JOURNAL OF PESTICIDE REFORM/ SUMMER 2002 ¥ VOL. 22, NO. 2

● INSECTICIDE SYNERGIST FACTSHEET PIPERONYL BUTOXIDE

Piperonyl butoxide (PBO) is a synergist used to increase the potency of insecticides like pyrethrins and pyrethroids. According to the U.S. Environmental Protection Agency (EPA), PBO is one of the most commonly used ingredients in household pesticide products.

PBO acts as a synergist by inhibiting the activity of a family of enzymes called P450s. These enzymes have many functions, including breakdown of toxic chemicals and transformation of hormones.

Symptoms of PBO exposure include nausea, diarrhea, and labored breathing.

EPA classifies PBO as a “possible human carcinogen” because it caused liver tumors and cancers in laboratory tests.

In a study conducted by PBO manufacturers, PBO caused atrophy of the testes in male rats. Other researchers found behavioral changes (a decrease in home recognition behavior) in the offspring of exposed mothers.

PBO affects a variety of hormone-related organs, including thyroid glands, adrenal glands and the pituitary gland.

PBO reduces the immune response of human lymphocytes, cells in our blood that help fight infections.

Concentrations of less than one part per million of PBO reduce fish egg hatch and growth of juvenile fish. PBO also inhibits hormone-related enzymes in fish and slows the breakdown of toxic chemicals in their tissues. PBO is very toxic to earthworms and highly toxic to aquatic animals.

BY CAROLINE COX taining products are Figure 1 made indoors every Piperonyl Butoxide year in the U.S, and Piperonyl butoxide (PBO) is an almost 60 million insecticide synergist, a chemical that O applications out- is used to make insecticides more po- doors.10 tent. (See Figure 1 for PBO’s molecu- O O In addition to O lar structure.) The discovery of PBO’s O these household properties as a synergist occurred in uses, other signifi- the 1940s, following the development 2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether cant uses include of aerosol cans to apply insecticides.1 use in public health PBO is now frequently used, particu- pest control, com- larly in aerosol products. About 1700 dichlorvos,7 linalool, and D-limonene,8 mercial indoor pest control, buildings insecticide products contain PBO,2 8 the insect growth regulators meth- that house animals, commercial land- percent of the over 20,000 pesticide oprene, hydroprene, and fenoxycarb,8 scape maintenance, and lettuce products3 registered in the U.S. as well as alpha-naphthylthiourea (for- production.12 Major U.S. manufacturers of PBO merly used as a rodenticide).9 pesticides include MGK (McLaughlin Mode of Action Gormley King Company), Prentiss, Inc. Use Piperonyl butoxide acts as a syner- and S.C. Johnson & Son, Inc.1 In a household pesticide use sur- gist by slowing the breakdown in PBO is often used as a synergist vey done for the U.S. Environmental insects of certain insecticides. The first with pyrethrins (JPR 22(1):14-20) and Protection Agency (EPA), products con- step in the breakdown of many drugs, the chemically related synthetic pyre- tained PBO more frequently than any pesticides, and other compounds is throids.4 However, it also can synergize other ingredient. Over 12 percent of oxidation by a family of enzymes called a variety of other pesticides, including the products used by households in the P450 mono-oxygenases. PBO in- the insecticides fipronil,5 parathion,6 the survey contained PBO.10 A recent hibits the activity of these enzymes. If Minnesota survey had similar results.11 the breakdown product is less toxic The EPA survey estimates that almost than the insecticide itself, the insecti- Caroline Cox is NCAP’s staff scientist. 300 million applications of PBO-con- cide remains toxic longer when PBO

NORTHWEST COALITION FOR ALTERNATIVES TO PESTICIDES/NCAP 12 P. O. BOX 1393, EUGENE, OREGON 97440 / (541)344-5044 JOURNAL OF PESTICIDE REFORM/ SUMMER 2002 ¥ VOL. 22, NO. 2 inhibits the P450 enzymes.13 of Hazardous ‘Inerts’,” below. P450 enzymes have important bio- Figure 2 logical functions. In addition to detoxi- Exposure Symptoms PBO Changes Behavior fication of synthetic compounds, they Symptoms caused by ingestion of 25 also transform sex hormones, vita- PBO include nausea, cramps, vomit- mins, and other naturally occurring ing, and diarrhea.16 Symptoms caused 13 molecules. by breathing PBO include tearing, sali- 20 vation, and labored breathing.17 Accu- Inert Ingredients mulation of fluids in the lungs can 18 Like most pesticides, commercial occur. PBO can also cause temporary 15 PBO-containing insecticides contain in- eye and skin irritation.16 gredients other than PBO many of which, according to U.S. pesticide law, Effects on the Nervous 14 System 10 Note: Lines above are called “inert.” Except for acute bars are standard toxicity testing, all toxicology tests re- PBO causes behavioral changes in errors. quired for registration of PBO prod- young laboratory animals. A researcher 5 ucts were conducted with PBO, not at the Tokyo Metropolitan Research with the combination of ingredients Laboratory of Public Health observed

Distance travelled (meters in 10 minutes) found in commercial products.15 behavior of mice after they had been 0 Most inert ingredients are not iden- fed PBO for six weeks. He found that Unexposed Exposed tified on product labels, and little exposed rats traveled longer distances Source: Tanaka, T. 1993. Behavioral information about them is publicly and turned more frequently than un- effects of piperonyl butoxide in male mice. available. exposed animals. (See Figure 2.) The Toxicol. Lett. 69: 155-161. For more information about the effects on travel distance occurred at 19 hazards of some of the inert ingredi- all doses tested in this experiment. In a laboratory study, PBO affected motor ents in PBO products see “Examples PBO also reduces the activity of the activity at every dose level tested.

