothrin in this study was 1 g/kg diet for
both sexes (55.4 mg/kg body weight per day for males and 63.3 mg/kg
body weight per day for females).
In a standard oncogenicity study, Fisher-344 rats (50 of each sex
per group) were fed d-phenothrin at dose levels of
0, 300, 1000 or 3000 mg/kg diet for at least 105 weeks in males and
at least 118 weeks in females. Additional rats (30 of each sex per
group) were assigned to a chronic toxicity study with a 52-week
interim sacrifice. There were no significant effects on clinical
signs mortality, food and water consumption, ophthalmology, blood
biochemistry, hematology, or urinalysis. However, the body weight
gain in females fed d-phenothrin at 3000 mg/kg was
reduced, and the relative liver weight was increased in females fed
3000 mg/kg for 52 weeks and, at the end of the oncogenicity study,
in males fed 3000 mg/kg. Microscopic examination revealed that the
incidence of cystic dilatation of the sinuses of the mesenteric
lymph nodes and of periacinar hepatocytic hypertrophy was higher in
males fed 3000 mg/kg for at least 105 weeks. d-Phenothrin
did not show any oncogenic activity to rats at up to 3000 mg/kg.
Although at this time and dose increase in the incidence of adenomas
and carcinomas of the preputial gland was seen in males, the 1988
Joint FAO/WHO Meeting on Pesticide Residues considered it unlikely
that this finding was of toxicological significance. The NOEL was
1000 mg/kg diet for both sexes (47 mg/kg body weight per day for
males and 56 mg/kg body weight per day for females).
Pregnant New Zealand White rabbits (15 per group) were orally
administered d-phenothrin by intubation (0, 10, 100
or 1000 mg/kg body weight per day) on days 6 to 18 of gestation, and
were sacrificed on day 29 or 30. Following caesarian section, 50% of
the pups were maintained for 24 h to evaluate survival. No
abnormalities were observed among the does (body weight, food
consumption, clinical observations, and necropsy) or fetuses
(implantation sites, corpora lutea, resorption sites, weight,
condition, and viability). Data on fetal survival and from internal
and external examinations for abnormalities showed no significant
effects from administrating d-phenothrin during
gestation.
d-Phenothrin was orally administered to pregnant
ICR mice (17 or 18 per group) at dose levels of 0, 30, 300, or 3000
mg/kg per body weight on days 7 to 12 of gestation (not covering the
whole period of organogenesis). The dams were sacrificed on day 18
of gestation and the pups were obtained by caesarian section. Other
mice (7 per group) were given d-phenothrin at dose
levels of 0, 300, or 3000 mg/kg to evaluate postnatal effects. These
mice were allowed to deliver naturally and the pups were kept for 29
days. At these levels, d-phenothrin showed no
adverse effects, as indicated by maternal growth, fetal mortality
and external and internal examination of fetuses for teratorgenic or
embryotoxic effects.
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/
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/
Following absorption through the chitinous exoskeleton of
arthropods, pyrethrins stimulate the nervous system, apparently by
competitively interfering with cationic conductances in the lipid
layer of nerve cells, thereby blocking nerve impulse transmissions.
Paralysis and death follow. /Pyrethrins/
Non-systemic insecticide with contact action. Causes paralysis
initially, with death occurring later. Has some acaricidal activity.
/Pyrethrins/
No d-phenothrin-attributable pharmacological
effects were detected in various tests (e.g., spontaneous movement
of isolated guinea pig ileum, contraction of the rat phrenic nerve
diaphragm preparation, cadiopulmonary physiology of anaesthetized
cats, coordination and spontaneous movement of mice, and rectal
temperature of rats) at doses of 100-300 ug/ml in vitro, 3 mg/kg
intravenous, or 100-300 mg/kg intraperitoneal. A tentative arousal
response was recorded in the electroencephalogram of cats given d-phenothrin
(4 mg/kg) intraperitoneally, as is commonly observed in animals
given synthetic pyrethroids.
The type I pyrethroids /including phenothrin/
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 assoc 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 incr.
