Landresources.montana.edu

Author's personal copy
Regulatory Toxicology and Pharmacology 51 (2008) 31–36 Contents lists available at ScienceDirect j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y r t p h Risk assessments for the insect repellents DEET and picaridin Frank B. Antwi a,1, Leslie M. Shama b,2, Robert K.D. Peterson a,* a Department of Land Resources and Environmental Sciences, Montana State University, 334 Leon Johnson Hall, Bozeman, MT 59717-3120, USAb Sacramento-Yolo Mosquito and Vector Control District, Elk Grove, CA 95624-1477, USA For the use of topical insect repellents, DEET and picaridin, human health risk assessments were con- ducted for various population subgroups. Acute, subchronic, and chronic dermal exposures were exam- ined. No-observed-effect-levels (NOELs) of 200, 300, and 100 mg/kg body weight (BW) were used asendpoints for DEET for acute, subchronic, and chronic exposures, respectively. For picaridin, a NOEL of 2000 mg/kg BW/day for acute exposure and a NOEL of 200 mg/kg BW/day for subchronic and chronic exposures were used. Daily exposures to several population subgroups were estimated. Risks were char- acterized using the Margin of Exposure (MOE) method (NOEL divided by the estimated exposure), whereby estimated MOEs were compared to an MOE of 100. Estimates of daily exposures ranged from 2 to 59 mg/kg BW/day for DEET and 2 to 22 mg/kg BW/day for picaridin. Children had the lowest MOEs.
However, none of the estimated exposures exceeded NOELs for either repellent. At 40% DEET for acute exposure, children 612 years had MOEs below 100. For subchronic and chronic exposures children atP25% DEET and at 15% picaridin had MOEs below 100. Therefore, we found no significant toxicologicalrisks from typical usage of these topical insect repellents.
Ó 2008 Elsevier Inc. All rights reserved.
practical (Debboun et al., 2006). Even when comprehensive mos-quito control measures are implemented, personal protective mea- DEET (N,N-diethyl-meta-toluamide or N,N-diethyl-3-methyl- sures can influence the infection rates of West Nile virus (WNV) benzamide) has been recognized widely as a broad spectrum insect and other arthropod vector-borne pathogens of disease (Gujral repellent since its introduction more than five decades ago. It is et al., 2007). Insect repellents are of benefit to civilians during out- efficacious against mosquitoes and other insects of medical and door activities and for military personnel during combat, peace- veterinary importance, and is used at least once in a season by keeping, and training (Frances et al., 2003; Debboun et al., 2005).
approximately 30% of the U.S. population (USEPA, 1998; Veltri Military personnel deployed to areas where malaria and other vec- tor-borne diseases are prevalent commonly use repellents as part Picaridin [2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1- methylpropyl ester] is a new insect repellent for human use Despite the extensive use and efficacy of DEET and its history of (Wahle et al., 1999; WHO, 2000; Scheinfeld, 2004; Carpenter seemingly safe use, there have been a few observations of high et al., 2005), with initial registration in the U.S. in 2001 (USEPA, exposures leading to potentially unacceptable health risks (Rob- 2005). It has been shown to be effective against mosquitoes and bins and Cherniack, 1986; Veltri et al., 1994; Qiu et al., 1998).
a wide range of hematophagous arthropods (Frances et al., 2004; These reports are associated with seizures and encephalopathy in Scheinfeld, 2004; Carpenter et al., 2005).
children (Moody, 1989; Osimitz and Grothaus, 1995; Osimitz and Topical application of insect repellents to exposed skin, as part Murphy, 1997; Sudakin and Trevathan, 2003) and extensive skin of personal protection measures, reduces human contact with vec- absorption that leads to entrance of large amounts of DEET into tor and nuisance arthropods (Gupta and Rutledge, 1994). Repel- systemic circulation (Robbins and Cherniack, 1986). This suggests lents are of primary importance when other methods of that exposures with frequent or prolonged topical applications of protecting humans against arthropod vectors are not possible or DEET may result in central nervous system toxicity in some indi-viduals. DEET, picaridin, IR 3535 (3-[-butyl-N-acetyl]-amino propi-onic acid), PMD (para-methane-diol), lemon eucalytus oil, and * Corresponding author. Fax: +1 406 994 3933.
citronella oil are among the few insect repellents registered for E-mail addresses: frank.antwi@montana.edu (F.B. Antwi), lmshama@hotmail.
topical applications to humans. The application of DEET and com (L.M. Shama), bpeterson@montana.edu (R.K.D. Peterson).