EXAMPLES OF HAZARDOUS “INERTS” IN PRODUCTS CONTAINING PIPERONYL BUTOXIDE Raid Flea Killer Plus (EPA Reg. No. 4822-273) con- causes headache, restlessness, lethargy, nausea, diarrhea, tains butane, propane, and isobutane as “inert” pro- and anemia. Anemia in newborns can be caused by expo- pellants.1 Butane, isobutane, and propane can cause sure during pregnancy.11 1,2,4-Trimethyl benzene is irritat- headache, dizziness, numbness, sleepiness, mental con- ing to eyes and skin. It can depress the central nervous fusion, poor coordination, and memory loss. They are system and cause headache, fatigue, nausea, and anxiety. “extremely flammable” and “will be easily ignited by It has also caused asthmatic bronchitis.12 2,3,4 heat, sparks, or flame.” 1. S.C. Johnson & Son, Inc. 2000. Material safety data sheet: Raid¨ Flea Pyrenone® Crop Spray (EPA Reg. No. 432-1033) and Killer Plus. Racine, Wisconsin. 800-725-6737. TM 2. Hazardous Substance Data Bank. 2002. Butane. http://toxnet.nlm.nih.gov. Prentox® Pyronyl Fogging & Contact Spray (EPA Reg. 3. Hazardous Substance Data Bank. 2002. Isobutane. http:// 5,6 No. 655-675) contain a petroleum solvent. This sol- toxnet.nlm.nih.gov. vent is called hydrotreated kerosene and its Chemical 4. Hazardous Substance Data Bank. 2001. Propane. http://toxnet.nlm.nih.gov. 7 5. Aventis. 2001. Material safety data sheet: Pyrenone¨ Crop Spray. Abstract Service number is 64742-47-8. This solvent has www.cdms.net/ldat/mp0GC000.pdf. caused skin tumors when applied to the skin of labora- 6. Prentiss, Inc. 1998. Material safety data sheet: Prentox¨ Pyronyl Fogging & tory mice.8 Exposure to this solvent also causes dizzi- Contact Spray. www.prentiss.com/msds/pdf/655_675.pdf. 7. National Institute for Occupational Safety and Health. Undated. The reg- ness, nausea, and headache. Breathing droplets of this istry of toxic effects of chemical substances: Kerosene (petroleum), solvent can cause aspiration pneumonia.6 hydrotreated. www.cdc.gov/niosh/rtecs/oa53fc00.html. 8. International Agency for Research on Cancer. 1989. Occupational expo- Scourge® Insecticide with SBP-1382®/PBO 1.5%+4.5% sures in petroleum refining. IARC Monographs 45:39. http://193.51.164.11/ Forla II (EPA Reg. No. 432-719) contains an aromatic htdocs/monographs/Vol45/45-01.htm. petroleum solvent with Chemical Abstract Services num- 9. Aventis. 2000. Material safety data sheet: Scourge¨ Insecticide with 9 SBP-1382¨/PBO 1.5%+4.5% Forla II. www.cdms.net/ldat/mp57D000.pdf. ber 64742-94-5 also called solvent naphtha. This solvent 10. Shell Chemical Company. 2002. Material safety data sheet: Shellsol¨ contains two aromatic hydrocarbons, naphthalene and 1,2,4- A150. www.euapps.shell.com/MSDS/GotoMsds. trimethylbenzene.10 Naphthalene is classified by EPA as a 11. Hazardous Substance Data Bank. 2002. Naphthalene. http:// toxnet.nlm.nih.gov. possible human carcinogen because it causes lung tumors 12. Hazardous Substance Data Bank. 2002. 1,2,4-trimethylbenzene. http:// in mice following inhalation. Naphthalene exposure also toxnet.nlm.nih.gov.

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enzyme cholinesterase. This enzyme Figure 3 plays a role in transmitting nerve im- Breathing Piperonyl Butoxide Damages the Larynx pulses from one nerve cell to another or to muscle cells.20 In a long-term feeding study with rats, researchers 100 from the laboratory mentioned in the previous paragraph found that female rats fed PBO had 30 percent less blood 80 cholinesterase activity than unexposed rats.21 In addition, PBO can increase the 60 neurotoxicity of other compounds. For example, pharmacologists at Virginia Commonwealth University fed rats 40 PBO and methylmercury, a neurotoxic metal. They found that rats fed the combination developed neurological

(metaplasia and hyperplasia,

males and females combined) 20 symptoms more frequently than rats

Percent of animals with larynx lesions fed methylmercury alone.22 Effects on the Digestive 0 0 0.2 0.4 0.6 System Piperonyl butoxide concentration (milligrams per liter) Researchers at the National Institute of Hygienic Sciences (Japan) found that Source: long-term exposure to PBO caused U.S. EPA. Office of Prevention, Pesticides and Toxic Substances. 1994. EPA Id# 067501. intestinal ulcers in rats. Intestinal bleed- Piperonyl butoxide. Review of a series 82-4 subchronic inhalation toxicity study in rats. Memo from J. Doherty, Health Effects Division, to A. Dixon and B. Sidwell, Special Review and ing was also more common in exposed Reregistration Division. Washington, D.C., June 22. rats than in unexposed ones.23

Piperonyl butoxide damaged the larynx at all dose levels tested. Effects on the Larynx The larynx is susceptible to dam- age from breathing PBO-contaminated Figure 4 air. A study conducted by a manu- Exposure to Piperonyl Butoxide Increases Cholesterol Levels facturers’ task force found damage at 24 200 all dose levels tested. (See Figure 3.) The damage consisted of metaplasia, transformation of cells to an atypical form, and hyperplasia, an abnormal increase in the number of cells in an organ.25 Effects on the Liver and 100 Kidney In laboratory toxicology studies, PBO often affects the liver. For ex- ample, in the study of the digestive

