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Piperonyl Butoxide

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A0005
116 Piperonyl butoxide
S0005 1. DESCRIPTION
P0005 Piperonyl butoxide (PBO) contains the methylenedioxyphenyl moiety,
a molecule found in sesame oil and later named sesamin, and thus is
classified as a member of the methylenedioxyphenyl group of
chemicals. In 1947, it was semisynthesized from safrole, the principal
component of camphor oil (Knowles, 1991; Tozzi, 1998).
P0010 Its molecular formula is C19H30O5; it has a molecular weight of
338.4 g/mol. The chemical structure is shown in Figure 116.1.
P0015 PBO is a colorless to pale yellow liquid and is moderately stable in
that it is resistant to hydrolysis, oxidation, and exposure to sunlight
(Kidd and James, 1994). Manufacturers include MGK and Prentiss
and Johnson (Tozzi, 1998). Since its discovery, and since pesticide
resistance has emerged as a problem, PBO has been frequently used as
an insecticide synergist, in over 1700 insecticides (USEPA, 2002). It is
commonly blended with pyrethrins and synthetic pyrethroids,
S0010 2. ANTIMICROBIAL ACTIVITY
P0025 Piperonyl butoxide does not have any antimicrobial activity on its
own. It is a synergist used to enhance the efficacy of other pesticides.
S0015 3. MECHANISM OF DRUG ACTION
P0030 PBO is a quasi-irreversible metabolic inhibitor, otherwise known as a
chemical synergist that enhances the killing power of pesticides by
inhibiting cytochrome P-450 dependent enzymes. These used to be
called mixed-function oxidases (MFOs), but are now also known as
polysubstrate monooxygenases (PSMOs). They are produced by
microsomes, which are subcellular units found in mammal livers and
in some insect tissues. PSMOs bind the oxidative enzymes and prevent
O O
O
O
F0005 Figure 116.1 Chemical structure of piperonyl butoxide. Reproduced
with permission from http://en.wikipedia.org/wiki/Piperonyl_butoxide.
Kucers’ the Use of Antibiotics 116
Deon V Canyon
Jorg Heukelbach
Essam S Shaalan
Richard Speare
including in human and veterinary medicine; in agriculture, it is
used with a wider range of pesticides including fipronil, parathion,
dichlorvos, linalool, D-limonene, methoprene, hydroprene and fenox-
ycarb, and alpha-naphthylthiourea (Levine and Murphy, 1977;
Carpenter and Roth, 1988; Farnham, 1998; Hainzal et al., 1998;
Keane, 1998; Tripathi and Agarwal, 1998).
PBO is a component in 8% of all US-registered pesticide products P0020
(Aspelin and Grube, 1999); it is also found in over 12% of pesticide
products commonly used in households (Whitmore et al., 1992;
Adgate et al, 2000). In fact, PBO was the most common ingredient
found in household pesticide products, and over 300 million indoor
applications and 60 million outdoor applications of PBO-containing
products are made in the United States every year (Whitmore et al.,
1992).
them from degrading selected foreign substances, such as pyrethroid
insecticides. This is the principal detoxification pathway for many
pesticides. When the detoxification pathway is inhibited, the
bioavailability of the unmetabolized active ingredient is enhanced,
resulting in increased temporal exposure due to more persistent
concentrations of the pesiticde (Hodgson and Philpot, 1974; Testa and
Jenner, 1981; Hodgson and Levi, 1998).
 2 Agents active against ectoparasites
S0020 4. MODE OF DRUG ADMINISTRATION AND DOSAGE
P0035 Pesticides containing PBO include those designed for human use, such
as pesticides for human clothing, bedding, and mattresses, and lotions
and other ectoparastic or repellent preparations; indoor home use,
such as dusts, sprays, and foggers; outdoor use, such as for gardens,
lawns, and decorative plants; agricultural use, for food and nonfood
crops; for mosquito control, for termite treatments, for veterinary
pesticide products, for animal ear tags and pest strips, animal houses
and for commercial landscape maintenance (NPTN, 2000; CDPR,
2001; Colt et al., 2007).
P0040 Exposure is closely affected by persistence. In field applications, PBO
breaks down or disperses with a half-life of 4–30 days depending on
environmental circumstances. This was reduced to a day in aquatic
environments (Arnold, 1998). Indoor applications typically have an
effective life of 14 days (Fischer and Eikmann, 1996). PBO is regularly
found on food. The US Department of Agriculture has found PBO on
spinach, peas, sweet potatoes, tomatoes, peaches, squash, strawberries,
bell peppers, grapes, and pineapples (USDA, 1997; USDA, 1998a;
USDA 1998b; USDA, 2000; USDA, 2001a; USDA, 2001b). PBO is
banned from use on organic produce (DiMatteo, 2004). Humans are
thus directly exposed to PBO through the application of personal or
household insecticides and indirectly from environmental sources that
have been contaminated.
S0025 Direct exposure
P0045 Direct deliberate exposure to PBO commonly occurs through
pediculosis drug therapy. Some brand names include: A200, Anti-