picaridin on the skin may be made at home, outdoors, and by chil- dren or untrained individuals who may apply them in a manner 0273-2300/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.yrtph.2008.03.002 Author's personal copy
F.B. Antwi et al. / Regulatory Toxicology and Pharmacology 51 (2008) 31–36 inconsistent with label statements. Although there is a restriction on how much active ingredient can be used in the products, there Dermal application of DEET to micropigsÒ for 13 weeks at dosage levels of 0, is no restriction on purchasing products containing these active 100, 300, or 1,000 mg/kg BW/day did not produce any systemic toxicity (USEPA,1998). Hence, the NOEL was determined to be 1000 mg/kg BW/day (USEPA, ingredients. These special situations point to the need for human 1998). At the skin application site, treated animals had an increase in desquamation health risk assessments for population subgroups.
and dry skin (USEPA, 1998). In the rat study using the same dosage levels as in the Although there have been some toxicity studies and safety re- micropig study, USEPA set the lowest-observed-effect-level (LOEL) at 1000 mg/kg views for DEET (Robbins and Cherniack, 1986; Osimitz and Grot- BW/day and the NOEL at 300 mg/kg BW/day based on a decrease in body-weight haus, 1995; Qiu et al., 1997, 1998; Fradin, 1998; Goodyer and gain and an increase in liver weight (USEPA, 1998).
Abou-Donia et al. (2001) observed that clinical conditions of rats treated with Behrens, 1998; USEPA, 1998; Young and Evans, 1998; McGready daily dermal applications of 4, 40, and 400 mg/kg BW DEET in ethanol were not et al., 2001; Health Canada, 2002; Koren et al., 2003; Sudakin and different from the controls. There were also no differences observed in the Trevathan, 2003; Blanset et al., 2007) and picaridin (Wahle et al., weight of treated animals when compared to the controls (Abdel-Rahman 1999; WHO, 2000), quantitative dermal risk assessments are lacking et al., 2001; Abou-Donia et al., 2001). However, Abou-Donia et al. (2001) sug-gested that exposures to DEET at 40 and 400 mg/kg BW for 60 days decreased in the scientific literature. Peterson et al. (2006), Davis et al. (2007), blood–brain barrier permeability in certain brain regions, which may have Macedo et al. (2007), and Schleier et al. (2008) have estimated hu- important physiological or pharmacological consequences. Abdel-Rahman et al.
man health and environmental risks from other mosquito manage- (2001) showed histopathological evidence that subchronic dermal exposure to ment and personal protective tactics. Therefore, in this study, we DEET (40 mg/kg BW/day), leading to significant neuronal cell death and cysto- assessed the risk of DEET and picaridin to human health.
skeletal abnormalities in surviving neurons, could compromise function of thebrain. However, severe signs of central nervous system toxicity due to DEETwere apparent only at high dosages (Abdel-Rahman et al., 2001). No exposure- related differences were observed in female and male body weights betweencontrol and exposed groups of animals during a subchronic aerosol study. The 13-week exposure to 250, 750, or 1500 mg/m3 of DEET resulted in no significantchanges in oxygen consumption (Macko and Bergman, 1979). Macko and Berg-man (1979), therefore, concluded that inhalation at 6750 mg/m3 presents little We focused our assessments on human health risks from the application of acute inhalation hazard to humans, and concentrations above this level may DEET and picaridin. These active ingredients are present in the largest number of cause transitory eye and respiratory irritation.
personal protective products currently registered by the United States Environmen-tal Protection Agency (USEPA) in the US for prevention of vector-borne diseases. IR3535, PMD, lemon eucalyptus oil, and citronella oil insect repellents were not in- cluded as part of our risk assessments, primarily because of the lack of robust tox- Even though the principal route of DEET exposure in humans is dermal, very lit- icity data. Our quantitative risk assessment examined acute, subchronic, and tle or no toxicity can be produced in laboratory animals by the dermal route of chronic dermal exposures. Acute exposures were defined as single-day exposures administration (Schoenig et al., 1999). These authors therefore used the oral route within 24 h of repellent application. Subchronic exposures were defined as expo- of administration to satisfy the criterion of evaluating chronic toxicity at a maxi- sure per day for <180 days. Chronic exposures were defined as exposure per day mum tolerance dose. Moreover, the data developed by oral route of administration can be extrapolated easily to potential dermal exposure and are amenable to hu-man risk assessments (Schoenig et al., 1999). The oral route of administration 2.2. Effect assessment and toxic endpoints avoids the problems associated with repeated dermal administration of undilutedDEET and skin irritation that might be produced.