Cholesterol concentration system mentioned above, liver weights males and females combined) in all exposed rats were greater than in unexposed rats. The researchers also (as percent of level in unexposed animals; 0 23 030100 500 observed liver damage. Other re- searchers in the same laboratory found Amount of piperonyl butoxide consumed for 25 weeks (milligrams per kilogram of body weight per day) that liver damage occurred following as little as one week of exposure.26 In Source: U.S. EPA. Office of Prevention, Pesticides and Toxic Substances. 1988. EPA Reg. No.: a study with dogs conducted by a 4816-72. Piperonyl butoxide. Review of a chronic feeding/oncogenicity study submitted by the manufacturers’ task force, liver dam- Piperonyl Butoxide Task Force. Memo from J. Doherty, Hazard Evaluation Division, to P. Hutton 27 and G. Werdig, Registration Division. Washington, D.C., Apr. 28. age occurred at all dose levels tested. A similar study with a lower dose level Piperonyl butoxide exposure increases cholesterol levels. found liver damage at all but the

NORTHWEST COALITION FOR ALTERNATIVES TO PESTICIDES/NCAP 14 P. O. BOX 1393, EUGENE, OREGON 97440 / (541)344-5044 JOURNAL OF PESTICIDE REFORM/ SUMMER 2002 ¥ VOL. 22, NO. 2 lowest level.27 Liver damage also oc- caused liver cancer.37 studies that found no evidence that curred in studies with mice.28 A contaminant of PBO causes can- PBO exposure caused cancer.42 Researchers from the Tokyo Metro- cer. The contaminant is safrole, which politan Research Laboratory studied ef- the National Toxicology Program clas- Mutagenicity fects of PBO on kidneys. In a three- sifies as “reasonably anticipated to be (Genetic Damage) month feeding study with rats, they a human carcinogen.”38 Researchers at While some tests for genetic damage found kidney damage at all dose lev- the UFR de Pharmacie (France) found have shown that PBO “does not dem- els tested. Damage included atrophy safrole in all of the PBO samples they onstrate any significant potential for and dilation of kidney structures.29 tested. The samples were provided mutagenicity,”43 this synergist does by European manufacturers.39 cause genetic damage in other tests. Effects on the In addition, PBO can increase the In 1995, researchers from the Tokyo Circulatory System carcinogenicity of other cancer-caus- Metropolitan Research Laboratory of Long-term feeding of PBO caused ing chemicals. Researchers at Harvard Public Health studied PBO’s effects anemia in rats in a study conducted Medical School and the National Can- on a cell culture derived from hu- by researchers from the Tokyo Metro- cer Institute found that the combina- man embryo cells. They found that politan Research Laboratory of Public tion of Freon (a refrigerant that was PBO caused mutations in a gene Health. The amount of hemoglobin (an also used as a propellant in aerosol called OuaR. Also, PBO caused mu- oxygen-carrying molecule in blood) pesticides) and PBO was more carci- tations in K-ras, a gene “believed to was lower in exposed rats than unex- nogenic than either chemical alone.40 be involved in neoplastic [tumorous] posed ones at all dose levels tested.30 The liver carcinogen N-hydroxy-2- changes.”44 In another study by the same group acetylaminofluorene also is more car- Another study from the same of researchers, a three-month expo- cinogenic when combined with PBO laboratory found that PBO caused sis- sure to PBO increased the blood lev- than it is alone.41 ter chromatid exchanges in cultures of els of cholesterol in rats. Cholesterol However, the carcinogenicity of PBO cells from hamster ovaries.45 (Sister levels at the highest dose were about is still controversial to some reviewers. chromatid exchanges are exchanges of double the level in unexposed rats.31 The World Health Organization, in a genetic material within a chromosome.46) A study by a manufacturers’ task 1995 review, identified five other PBO’s contaminant safrole also force also found that PBO increased cholesterol. Rats exposed in a long- term study had higher cholesterol lev- Figure 5 els than unexposed rats at all but the Exposure to Piperonyl Butoxide Causes Cancer lowest dose tested.32 (See Figure 4.) 35 Carcinogenicity

Since 1995, EPA has classified pip- 30 eronyl butoxide as carcinogen (a chemical that causes cancer). EPA’s 25 classification of piperonyl butoxide is “Group C,” a possible human carcino- gen. EPA based its evaluation on a 20 study of mice conducted by a manufacturers’ task force. The study 15 found that piperonyl butoxide caused 33,34 10

liver tumors and cancer. (See (both sexes combined) Figure 5.) PBO also caused liver cancer in 5 mice in a study conducted by research-

ers from the Tokyo Metropolitan Re- Percent of animals with liver tumors and cancer 0 search Laboratory. At the highest dose level, almost half of the mice tested 0 100 200 300 developed liver cancer.35 Amount of piperonyl butoxide consumed PBO has also caused cancer in rats. (milligrams per kilogram of body weight per day) A study conducted by PBO manufac- turers found the incidence of lymph Source: U.S. EPA. Office of Prevention, Pesticides and Toxic Substances. 1995. Carcinogenicity peer review of piperonyl butoxide. Memo from J. Doherty and E. Rinde , Health and thyroid tumors increased with in- Effects Division, to R. Keigwin, Registration Division, and A. Dixon and B. Sidwell, Special creasing exposure to PBO.36 A second Review and Reregistration Division. Washington, D.C., June 7. study, by the Japanese researchers mentioned above, found that PBO EPA classifies PBO as a carcinogen because it causes liver tumors and cancer.