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/
The symptoms of pyrethrin poisoning follow the typical pattern of
nerve poisoning: (1) excitation, (2) convulsions, (3) paralysis, and
(4) death. The effects of pyrethrins on the insect nervous system
closely resemble those of DDT, but are apparently much less
persistent. Regular, rhythmic, and spontaneous nerve discharges have
been observed in insect and crustacean nerve-muscle preparations
poisoned with pyrethrins. The primary target of pyrethrins seems to
be the ganglia of the insect central nervous system although some
pyrethrin-poisoning effect can be observed in isolated legs.
/Pyrethrins/
Non-Human Toxicity Values:
LD50 Rat oral greater than 500 mg/kg
LD50 Mouse oral greater than 500 mg/kg
LD50 Rat oral greater than 10000 mg/kg /(1R)-cis,trans-isomeric
mixture/
LD50 Mouse oral greater than 10000 mg/kg /(1R)-cis,trans-isomeric
mixture/
LD50 Mouse (male) iv 470 mg/kg /Racemic/
LD50 Mouse (female) iv 600 mg/kg /Racemic/
LD50 Mouse (male) iv 265 mg/kg
LD50 Mouse (female) iv 315 mg/kg
LC50 Rat (Sprague Dawley) >1210 mg/cu m/4 hr /Racemic/
(14)C-PHENOTHRIN ... WAS ORALLY ADMIN AT ... 200
MG/KG TO MALE SPRAGUE-DAWLEY RATS. ... URINE CONTAINED LOW LEVELS OF
3-PHENOXYBENZOIC ACID & ITS GLYCINE CONJUGATE & SOME ETHER & WATER
SOL MATERIAL. IN ADDN ...3-(4'-HYDROXYPHENOXY)BENZOIC ACID WAS
PRESENT & ACCOUNTED FOR 42.3% OF RADIOACTIVITY ... THIS COMPD WAS
... MAJOR METAB IN FECES BUT ACCOUNTED FOR ONLY 11.9% OF ...
RADIOACTIVITY. IN ADDN TO UNCHANGED PHENOTHRIN &
UNIDENTIFIED WATER & ETHER SOLUBLES, FECES CONTAINED
3-PHENOXYBENZOIC ACID & THE GLYCINE CONJUGATE. 3-PHENOXYBENZYL
ALCOHOL WAS NOT OBSERVED IN URINE OR FECES.
DERMAL & ORAL ADMIN OF (+)TRANS- & (+)CIS-PHENOTHRIN
TO MALE RATS FROM DUST OR EMULSIFIABLE CONCENTRATE PRODUCED NEARLY
THE SAME METABOLITES. MAJOR METABOLITES FROM (+)TRANS-ISOMER WERE
3-PHENOXYBENZOIC ACID & ITS GLYCINE CONJUGATE &
(3,4'-HYDROXYPHENOXY)BENZOIC ACID & ITS SULFATE. THE CIS-ISOMER GAVE
LARGER AMOUNTS OF ESTER METABOLITES.
When [1R,trans]-phenothrin was given to rats at
4, 10, or 200 mg/kg body weight (oral single dose) or 4 mg/kg body
weight (repetitive oral dose for 14 days), the sulfate conjugate of
4'-OH-phenoxy benzoic acid was predominant, accounting for 28, 43,
28, and 55%, respectively, of the dose. In addition, phenoxy benzoic
acid (4, 10, 5, and 6%), its glycine conjugate (1,3,2, and 2%) and
glucuronide (2,3,1, and 3%), and free 4'-OH-phenoxybenzoic acid
(2,11,3, and 3%) were found. The sulfate conjugate of
3-(2'-hydroxyphenoxy)benzoic acid (2'-OH-PBacid) was also found as a
minor metabolite.
When Sprague Dawley rats were administered a single oral dose of
[1R,trans]-phenothrin at 4 or 200 mg/kg body weight
level or given an oral dose of 4 mg/kg body weight per day for 14
days, unmetabolized compound was found in the feces (44-45, 44-60,
and 14-16% of the dose, respectively). An ester-form metabolite, the
4'-hydroxy phenoxy benzoic acid derivative of trans-phenothrin,
was also detected (0.4-0.6%).