In a 2-year feeding study using rat, mouse, and dog, depressed body weights To determine toxic endpoints, we conducted a MEDLINE search with the key- and food consumption and slight increases in serum cholesterol were observed in words DEET, picaridin, and insect repellents. Articles published in English language female rats at the high-dose level (400 mg/kg BW/day) (Schoenig et al., 1999).
journals between 1968 and 2007 were identified and reviewed. The World Wide The NOEL was determined to be 100 mg/kg BW/day (Schoenig et al., 1999). The only Web, World Health Organization (WHO), U.S. Armed Forces Pest Management treatment-related effect in the mouse feeding study was a slight decrease in body Board (AFPMB), ISI Web of Knowledge, U.S. Centers for Disease Control (CDC), weight and food consumption at the highest dose level (1000 mg/kg BW/day) in U.S. Environmental Protection Agency (USEPA), U.S. Food and Drug Administration, both males and females. Therefore, the NOEL in this study was 500 mg/kg BW/ and Health Canada databases were searched for toxicology and other pertinent day (Schoenig et al., 1999). The chronic toxicity study in dogs revealed an increased information. References of relevant articles also augmented the database search.
incidence of emesis and ptyalism, decreases in body weight and food consumption,and changes in several clinical pathology parameters at 400 mg/kg BW/day. The NOEL was 100 mg/kg BW/day (Schoenig et al., 1999).
Relevant toxicological endpoints and critical no-observed-adverse-effect-levels NOAELs for DEET from existing animal studies have been defined and discussed in For acute and subchronic exposures, we used a NOEL of 200 and 300 mg/kg BW/ depth elsewhere (USEPA, 1998; Tice and Brevard, 1999; Imperial College, 2002). Be- day (USEPA, 1998) as endpoints, based on the rat acute neurotoxicity and sub- cause of this, we will only present an overview of toxicological effects for our risk chronic dermal toxicity, respectively (Table 1). For chronic exposures, we used a NOEL of 100 mg/kg BW/day (Schoenig et al., 1999), based on the rat and dog chronictoxicity studies (Table 1).
McCain et al. (1997) reported an oral LD50 of 3664 mg/kg body weight (BW) in the rat. Mount et al. (1991) examined acute dermal toxicity in dogs with dosages of356, 1426, 1782, and 7128 mg/kg BW. Dogs receiving the highest dosage of7128 mg/kg BW were affected mildly with signs of hypersalivation, restlessness, uncoordination, and depression. However, all dogs recovered after 19 h. Dogs that Picaridin is of low toxicity in rats and mice after oral administration (LD50: received as much as 1782 mg/kg BW showed no clinical signs of toxicity. In a 4743 mg/kg BW), and in rats after dermal (LD50: >5000 mg/kg BW), and inhalation range-finding toxicity test, Carpenter et al. (1974) reported a dermal LD 50: >4364 mg/kg BW) (WHO, 2000). In rabbits, the chemical has negli- 3180 mg/kg BW for rabbits. Dermal application of DEET caused no sensitization gible dermal and limited ocular irritation (WHO, 2000; USEPA, 2005). Picaridin reactions in guinea pigs and slight to no irritation in rabbits at 75% and 100% DEET showed no skin sensitization or phototoxicity (WHO, 2000; USEPA, 2005). In an (Harvey, 1987). Macko and Bergman (1979) did not observe significant differences acute dermal toxicity test, no sign of behavioral or pathological anatomical neuro- in organ-to-body-weight ratios in rats after inhalation (750 mg/m3) exposures to toxicity was observed at 2000 mg/kg BW (WHO, 2000; USEPA, 2005).
saturated vapor. In an acute neurotoxicity screening study, rats with a single doseof DEET by gavage at 0, 50, 200, and 500 mg/kg were observed for 14 days (USEPA, 1998). One hour after dosing, rats showed signs of piloerection, increased vocaliza- Low toxicity was observed in a 13-week rat dermal study (WHO, 2000).
tion, a decrease in horizontal and vertical activity, and an increase in the response Upon cessation of treatment, local skin changes subsided for all treatment groups time to heat, and all recovered 24 h after dosing. Decrease in vertical activity was including the lowest dosage of 80 mg/kg BW/day. Repeated administration of observed during the first 15 minutes at 200 mg/kg. The USEPA concluded that this picaridin showed induction of hepatic cytochrome P450 dependent reactions effect was isolated, transient, and its toxicological significance was not certain.
and an increase in liver weight at the lowest dosage (WHO, 2000). At 200 mg/ Hence the no-observed-effect-level NOEL for this study was set at 200 mg/kg, and kg BW/day, no sign of behavioral or pathological anatomical neurotoxicity was the lowest-effect-level (LEL) set at 500 mg/kg.