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caused sister chromatid exchanges in Metropolitan Research Laboratory ing of the third generation.) Also, nurs- this study.45 found other effects on reproduction. ing pups of exposed mothers weighed In addition, a study conducted by a The offspring of mice that were fed less than pups with unexposed PBO manufacturer found that the fre- PBO before, during, and after preg- mothers. In the third generation, sev- quency of a mutation called HGPRT nancy weighed less than the offspring eral behaviors, including the olfactory was 2 to 4 times higher in hamster of unexposed mice. This decrease oc- home-recognition behavior mentioned ovary cells exposed to PBO than in curred at all the dose levels tested in above, were also affected by PBO ex- unexposed cells. However, EPA agreed this experiment. In addition, PBO posure. The effects on the weight of with the study authors that this was caused changes in the home recogni- nursing pups occurred at all dose lev- “not of biological significance.”47 tion olfactory behavior of the offspring els tested, the behavioral effects oc- of exposed mothers. In a test where curred at all but the lowest dose Effects on Reproduction the mice had a choice of entering a level.51 In laboratory tests, PBO has ad- compartment with wood chips from A third study from the same labora- versely affected a variety of reproduc- their home cage or entering a com- tory used a different kind of expo- tive functions. partment with fresh (unused) chips, sure. In this study, pregnant mice were Atrophy of the testes was observed the offspring of exposed mothers were given a single dose of PBO on the in a two-year feeding study with rats less likely to enter the compartment ninth day of their pregnancy. The conducted by a manufacturers’ task that smelled like home than the off- weight of fetuses from exposed moth- force,48 along with some decreases in spring of unexposed mothers. This ers was less than the weight of fe- weight of the seminal vesicles (sperm- behavioral change occurred at all but tuses from unexposed mothers. This producing structures).49 (See Figure 6.) the lowest dose level tested.50 effect occurred at all dose levels tested Increased incidence of testicular atro- A three-generation study by re- for female fetuses and all but the low- phy occurred at all dose levels tested. searchers from the same laboratory est dose level for males. The number However, because the average weight found that litter size and weight were of fetal deaths was also higher for ex- of the testes did not decrease, EPA less for exposed mothers than for un- posed mothers. These increased fetal concluded that “the data did not exposed ones. (Animals were fed PBO deaths occurred at all but the lowest provide conclusive evidence.”48 continuously from an age of 5 days in dose level tested. These researchers A series of studies at the Tokyo the first generation through the wean- also found that the frequency of fe- tuses with defective or missing fingers was higher for mothers exposed at all Figure 6 but the lowest dose level.52 Exposure to Piperonyl Butoxide Causes Atrophied Testes A study conducted by a manu- facturers’ task force found that the in- 30 cidence of a bone defect was higher in the offspring of rats exposed dur- ing pregnancy than in the offspring of unexposed rats. The incidence was dose-related and was 2 to 4 times 20 higher for exposed rats than for unex- posed ones. However, EPA concurred “with the study author’s conclusions that these effects were not related to treatment.”53 10 Effects on the Immune System Medical researchers first docu-

(both right and left testes damaged) mented PBO’s ability to inhibit normal functions of the immune system in

Number of animals with bilateral testicular atrophy 0 030100 500 1979. Physicians from the State Uni- Amount of piperonyl butoxide consumed versity of New York (Buffalo) showed (milligrams per kilogram of body weight per day) that PBO inhibited the immune re- sponse of human blood cells called Source: U.S. EPA. Office of Prevention, Pesticides and Toxic Substances. 1988. EPA Reg. No.: lymphocytes. PBO caused stronger in- 4816-72. Piperonyl butoxide. Review of a chronic feeding/oncogenicity study submitted by the Piperonyl Butoxide Task Force. Memo from J. Doherty, Hazard Evaluation Division, to P. Hutton hibition (25 percent) than the seven and G. Werdig, Registration Division. Washington, D.C., Apr. 28. p. R12-R13. other pesticide chemicals tested.54 In a recent (1999) study, researchers Piperonyl butoxide caused atrophied testes in a long-term feeding study of rats. from the University of Applied Sciences

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(Germany) found similar results: PBO caused about a 50 percent reduction Figure 7 in the immune response of human Piperonyl Inhibits Immune System Function lymphocytes.55 (See Figure 7.) 100 Effects on Hormones The impact of environmental con- taminants on the normal function of 80 human and animal hormone systems has been a significant concern in the 56 last decade. Hormones are biologi- 60 cally active molecules that control all responses and functions of the body. Dramatic changes in the activity of cells 40 in humans and other animals “are caused by extremely small amounts”