When Sprague Dawley rats were given a single oral dose of
[1R,cis]-phenothrin at 4 or 200 mg/kg body weight
level or an oral dose of [1R,cis]-phenothrin at 4
mg/kg body weight per day for 14 days, ester-form metabolites (1-9%
of the dosed radioactivity) were found, in additon to unmetabolized
compound (17-50% of the dose). The urine contained
4'-OH-phenoxybenzoic acid as a sulfate conjugate (7-18%) and in the
free form (0.3-1%), and phenoxy benzoic acid as glycine or
glucuronide conjugates and in the free form (0.3-1%).
(IR,trans)-Phenothrin (1 mmol/l) was incubated
with the 8000 g supernatant from a liver homogenate of rats, mice,
guinea-pigs, rabbits, or dogs at 37 deg C for 60 min in the absence
of NADPH. the supernatant from the guinea-pig was the most active in
degrading [1R,trans]-phenothrin, followed by that
of dog, rabbit, rat, and mouse. The major metabolite in all the
mammalian species tested was 3-phenoxybenzyl alcohol (PBalc).
Smaller amounts of PBacid and trace amounts of 4'-OH-PBacid were
also found. However, in the presence of NADPH, the amounts of PBacid
and unidentified ether-soluble metabolites increased in all species
except dog. In contrast to (1R-trans)-phenothrin,
(1R,cis)-phenothrin was hardly metabolized at all
by the rat liver preparation in the absence of NADPH. NADPH enhanced
the degradation rate of the cis isomer, leading to the formation of
unidentified metabolites, while estercleaved metabolites such as
PBacid, PBalc and 4'-OH-PBacid were found in very small amounts.
When (1R,trans)-, [1R,cis]-, [1S,trans]-, and [1S,cis]-phenothrin
were incubated with rat liver microsomes at 37.5 deg C for 30-60 min
to estimate Km and Vmax using a Lineweaver-Burk plot, the values for
Km (0.11-0.17 mmol/litre) were similar for the four isomers, whereas
the values for Vmax were different both the trans isomers values for
Vmax 20-30 times larger than did the cis isomers.
When male Sprague Dawley rats were given cis-phenothrin
(200 mg/kg body weight), three ester-form metabolites, which
accounted for 14% of the dosed radioactivity, were found in the
feces. These were 4'hydroxy-cis-phenothrin
(4'-OH-c-phe), an ester-form derivative with the trans methyl of the
isobutenyl group being oxidized to carboxyl gorup, and a compound
with the geminaldimethyl groups oxidized (2-OH-) in addition to both
of the above modifications (4'-OH,wt-acid, 2-OH(t)-c-phe).
The relative resistance of mammals to the pyrethroids is almost
wholly attributable to their ability to hydrolyze the pyrethroids
rapidly to their inactive acid and 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 intravenous route, moderate by slower
oral absorption, and 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/
Pyrethrins are reportedly inactivated in the GI tract following
ingestion. In animals, pyrethrins are rapidly metabolized to water
soluble, inactive compounds. /Pyrethrins/
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/
The metabolic pathways for the breakdown of the pyrethroids vary
little between mammalian species but vary somewhat with structure.
... Essentially, pyrethrum and allethrin are broken down mainly by
oxidation of the isobutenyl side chain of the acid moiety and of the
unsaturated side chain of the alcohol moiety with ester hydrolysis
playing and important part, whereas for the other pyrethroids ester
hydrolysis predominates. /Pyrethrum and pyrethroids/
The low toxicity of pyrethroids in mammals is due largely to
their rapid biotransformation by ester hydrolysis and/or
hydroxylation. /Pyrethroids/
Absorption, Distribution & Excretion:
(14)C-PHENOTHRIN LABELED AT THE HYDROXYMETHYL
GROUP OF THE ALCOHOL MOIETY, WAS ORALLY ADMIN AT ... 200 MG/KG TO
MALE SPRAGUE-DAWLEY RATS. ABSORPTION & ELIMINATION WAS RAPID. ABOUT
60% OF RADIOACTIVITY WAS ELIMINATED IN URINE & 40% IN FECES IN 3
DAYS. IN ADDN TO PHENOTHRIN, 3-PHENOXYBENZYL
ALCOHOL & 3-PHENOXYBENZOIC ACID WERE FOUND IN BRAIN, LIVER, KIDNEY &
BLOOD. UNIDENTIFIED WATER & ETHER SOLUBLES WERE ALSO PRESENT.