Lice, Banlice, Clear, Lice-X, Licide, Medi-Lice, Paralice, Pronto,
Pyrinex, Pyrenel, Pyrinyl, R&C, Rid, and Tisit. The forms range from
shampoo to gel to liquid to foam, and usually contain permethrin or
pyrethroids as the active ingredient. These preparations and others are
used to treat head, body, and pubic lice, and scabies infections. While
pediculicides are available without prescription, allergic history needs
to be considered and prolonged exposure should be avoided in
children. Products containing PBO should be used with caution in
pregnant and breastfeeding women because animal studies have shown
adverse effects in all trimesters. Repeated long-term exposure is
frequent in children experiencing ectoparasites reinfestation or
resistance and other nonchemical control methods need to be
suggested in this situation.
S0035 5. PHARMACOKINETICS AND PHARMACODYNAMICS
P0065 Fishbein et al. (1969) and Kamienski and Casida (1970) performed
several metabolic experiments on mice and rats with PBO labelled
with 14C and assessed expired air, urine, and fecal matter for
radioactivity to determine recovery rates. From these results, the
latter researchers developed and proposed a metabolic pathway in
mammals (see Figure 116.2). A subsequent similar study by Selim et al.
(1999) did not result in any change to this pathway. Figure 116.2.
P0070 A study of dermal absorption, metabolism, and excretion on exposed
human volunteers (Selim et al., 1999) determined that absorption of
PBO through the skin was very low as demonstrated by the
radioactivity excreted in urine, and that there was no evidence of
S0040 6. TOXICITY
P0080 PBO can be absorbed through skin, eye contact, inhalation, and
ingestion. Several acute toxicity studies were conducted in the 1940s
and 1950s, with the aim of determining lethal doses (Moretto, 1995).
The only acute study to report on symptoms remains unpublished.
Kucers’ the Use of Antibiotics 116
Indirect exposure S0030
In 2004, a study by Karpati et al. (2004) investigated concern for P0050
asthmatic repercussions of pyrethroid-PBO spraying for West Nile
Virus control. Results indicated no increase in population-level
emergency department visits to public hospitals. Secondary analysis
for chronic obstructive pulmonary disease in children likewise
demonstrated no association. Another study by Peterson et al.
(2006) investigated the same issue, but collected more data. They
determined the 1-day application rate of PBO to be 0.525 mg/kg which
was below the no observed adverse effect level (NOAEL) of 630 mg/kg
per day above which toxic effects are expected, but well above the
acceptable daily intake (ADI) of 0.2 mg/kg (Moretto, 1995).
Indirect exposure occurs most often in households where insecti- P0055
cidal spraying and ‘‘bombing’’ are frequent and where chemicals are
less exposed to break down by environmental factors such as UV light.
Indoor studies have focussed on appraising air and dust to get a more
accurate idea of exposure concentrations. Whyatt et al. (2002)
postulated that arthropod-infested homes would be subjected to
increased use of insecticides which could lead to adverse health effects.
Further studies showed widespread insecticide use and detected
insecticide chemicals in 99–100% of all females tested (Whyatt et al.,
2007). Several effects were reported. For instance, infants with high
levels of chlorpyrifos had lower weight and length, and poorer mental
and motor development at three years of age (Rauh et al., 2006). PBO
was the fourth most common pesticide detected near 80% of the New
York study participants. It was detected in 45.5% of indoor air samples
and 68.5% of personal air samples at a mean concentration of
3.9 7 16.9 ng/m3. PBO levels were generally o90 ng/m3, but there
was one high of > 600 ng/m3. Concentrations were higher in homes
that used insecticide products.
In a 1996 study of a German kindergarten environment, Fischer and P0060
Eikmann reported o10 mg/m2 on a wood toy and 690 mg/kg in floor
dust. This extremely high level may have been reported incorrectly
since Riechelmann et al. (2007) reported 600 7 52 ng/g in German
household dust, which is a thousand-fold less.
bioaccumulation in the skin. Fecal excretion was minimal. Absorbed
PBO was completely metabolized prior to excretion in the urine. In a
rat oral dosing study (Byard and Needham, 2006), approximately 90%
of PBO was extensively and rapidly excreted, primarily in feces, after
48 hours. They demonstrated that PBO metabolism proceeds down
the same route to similar metabolic products in plants, domestic
animals, and rats, and concluded that rat testing can be used
effectively to test exposure to PBO in plant and animal residues.
There are no known drug–drug interactions with piperonyl P0075
butoxide.
Hoffman (1991) exposed rats by inhalation for 4 hours to 5.9 mg/l
PBO. All animals survived exposure and the subsequent 15-day
 Piperonyl butoxide 3