of hormones or other chemicals that (percent of unexposed cells) 57 20 disrupt this system. stimulation by phytohemagglutinin Since the P450 enzymes inhibited by PBO break down steroids (a class Proliferation of lymphocytes in response to 0 of chemicals that includes many sex Unexposed Exposed hormones),13 it is not surprising that PBO can have this kind of hormonal Source: Diel, F. et al. 1999. Pyrethroids and piperonyl-butoxide affect human T-lymphocytes in effect. A study conducted by a task vitro. Toxicol. Lett. 107: 65-74. force of PBO manufacturers showed that long-term exposure of rats to PBO Piperonyl butoxide reduces the activity of immune system cells in human blood. damages hormone-related organs. In exposed animals, thyroid glands were occur in the noses of many species, monly detected pesticide. PBO con- larger than in unexposed animals. Also, and some of these enzymes are centrations were highest in homes that adrenal glands in exposed females inhibited by PBO.60 had been treated with insecticide aero- were larger than in unexposed females, Finally, PBO can inhibit the break- sol spray cans or “bombs.”62 and pituitary glands were smaller in down of toxic chemicals in the soil by exposed males.58 inhibiting the enzymes in microorgan- isms that usually do the detoxifica- “The monitoring Increasing Exposure to tion. For example, researchers at the Potentially Toxic Chemicals Institute for Environmental Studies (Il- found PBO in air PBO can increase exposure of linois) found that about 1 1/2 times as samples from people and other species to toxic much benzidine, a carcinogen, per- over 80 percent chemicals in several different ways. sisted for a month when the soil was First, this synergist affects the treated with both benzidine and PBO of the women in amount of certain toxic chemicals that as persisted when the treatment used the study.” are absorbed through skin. Veterinar- only benzidine.61 ians at North Carolina State University Exposure Contamination of Food found that PBO exposure increased the absorption of the insecticide car- Because PBO is frequently used for PBO is regularly found on food. baryl through skin. When exposure to household pesticide treatments, people The U.S. Department of Agriculture has PBO occurred, skin absorption was are frequently exposed. A recent (2002) found PBO on spinach,63 peas, sweet about double the rate without PBO study of pregnant women conducted potatoes,64 tomatoes, peaches, exposure. The veterinarians believe by researchers from Columbia Univer- squash,65 strawberries,66 bell peppers,67 that the increased absorption was sity documented how often this expo- grapes, and pineapples.68 caused by PBO’s ability to irritate the sure occurs. In this study, women from Effects on Birds skin.59 northern Manhattan and the South Second, PBO can inhibit the activ- Bronx (New York) wore personal air According to a study conducted by ity of P450 enzymes in the nose that monitors for two days and left the a manufacturers’ task force, PBO would otherwise detoxify chemicals monitor near their beds at night. The adversely affected reproduction in mal- that are inhaled. Researchers from the monitoring found PBO in air samples lard ducks. PBO affected the number Lovelace Respiratory Institute showed from over 80 percent of women in the of eggs laid, the number of eggs that that high levels of detoxifying enzymes study. PBO was the fourth most com- cracked while being hatched, and the

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2,3,7,8-TCDD) into a form that gold- Figure 8 fish can eliminate.76 This resulted in Effects of Piperonyl Butoxide on Fish higher bioaccumulation of the dioxin. Activity of a hormone- Bioconcentration (See Figure 8.) Researchers at the Medi- transforming enzyme of a dioxin cal College of Wisconsin found that PBO inhibited the breakdown of di-2- 100 150 ethylhexyl phthalate77 (DEHP, a chemi- cal that causes cancer and genetic dam- age)78 and nonyl phenol (an estrogen 80 mimic that disrupts normal hormone function) in rainbow trout.79

-hydroxylase 100

Β In addition, PBO can disrupt fish 60 hormone systems. Researchers from Oregon State University showed that PBO strongly inhibits the activity of 40 an enzyme called progesterone-6ß-hy- 50 droxylase in rainbow trout livers.80 (See

Bioconcentration factor Figure 8.) Progesterone regulates egg 20 maturation in fish.81

Activity of progesterone-6

(percent of the activity in unexposed cells) (concentration in fish/concentration in water) Effects on Other Aquatic 0 0 Animals Unexposed Exposed Unexposed Exposed PBO is “highly” acutely toxic to Sources: water fleas, shrimp and oysters. Stud- Sijm, D.T.H.M., G. Schaap, and A. Opperhuizen. 1993. The effect of the biotransformation ies conducted by a manufacturers’ task inhibitor piperonyl butoxide on the bioconcentration of 2,8-dichlorodibenzo-p-dioxin and force found that concentrations of less pentachlorobenzene in goldfish. Aquat. Toxicol. 27: 345-360. Miranda, C.L., M.C. Henderson, and D.R. Buhler. 1998. Evaluation of chemicals as inhibitors of than one ppm killed all three of these trout cytochrome P450s. Toxicol. Appl. Pharmacol. 148: 237-244. species.69 Another of the task force’s studies Piperonyl butoxide can disrupt fish hormone systems and increase the concentration of toxic found adverse effects on water flea chemicals in fish tissues. reproduction at concentrations as low as 12 parts per billion.69 Supporting thickness of the eggshells.69 minnow, a standard test fish.69 these results, a study from North Caro- Researchers from the Indian Insti- PBO also increases the toxicity to lina State University found that expo- tute of Chemical Technology found fish of a variety of pesticides. For ex- sure of water fleas to PBO altered the that PBO inhibited “important detoxi- ample, studies done by the New York transformation of the sex hormone fication enzymes” in the kidney, lung, Department of Environmental Conser- testosterone. Less than one ppm brain, and heart of pigeons. These en- vation found that, compared to fish inhibited most enzymes that transform zymes “protect the cell against chemi- exposed to the insecticide resmethrin testosterone over 60 percent.82 cally induced damages” so that inhibi- alone, mortality was higher and swim- tion of their activity could make the ming stamina less in fish exposed to Effects on Insects birds more susceptible to a variety of both PBO and resmethrin.71,72 PBO In addition to making other insecti- toxic chemicals.70 also increased bioconcentration of the cides more toxic to pest insects, PBO insecticide phenothrin in a study of can increase the toxicity of insecticides Effects on Fish carp conducted by the Sumitomo to beneficial insects, such as honey In terms of its acute toxicity (ability Chemical Co., Ltd.73 Other studies (by bees and water beetles.83,84 to cause mortality in a time period up researchers at the University of Wis- PBO also has more unexpected ef- to 96 hours long), PBO is classified as consin-Milwaukee and the Illinois Natu- fects. Researchers from the University “moderately toxic” to fish. Concentra- ral History Survey) found that PBO of South Australia showed that PBO tions between 3 and 7 parts per mil- decreased the ability of fish to detoxify exposure of fruit flies increased the lion (ppm) are sufficient to kill fish.69 the pesticides rotenone, aldrin, meth- genetic damage caused by X-rays and PBO affects the ability of fish to oxychlor, and trifluralin.74,75 the mutagenic chemical heliotrine.85 successfully reproduce at much lower PBO increases the toxicity of other U.S. Dept. of Agriculture researchers concentrations than are required for chemicals to fish. A study from the showed that PBO inhibits the activity mortality. In a study conducted by a University of Utrecht (The Netherlands) of enzymes involved in the breakdown manufacturers’ task force, concentra- found that PBO slowed the transfor- or synthesis of insect sex phero- tions of less than 1 ppm reduced egg mation of the dioxin 2,8-DCDD (a mones,86 chemicals insects use for hatch and larval growth in the fathead chemical relative of the notorious communication between males and