DERMAL ADSORPTION OF (+)TRANS- & (+)CIS-PHENOTHRIN
INTO BODY OF MALE RATS FROM DUST OR EMULSIFIABLE CONCENTRATE (EC)
WAS ESTIMATED TO BE 3-7% & 8-17%. RATE OF ABSORPTION WAS 4-5 TIMES
FASTER WITH EC THAN WITH DUST. AMOUNT ABSORBED THROUGH SKIN WAS
ALMOST COMPLETELY EXCRETED INTO URINE & FECES WITHIN 6 DAYS. WHEN
ADMIN ONCE ORALLY, AT RATE OF 2 MG/KG (EITHER ISOMER), ABOUT 96% OF
DOSE WAS RECOVERED IN EXCRETA DURING FOLLOWING 6 DAYS. A LARGER AMT
OF (+)CIS-ISOMER WAS EXCRETED IN FECES THAN (+)TRANS-ISOMER & A
LARGER AMT OF (+)TRANS-ISOMER WAS EXCRETED IN URINE THAN
(+)CIS-ISOMER.
The tissue residues in rats 7 days after a single oral dose of
(14)C-(1R,cis)- or (14)C-(1R,trans)-phenothrin at
10 mg/kg body weight were generally very low although the fat showed
somewhat higher residue levels (1-2.5 mg/kg). Similarly, high 14C
residue levels (up to 23 mg/kg) were found in the fat, 7 days after
a single oral dose of the [1R,cis] isomer at 200 mg/kg body weight.
Information concerning the comparative metabolism of racemic
(1RS) phenothrin and its d-isomer (1R) was obtained
through a study of CD rats and ddY mice given a single oral dose of
either [1R,trans]-, [1S,trans]-, [1RS,trans]-, [1R,cis]-, [1S,cis]-,
or [1RS,cis]-phenothrin. The radiocarbon derived
from each isomer was almost completely eliminated from the rats and
mice within six days after dosing. The trans isomers were mainly
eliminated in the urine (rat, 85-88%; mice, 65-75%) and the cis
isomers mainly in the feces (rat, 57-71%; mice, 54-71%). The amounts
of (14)C in the urine and feces of rats and mice treated with the
[1R,trans] and [1R,cis] isomers did not differ significantly from
those corresponding to the [1RS,trans] and [1RS,cis] isomers,
respectively. The (14)C tissue residues were very low, except in the
fat. There were no striking differences in (14)C levels among the
three trans isomers and the three cis isomers. The (14)C levels of
the cis isomers in fat (maximum 3.5 mg/kg) were three to seven times
higher than those of the trans isomers (less than 1 mg/kg). The
major urinary and fecal metabolities were remarkably similar in both
rats and mice. In both rats and mice, there were virtually no
differences in the metabolic fate of the [1R,trans] and [1RS,trans]
isomers or of the [1R,cis] and [1RS,cis] isomers.
Following the dermal treatment of male Sprague Dawley rats with
dust or emulsifiable concentrates (EC) of either (14)C-[1R,trans]-
or (14)C-[1R,cis]- phenothrin at 10 mg/kg body
weight, the (14)C absorption into the body was estimated to be 3-7%
of the initial dose with dust and 8-17% with the EC. After both dust
and ECtreatments, the radiocarbon excreta (as a percentage of the
initial dose) recovered in the urine was 2.6-8.7% for the trans
isomer, and 1.5-4.8% for the cis isomer, and in the feces was
0.6-2.2% for the trans isomer, and 3.0-12.3% for the cis isomer.
Since the same metabolites are formed following either oral exposure
or dermal treatment, it appears that both phenothrin
isomers undergo the same metabolism once in the systemic
circulation, regardless of the route of administration.
When (14)C-[1R,cis]-phenothrin in corn oil was
administered once orally to Sprague Dawley male and female rats at 4
or 200 mg/kg body weight, the radiocarbon was excreted into the
urine (11-18%) and feces (81-87%) within 7 days. Similarly, when
Sprague Dawley rats were treated repeatedly with (14)C-[1R, trans]
or (14)C-[1R,cis] isomers at 4 mg/kg body weight per day for 14
days, the radiocarbon was rapidly and almost completely excreted:
75-70% in urine and 24-29% in feces for the trans isomer, and 24% in
the urine and 72-73% in feces for the cis isomer.