O O
(CH2)2CH3 (CH2)2CH3
∗ ∗ ∗ ∗
CH2OCH2CHO CONHCH2COOH
O H O

O O
(CH2)2CH3 (CH2)2CH3
∗ ∗ ∗ ∗
CH2O(CH2)2OCH2CHO COOH
O H O

piperonyl butoxide
O
(CH2)2CH3
∗ ∗ > 8 methylene-dioxyphenol
∗
CH2O(CH2)2O(CH2)2O(CH2)3CH3 urinary metabolites
= position O
of radiolabel

∗ ∗ HO
CO2 HCOOH + (CH2)2CH3
∗ > 7 urinary metabolites
CH2O(CH2)2O(CH2)2O(CH2)3CH3
HO
F0010 Figure 116.2 Proposed metabolic pathway for piperonyl butoxide in mammals. Adapted with permission from Kamienski and Casida (1970).

observation period. Physical effects included excessive lacrimation and 6a. Acute toxicity in humans S0045
salivation, nasal discharge, and labored breathing and no remarkable
signs were seen post mortem. According to the WHO-FAO (1996), symptoms caused by breathing P0095
P0085 Most toxicological studies have been short or long term and have PBO include tearing, salivation, and labored breathing. Accumulation
found a wide array of effects. A complete review of all historical studies of fluids in the lungs can occur (Batemen, 2000). The material safety
can be found in Moretto (1995). Moretto (1995), Breathnach (1998), data sheet (MSDS) from www.prentiss.com states, ‘‘Ingestion: May
Butler et al. (1998), and five other studies reported in 1995 (WHO- cause gastrointestinal effects, such as nausea, cramps, vomiting and
FAO, 1996) found no evidence that PBO was a carcinogen. diarrhea. Eyes: May cause temporary eye irritation. Skin: May cause
Breathnach (1998) also stated that PBO ‘‘does not demonstrate any skin irritation after repeated contact. Inhalation: May cause nasal and
significant potential for mutagenicity’’. Osimitz et al. (2007) found that respiratory irritation.’’
‘‘laryngeal metaplasia can be produced by a wide range of chemically
dissimilar substances, and even by ‘non-chemical’ means, such as
irritation by aerosols and particles, and dehydration by alcohols or low
humidity air.’’ They concluded this response is adaptive and should not
be considered to be indicative of significant human risk. Mitsumori et
al. (1996) also observed changes in lymphohematopoietic organs in
rats given PBO and concluded that lymphohematopoietic findings in
rats receiving 2.5% PBO are probably due to undernutrition resulting
from reduced food intake. 6b. Chronic human symptoms S0050
P0090 The International Programme on Chemical Safety reviewed PBO
and determined that an ADI for humans of 0–0.2 mg/kg was There is some debate as to whether PBO is oncogenic or mutagenic in P0100
established on the basis of the NOAEL of 600 ppm (equal to 16 mg/ humans. In 1995, the Environmental Protection Agency classified
kg per day) in the 1-year study in dogs, with a 100-fold safety factor PBO as possibly carcinogenic. However, current MSDSs state that
(Moretto, 1995). there is no evidence of carcinogenic or mutagenic effects.

S0055 7. CLINICAL USES OF THE DRUG

P0105 PBO does not have clinical uses alone, but is always used in
combination with pyrethrins for treating parasitic lice. Several clinical
trials, including blinded randomized comparative and controlled trials
have been conducted on head lice products based on pyrethrins
(Cordero and Zaias 1987; Carson et al. 1988; Mumcuoglu et al. 2002;
Heukelbach et al. 2007) While there are no head-to-head studies of
permethrin or pyrethroids formulated with or without PBO, the
consensus is that PBO-synthesized pyrethrins and pyrethrins are more
effective against head lice.

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