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females.87 University (Germany) found that PBO World Health Organization. Pp. 282. persisted for at least two weeks after 18. Bateman, D.N. 2000. Management of pyrethroid Toxicity to Earthworms exposure. Clin. Toxicol. 38: 107-109. a cockroach treatment on toys and in 19. Tanaka, T. 1993. Behavioral effects of piperonyl University of Kentucky researchers dust in a kindergarten.98 butoxide in male mice. Toxicol. Lett. 69: 155- tested the acute toxicity of a variety of 161. 20. Ware, G.W. 2000. The pesticide book. Fresno chemicals to a common earthworm, References CA: Thomson Publications. p. 379. Eisenia foetida. They found that pip- 21. Takahashi, O. et al. 1994. Chronic toxicity stud- eronyl butoxide was “very toxic” to 1. Tozzi, A. 1998. A brief history of the develop- ies of piperonyl butoxide in F344 rats. Induction 88 ment of piperonyl butoxide as an insecticide syn- of hepatocellular carcinoma. Fund. Appl. this earthworm. ergist. In D.G. Jones, ed. Piperonyl butoxide: Pharmacol. 22: 291-303. The insecticide synergist. San Diego: Academic 22. Friedman, M.A. and L. R. Eaton. 1978. Poten- Effects on Plants Press. Pp. 1-5. tiation of methyl mercury toxicity by piperonyl 2. U.S. EPA. Office of Pesticide Programs. 2002. butoxide. Bull. Environ. Contam. Toxicol. 20: 9- Although it is perhaps unexpected USEPA/OPP chemical ingredients database. 10. for a chemical usually used as an in- www.cdpr.ca.gov. 23. Maekawa, A. et al. 1985. Lack of evidence of secticide synergist, PBO can affect plant 3. Aspelin, A.L. and A.H. Grube. 1999. Pesticides carcinogenicity of technical-grade piperonyl bu- industry sales and usage: 1996 and 1997 mar- toxide in F344 rats: Selective induction of physiology. For example, researchers ket estimates. U.S. EPA. Office of Pesticide Pro- ileocaecal ulcers. Fd. Chem. Toxic. 23: 675-682. at Ibaraki University (Japan) found that grams. p. 20. www.epa.gov/pesticides. 24. U.S. EPA. Office of Prevention, Pesticides and PBO inhibited P450 enzymes in rice 4. Farnham, A.W. 1998. The mode of action of Toxic Substances. 1994. EPA Id# 067501. Pip- piperonyl butoxide with reference to studying eronyl butoxide. Review of a series 82-4 leaves that produce phytoalexins, com- pesticide resistance. In D.G. Jones, ed. Pipero- subchronic inhalation toxicity study in rats. Memo pounds that inhibit the germination of nyl butoxide: The insecticide synergist. San Di- from J. Doherty, Health Effects Division, to A. disease-causing fungus spores.89 PBO ego: Academic Press. Pp. 199-213. Dixon and B. Sidwell, Special Review and 5. Hainzal, D., L.M. Cole, and J.E. Casida. 1998. Reregistration Division. Washington, D.C., June causes flowering in asparagus, also by Mechanisms for selective toxicity of fipronil in- 22. inhibiting P450 enzymes.90 secticide and its sulfone metabolite and desulfinyl 25. National Cancer Institute. Undated. Cancer.gov PBO also increases herbicide dam- photoproduct. Chem. Res. Toxicol. 11: 1529- dictionary. www.nci.nih.gov/dictionary. 1535. 26. Fujitani, T., Y. Tada, and M. Yoneyama. 1993. age to plants. It increases the damage 6. Levine, B.S. and S.D. Murphy. 1977. Esterase Hepatotoxicity of piperonyl butoxide in male F344 to corn caused by the sulfonylurea inhibition and reactivation in relation to pipero- rats. Toxicol. 84: 171-183. 91 nyl butoxide-phosphorothionate interactions. 27. Ref. #17, p. 287-288. herbicides primisulfuron and Toxicol. Appl. Pharmacol. 40: 379-391. 92 28. Fujitani, T., T. Tanaka, Y. Hashimoto, and M. tribenuron, the thiocarbamate herbi- 7. Tripathi, A.M. and R.A. Agarwal. 1998. Mollus- Yoneyama. 1993. Subacute toxicity of piperonyl cide EPTC,93 and the triazine herbi- cicidal and anti-AChE activity of tertiary mixtures butoxide in ICR mice. Toxicol. 83: 93-100. of pesticides. Arch. Environ. Contam. Toxicol. 29. Fujitani, T., Y. Tada, and M. Yoneyama. 1993. cides atrazine, terbutryn, and pro- 34: 271-274. 94 Hepatotoxicity of piperonyl butoxide in male F344 metryn. Similar increases in the tox- 8. Keane, P. 1998. The use of piperonyl butoxide rats. Toxicol. 