/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/
Pyrethrins are absorbed through intact skin when applied
topically. When animals were exposed to aerosols of pyrethrins with
piperonyl butoxide being released into the air, little or none of
the combination was systemically absorbed. /Pyrethrins/
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/
Biological Half-Life:
DERMAL ADSORPTION OF (+)TRANS- & (+)CIS-PHENOTHRIN
INTO BODY OF MALE RATS FROM DUST OR EMULSIFIABLE CONCENTRATE (EC)
WAS ESTIMATED TO BE 3-7% & 8-17%. RATE OF ABSORPTION WAS 4-5 TIMES
FASTER WITH EC THAN WITH DUST & T/2 IN BLOOD WAS 2-3 TIMES LONGER.
Mechanism of Action:
ALL PYRETHROIDS (WHICH INCL PHENOTHRIN) TESTED
ON DESERT LOCUST (SCHISTOCERCA GREGARIA) BLOCKED NEURALLY EVOKED
MUSCLE CONTRACTIONS WITHIN 20 MIN. AMONG PYRETHROIDS TESTED 4
DIFFERENT EFFECTS WERE OBSERVED. KNOCKDOWN ACTIVITY OF ALL
PYRETHROIDS WAS ASSOC WITH 1 PARTICULAR EFFECT, THE BLOCK OF
NEURALLY EVOKED CONTRACTIONS.
Some synthetic pyrethroids given intravenously to rats cause
either tremor (T-syndrome) or choreoathetosis with salivation
(CS-syndrome). However, d-phenothrin (>600 mg/kg
body weight) injected intravenously into the lateral tail vein
caused neither T-syndrome nor CS syndrome, due to its very low acute
toxicity. From a study involving intracerebral dosing with [1R,cis]-
or [1R, trans]-phenothrin in mice, both compounds
were classified as Type I pyrethroids based on the occurrence of
tremors and on neurophysiological studies in cockroach cercal
sensory nerves.
The effects of 4 different pyrethroid insecticides on sodium
channel gating in internally perfused, cultured mouse neuroblastoma
cells (N1E-115) were studied using the suction pipette, voltage
clamp technique. Pyrethroids increased the amplitude of the sodium
current, sometimes by more than 200%. Activation of the sodium
current occurred at more hyperpolarized potentials than under
control conditions. The declining phase of the sodium current during
depolarization was markedly slowed down and after repolarization of
the membrane a large, slowly decaying sodium tail current developed.
Pyrethroids did not affect the sodium current reversal potential,
steady-state sodium inactivation or recovery from sodium channel
inactivation. The amplitude of the pyrethroid-induced slow tail
current was always proportional to the sodium current at the end of
the preceding depolarizing pulse. The rate of decay of the slow tail
current strongly depended on pyrethroid structure and increased in
the order deltamethrin, cyphenothrin, fenfluthrin and
phenothrin. The rate of decay further depended on membrane
potential and temperature. Below -85 m V the instantaneous
current-voltage relationship of the slow tail current showed a
negative slope conductance. The tail current decayed more slowly at
low temperatures. Arrhenius plots indicated that the relaxation of
open sodium channels to a closed state involved a higher energy
barrier for pyrethroid-affected than for normal channels. The energy
barrier was higher after deltamethrin than after the non-cyano
pyrethroid fenfluthrin. It is concluded that in mammalian neuronal
membrane pyrethroids selectively reduce the rate of closing of
sodium channels both during depolarization and after repolarization
of the nerve membrane.