84: 171-183. icity of sulfonylurea herbicides have in formulations for the control of pests of hu- 30. Takahashi, O. et al. 1994. Chronic toxicity stud- been documented in soybeans, mans, domestic pets and food animals. In D.G. ies of piperonyl butoxide in F344 rats: Induction Jones, ed. Piperonyl butoxide: The insecticide of hepatocellular carcinoma. Fund. Appl. lambsquarter, and a variety of weedy synergist. San Diego: Academic Press. Pp. 290- Pharmacol. 22: 291-303. 95,96 grasses. 300. 31. Fujitani, T. et al. 1992. Sub-acute toxicity of pip- 9. Carpenter, L.J. and R.A. Roth. 1988. Potentia- eronyl butoxide in F344 rats. Toxicol. 72: 291- Persistence tion by piperonyl butoxide of alpha- 298. naphthylthiourea toxicity in the isolated, perfused 32. U.S. EPA. Office of Prevention, Pesticides and Outdoors: PBO’s half-life (the time rat lung. Biochem. Pharmacol. 37: 771-772. Toxic Substances. 1988. EPA Reg. No.: 4816- required for half of applied PBO to 10. Whitmore, R.W., J.E. Kelly, and P.L. Reading. 72. Piperonyl butoxide. Review of a chronic feed- 1992. National home and garden pesticide use ing/oncogenicity study submitted by the Pipero- break down or move away from the survey. Final report, vol. 1: Executive summary, nyl Butoxide Task Force. Memo from J. Doherty, application site) is about 4 days in results, and recommendations. Research Tri- Hazard Evaluation Division, to P. Hutton and G. field tests of agricultural soils con- angle Park NC: Research Triangle Institute. Werdig, Registration Division. Washington, D.C., Table G-1. Apr. 28. ducted by a manufacturers’ task force. 11. Adgate, J.L. et al. 2000. Pesticide storage and 33. U.S. EPA. Office of Prevention, Pesticides and In the same tests, conducted in Cali- use patterns in Minnesota households with chil- Toxic Substances. 1995. Carcinogenicity peer fornia, Georgia, and Michigan, PBO dren. J. Exp. Anal. Environ. Epidemiol. 10: 159- review of piperonyl butoxide. Memo from J. 167. Doherty and E. Rinde , Health Effects Division, persisted (measured as the time re- 12. Calif. Dept. of Pesticide Regulation. 2001. Sum- to R. Keigwin, Registration Division, and A. Dixon quired for all applied PBO to dissi- mary of pesticide use report data 2000. Indexed and B. Sidwell, Special Review and pate) up to 30 days.97 by chemical. Preliminary data. www.cdpr.ca.gov. Reregistration Division. Washington, D.C., June 13. Hodgson, E. and P.E. Levi. 1998. Interactions 7. The manufacturers’ task force also of piperonyl butoxide with cytochrome P450. In 34. National Cancer Institute. Undated. Cancer.gov measured PBO’s half-life and persis- D.G. Jones, ed. Piperonyl butoxide: The insecti- dictionary. www.nci.nih.gov/dictionary. tence in water and aquatic sediments. cide synergist. San Diego: Academic Press. Pp. 35. Takahashi, O. et al. 1997. Chronic toxicity stud- 41-54. ies of piperonyl butoxide in CD-1 mice: Induc- In water tested in California, Arkan- 14. Federal Insecticide, Fungicide, and Rodenticide tion of hepatocellular carcinoma. Toxicol. 124: sas, and Mississippi, the half-life was Act Sec. 2(m). 95-103. about a day. In sediments, the half- 15. 40 Code of Federal Regulations ¤ 158.340. 36. Ref. #17, p. 291 16. Prentiss, Inc. 1998. Material safety data sheet: 37. Takahashi, O. et al. 1994. Chronic toxicity stud- life was up to 24 days and PBO 655-113 Prentox¨ piperonyl butoxide technical. ies of piperonyl butoxide in F344 rats. Induction persisted up to 120 days.97 www.prentiss.com/msds/pdf/655_113.pdf. of hepatocellular carcinoma. Fund. Appl. Indoors: There is less information 17. World Health Organization and Food and Agri- Pharmacol. 22: 291-303. cultural Organization. 1996. Pesticide residues 38. U.S. Department of Health and Human Services. available about PBO’s persistence in- in food — Evaluations 1995. [Part II] Toxicologi- Public Health Service. National Toxicology Pro- doors, but a study from Justus Liebig cal and environmental. Geneva, Switzerland: gram. 2001. 9th report on carcinogens. Safrole.