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 (eg,
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 central
nervous system 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, and most neurotransmitter release is secondary to
increased sodium entry. /Pyrethroids/
Electrophysiologically, pyrethrins cause repetitive discharges
and conduction block. /Pyrethrins/
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 interactions of natural pyrethrins and 9 pyrethroids with the
nicotinic acetylcholine (ACh) receptor/channel complex of Torpedo
electronic organ membranes were studied. None reduced (3)H-ACh
binding to the receptor sites, but all inhibited (3)H-labeled
perhydrohistrionicotoxin binding to the channel sites in presence of
carbamylcholine. Allethrin inhibited binding noncompetitively, but
(3H)-labeled imipramine binding competitively, suggesting that
allethrin binds to the receptor's channel sites that bind
imipramine. The pyrethroids were divided into 2 types according to
their action: type A, which included allethrin, was more potent in
inhibiting (3)H-H12-HTX binding and acted more rapidly. Type B,
which included permethrin, was less potent and their potency
increased slowly with time. The high affinities that several
pyrethroids have for this nicotinic ACh receptor suggest that
pyrethroids may have a synaptic site of action in addition to their
well known effects on the axonal channels. /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/
At dietary level of 1000 ppm pyrethrins & 10000 ppm piperonyl
butoxide ... /enlargement, margination, & cytoplasmic inclusions in
liver cells of rats/ were well developed in only 8 days, but ...
were not maximal. Changes were proportional to dosage & similar to
those produced by DDT. Effects of the 2 ... were additive.
/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/
At dietary level of 1000 ppm pyrethrins & 10000 ppm piperonyl
butoxide ... /enlargement, margination, & cytoplasmic inclusions in
liver cells of rats/ were well developed in only 8 days, but ...
were not maximal. Changes were proportional to dosage & similar to
those produced by DDT. Effects of the 2 ... were additive.
/Pyrethrins/
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Phenothrin's production and use as an
insecticide is expected to result in its direct release to the
environment. If released to air, a vapor pressure of 1.43X10-7 mm Hg
at 21 deg C indicates phenothrin will exist in both
the vapor and particulate phases in the ambient atmosphere.
Vapor-phase phenothrin will be degraded in the
atmosphere by reaction with photochemically-produced hydroxyl
radicals and ozone; the half-lives for these reactions in air are
estimated to be 4 hours and 38 minutes, respectively.
Particulate-phase phenothrin will be removed from
the atmosphere by wet and dry deposition. If released to soil,
phenothrin is expected to have no mobility based
upon an estimated Koc of 56,000. Volatilization from moist soil
surfaces is expected to be an important fate process based upon an
estimated Henry's Law constant of 6.80X10-6 atm-cu m/mole. However,
adsorption to soil is expected to attenuate volatilization.
Pyrethrins, such as phenothrin, are expected to
undergo rapid photodecomposition and biomineralization in soils and
aqueous systems. For example, residues of trans-phenothrin
fell to <10 ppb (initial concn unspecified) within 45 days in an
aerobic soil. If released into water, phenothrin is
expected to adsorb to suspended solids and sediment based upon the
estimated Koc. Volatilization from water surfaces is expected to 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 7 and 81 days, respectively. However,
volatilization from water surfaces is expected to be attenuated by
adsorption to suspended solids and sediment in the water column. An
estimated BCF of 266 suggests the potential for bioconcentration in
aquatic organisms is high. However, bioconcentration studies on
compounds which are structurally similar suggest that
bioconcentratoin may be lower than that indicated, due to the
ability of aquatic organisms to metabolize this class of compounds
readily. Hydrolysis half-lives for the d-trans-phenothrin
are 301, 495-578, and 91-120 days at pH values of 5, 7 and 9,
respectively. Occupational exposure to phenothrin
may occur through inhalation and dermal contact with this compound
at workplaces where phenothrin is produced or used.
The general population may be exposed to phenothrin
via dermal contact with insecticides containing phenothrin.
(SRC)
Probable Routes of Human Exposure:
Occupational exposure to phenothrin may occur
through inhalation and dermal contact with this compound at
workplaces where phenothrin is produced or used.
The general population may be exposed to phenothrin
via inhalation and dermal contact with insecticides containing
phenothrin. (SRC)
Artificial Pollution Sources:
Phenothrin's production and use as an
insecticide(1) is expected to result in its direct release to the
environment(SRC).
Environmental Fate:
TERRESTRIAL FATE: Based on a classification scheme(1), an
estimated Koc value of 56,000(SRC), determined from a water
solubility of 9.70X10-3 mg/l(2) and a regression-derived
equation(3), indicates that phenothrin is expected
to be immobile in soil(SRC). Volatilization of phenothrin
from moist soil surfaces is expected to be an important fate
process(SRC) given an estimated Henry's Law constant of 6.80X10-6
atm-cu m/mole(SRC), derived from its vapor pressure, 1.43X10-7 mm
Hg(2), and water solubility, 9.70X10-3 mg/l(2). However, adsorption
to soil is expected to attenuate volatilization(SRC).