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http://ehp.niehs.nih.gov/roc/ninth/rahc/safrole.pdf. comparisons of xenobiotic-metabolizing en- isomers by rainbow trout (Oncorhynchus mykiss): 39. Schreiber-Deturmeny, E.M., A.M. Pauli, and zymes. Mut. Res. 380: 43-59. In vivo and in vitro microsomal metabolites. J.L. Pastor. 1993. Determination of safrole, 61. Lu, P.-Y. 1977. The environmental fate of three Xenobiotica 26: 1167-1180. dihydro-safrole, and chloromethyldihydrosafrole carcinogens: benzo-(a)-pyrene, benzidine, and 80. Miranda, C.L., M.C. Henderson, and D.R. Buhler. in piperonyl butoxide by high-performance liq- vinyl chloride evaluated in laboratory model eco- 1998. Evaluation of chemicals as inhibitors of uid chromatography. J. Pharmaceut. Sci. 82: systems. Arch. Environ. Contam. Toxicol. 6: 129- trout cytochrome P450s. Toxicol. Appl. 813-816. 142. Pharmacol. 148: 237-244. 40. Epstein, S. et al. 1967. Synergistic toxicity and 62. Whyatt, R.M. 2002. Residential pesticide use 81. Paolucci, M., N. Custodia, and I.P. Callard. 1998. carcinogenicity of ‘Freons’ and piperonyl butox- during pregnancy among a cohort of urban mi- Progesterone effects and receptors, subavian ide. Nature 214: 526-528. nority women. Environ. Health Persp. 110: 507- species. In Knobil, E. and J.D. Neill. Encyclope- 41. Fujii, K. and S. Epstein. 1979. Effects of pipero- 514. dia of reproduction. Vol. 4. San Diego: Academic nyl butoxide on the toxicity and hepato- 63. U.S. Dept. of Agriculture. Agricultural Marketing Press. Pp. 16-23. carcinogenicity of 2-acetylaminofluorene and 4- Service. Science and Technology Division. 1997. 82. Baldwin, W.S. and G. A. LeBlanc. 1994. Identifi- acetylaminobiphenyl, and their N-hydroxylated Pesticide data program: Annual summary cal- cation of multiple steroid hydroxylases in Daph- derivatives, following administration to newborn endar year 1995. Appendix E. p. 9. nia magna and their modulation by xenobiotics. mice. Oncol. 36: 105-112. 64. U.S. Dept. of Agriculture. Agricultural Marketing Environ. Toxicol. Chem. 13: 1013-1021. 42. Ref. #17, pp. 288-293. Service. Science and Technology Division. 1998. 83. Hagler, J.R., G.D. Waller, and B.E. Lewis. 1989. 43. Breathnach, R. 1998. The safety of piperonyl Pesticide data program: Annual summary cal- Mortality of honeybees (Hymenoptera: Apidae) butoxide. In D.G. Jones, ed. Piperonyl butoxide: endar year 1996. Appendix D. p. 23. exposed to permethrin and combinations of The insecticide synergist. San Diego: Academic 65. U.S. Dept. of Agriculture. Agricultural Marketing permethrin with piperonyl butoxide. J. Apicult. Press. p. 23. Service. Science and Technology Division. 1998. Res. 28: 208-211. 44. Suzuki, H. and N. Suzuki. 1995. Piperonyl bu- Pesticide data program: Annual summary cal- 84. Federle, P.F. and W.J. Collins. 1976. Insecti- toxide mutagenicity in human cells. Mut. Res. endar year 1997. Appendix E. p. 23. cide toxicity to three insects from Ohio ponds. 344: 27-30. 66. U.S. Dept. of Agriculture. Agricultural Marketing Ohio J. Sci. 76: 19-24. 45. Tayama, S. 1996. Cytogenetic effects of pipero- Service. Science and Technology Division. 2000. 85. Lindsay, R.J. and A.M. Clark. 1978. The effect nyl butoxide and safrole in CHO-K1 cells. Mut. Pesticide data program: Annual summary cal- of microsomal enzyme inhibitor, piperonyl bu- Res. 368: 249-260. endar year 1998. Appendix E. p. 29. toxide, on mutagenesis in Drosophila 46. U.S. EPA. Prevention, Pesticides and Toxic Sub- 67. U.S. Dept. of Agriculture. Agricultural Marketing melanogaster. (Abstract.) Mut. Res. 53: 221. stances. 1998. Health effects test guidelines: Service. Science and Technology Division. 2001. 86. Fang, N., P.E.A. Teal, and J.H. Tumlinson. 1995. OPPTS 870.5915. In vivo sister chromatid ex- Pesticide data program: Annual summary cal- Characterization of oxidase(s) associated with change assay. www.epa.gov/pesticides. endar year 1999. Appendix E. p. 30. the sex pheromone gland in Manduca sexta (L.) 47. U.S. EPA. Office of Pesticides and Toxic Sub- 68. U.S. Dept. of Agriculture. Agricultural Marketing females. Arch. Insect Biochem. Physiol. 29: 243- stances. 1985. Piperonyl butoxide-mutagenicity Service. Science and Technology Division. 2001. 257. study submitted in response to Special Review Pesticide data program: Annual summary cal- 87. Ref. # 20, p. 387. DCI. Accession No. 257430. Registration No. endar year 2000. Appendix E. p. 39. 88. Roberts, B.L. and H.W. Dorough. 1984. Rela- 1021-974. Caswell: 670. Memo from I. Mauer, 69. Osimitz, T.G. and J.F. Hobson. 1998. An eco- tive toxicities of chemicals to the earthworm Hazard Evaluation Div. to T. Gardner and P. logical risk assessment of piperonyl butoxide. In Eisenia foetida. Environ. Toxicol. Chem. 3: 67- Shroeder, Registration Div. Washington, D.C., D.G. Jones, ed. Piperonyl butoxide: The insecti- 78. June 27. cide synergist. San Diego: Academic Press. Pp. 89. 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Pyrethroids and piperonyl- of the pesticide synergist piperonyl butoxide on nyl butoxide. Phytoparasitica 19: 225-236. butoxide affect human T-lymphocytes in vitro. metabolism of pesticides in green sunfish. Pest. 95. Kwon, C.S., J.J. Kells, and D. Penner. 1995. Toxicol. Lett. 107: 65-74. Biochem. Physiol. 6: 401-412. Combined effects of acetolactate synthase-in- 56. National Research Council. Commission on Life 76. Sijm, D.T.H.M., G. Schaap, and A. Opperhuizen. hibiting herbicides with terbufos and piperonyl Sciences. Board on Environmental Studies and 1993. The effect of the biotransformation inhibi- butoxide on corn (Zea mays) and soybean (Gly- Toxicology. Committee on Hormonally Active tor piperonyl butoxide on the bioconcentration cine max). Weed Technol. 9: 696-702. Agents in the Environment. 1999. Hormonally of 2,8-dichlorodibenzo-p-dioxin and penta- 96. Kwon, C. and D. Penner. 1996. The effect of active agents in the environment. Washington, chlorobenzene in goldfish. Aquat. 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