Phenothrin is not expected to volatilize from dry soil
surfaces(SRC) based upon its vapor pressure(2). Although
environmental biodegradation data specific to phenothrin
are not available, the pyrethroid class of insecticides is readily
degraded by environmental microorganisms(4,5); based upon its
structure, phenothrin are also expected to readily
biodegrade(4,5). For example, residues of trans-phenothrin
fell to <10 ppb (initial concn unspecified) within 45 days in an
aerobic soil(4). Residues of trans-phenothrin
remained close to 300 ppb (initial concn unspecified) after 60 days
in an anaerobic soil(4). Thus, degradation of phenothrin
under anaerobic conditions is expected to be slower than under
aerobic conditions(SRC).
AQUATIC FATE: Based on a classification scheme(1), an estimated
Koc value of 56,000(SRC), determined from a water solubility of
9.70X10-3 mg/l(2) and a regression-derived equation(3), indicates
that phenothrin is expected to adsorb to suspended
solids and sediment(SRC). Volatilization from water surfaces is
expected(3) based upon an estimated Henry's Law constant of
6.80X10-6 atm-cu m/mole(4) derived from its vapor pressure,
1.43X10-7 mm Hg(2), and its water solubility(2). Using this Henry's
Law constant and an estimation method(3), volatilization half-lives
for a model river and model lake are 7 and 81 days,
respectively(SRC). However, volatilization from water surfaces is
expected to be attenuated by adsorption to suspended solids and
sediment in the water column. The estimated volatilization half-life
from a model pond is 1.47X10+4 years if adsorption is considered(4).
According to a classification scheme(5), an estimated BCF of
266(SRC), from an estimated log Kow and a regression-derived
equation(6), suggests the potential for bioconcentration in aquatic
organisms is high(SRC). However, bioconcentration studies on
compounds which are structurally similar suggest that
bioconcentration may be lower than that indicated by the
regression-derived equations due to the ability of aquatic organisms
to readily metabolize this class of compounds(7). Hydrolysis
half-lives for (cyclopropyl-1-14C)-d-trans-phenothrin
are 301, 495, and 120 days at pH values of 5, 7 and 9,
respectively(8); for (benzyl-14C)-d-trans-phenothrin,
301, 578, and 91 days at pH values of 5, 7 and 9, respectively(9).
Based on these results, hydrolysis is not an important environmental
fate process for phenothrin(SRC). Although
environmental biodegradation data specific to phenothrin
are not available, the pyrethroid class of insecticides is readily
degraded by environmental microorganisms(7,10); based upon its
structure, phenothrin are also expected to readily
biodegrade(7,10).
ATMOSPHERIC FATE: According to a model of gas/particle
partitioning of semivolatile organic compounds in the atmosphere(1),
phenothrin, which has a vapor pressure of 1.43X10-7
mm Hg at 21 deg C(2), will exist in both the vapor and particulate
phases in the ambient atmosphere(SRC). Vapor-phase
phenothrin is degraded in the atmosphere by reaction with
photochemically-produced hydroxyl radicals(SRC); the half-life for
this reaction in air is estimated to be 4 hours(SRC), calculated
from its rate constant of 1.06X10-10 cu cm/molecule-sec at 25 deg
C(SRC) determined using a structure estimation method(3).
Vapor-phase phenothrin is degraded in the
atmosphere by reaction with photochemically-produced ozone(SRC); the
half-life for this reaction in air is estimated to be 38
minutes(SRC), calculated from its rate constant of 4.30X10-16 cu
cm/molecule-sec at 25 deg C(SRC) determined using a structure
estimation method(3). Particulate-phase phenothrin
may be removed from the air by wet and dry deposition(SRC).
Pyrethrins, such as phenothrin, undergo rapid
decomposition primarily from UV-energized autooxidation (direct
reaction with atmospheric triplet oxygen)(4).
Environmental Biodegradation:
Although environmental biodegradation data specific to
phenothrin are not available, the pyrethroid class of
insecticides is readily degraded by environmental
microorganisms(1,2); based upon its structure, phenothrin
are also expected to readily biodegrade(1,2). For ex