Author's personal copy
F.B. Antwi et al. / Regulatory Toxicology and Pharmacology 51 (2008) 31–36 Table 1Toxicologic effects and endpoints for DEET Acute toxicityAcute neurotoxicity screening No gross or microscopic alterations were observed in the central or peripheral nervous system in comparison with controls Subchronic toxicity90-day dermal toxicity study in rats NOEL = 300 mg/kg BW/dayb; LEL = 1000 mg/kg Based on decrease in body-weight gain and increase in liver weightsb Based on 13-week study in micropigs; No renal lesions in micropigsb Based on decreased body weights and food consumption, and increased cholesterol Based on decreases in food consumption and body weights, increase in the incidence of ptyalism and a decrease in cholesterol levels a Endpoint abbreviations: BW, body weight; NOEL, no-observed effect-level; LEL, lowest effect-level.
This study also observed that the difference between population groups (men vs Picaridin was administered at dosages of 0, 50, 100, and 200 mg/kg BW/day in a women vs children) in the amount of product applied during a single usage was 2-year dermal toxicity study in rats (Wahle et al., 1999). Body-weight gain, food not significantly different (Health Canada, 2002).
consumption, clinical observations, and survival were unaffected at all ages for both Therefore, the amount of active ingredient (DEET or picaridin) deposited on the sexes. Picaridin did not induce ophthalmic toxicity. Laboratory clinical tests, gross lesion incidence, and organ-weight data did not suggest a compound-related effect.
mg active ingredient ¼ 3700 mg à % concentration of active ingredient in product Increased incidence of cystic degeneration of the liver was observed at 200 mg/kgBW/day. The authors also noted several possible treatment-related effects which We estimated dermal exposures for adults and children for one application per were attributed to methodology and inherent difficulties associated with lifetime bioassay tests via dermal route. Therefore, the changes at the dosage sites associ-ated with picaridin were non-dose responsive, and could be described as adaptive, Dermal exposure ¼ ½amount of active ingredient deposited on skinðmgފ non-adverse, predictable responses to chronic exposure (Wahle et al., 1999).
Daily exposures to several population subgroups were estimated to account for potential age-related differences in exposure. Groups included adult males, females, For acute exposure, we used a NOEL of 2000 mg/kg BW/day (USEPA, 2005) as and children (612 and 13–17 years of age). Adult males and females were assumed the endpoint, based on no signs of behavioral or pathological anatomical neurotox- to weigh 78.7 and 67.1 kg, respectively (USEPA, 1998). Children 612 and 13–17 icity (WHO, 2000). For subchronic and chronic exposures, we used a NOEL of years of age were assumed to weigh 25 and 50.6 kg, respectively (USEPA, 1998).
200 mg/kg BW/day as the endpoint (Table 2), based on the lack of adverse andnon-skin compound-related effects (Wahle et al., 1999) and no signs of behavioralor pathological anatomical neurotoxicity (WHO, 2000).
We assessed human health risks in this study by integrating toxicity and expo- sure. Risks were assessed using the Margin of Exposure (MOE) method. An MOE foreach population subgroup was calculated by dividing the appropriate toxic end- Health Canada (2002) estimated human exposure potential of DEET using sur- point (i.e. the NOEL) by the daily exposure. We calculated the dermal MOEs using vey and usage data. The study involved 540 subjects (men, women, and children) at three locations (Wisconsin, Oregon, and Florida) in the U.S. The difference betweenthe weight of the products for pre- and post-application provided an estimate for MOE ¼ ½oral NOEL  5ðrat oral-to-dermal conversion factorÞ the amount of product used per application. Based on all formulation types, the  5ðrat-to-human dermal absorption correction factorފ estimated mean amount of product applied was 3.7 g per person per application.
Table 2Toxicologic effects and endpoints for picaridin No signs of behavioral or pathological anatomical neurotoxicity was observedc Subchronic toxicityDermal neurotoxicity study No signs of behavioral or pathological anatomical neurotoxicity was observedc Based on diffuse liver hypertrophy, individual necrotic liver cells, hyaline kidney degeneration, increase incidence of foci of tubular regeneration, and chronic kidney inflamationb Chronic toxicityDermal chronic toxicity-dog BW/dayNOAEL (dermalirritation) = 200 mg/kg BW/day Based on cystic degeneration of the liver with no corroborating liver weight or clinical pathology a Endpoint abbreviations: BW, body weight; NOEL, no-observed-effect-level; NOAEL, No-observed-adverse-effect-level; LOAEL, lowest-observed-adverse-effect-level; LEL, Author's personal copy
F.B. Antwi et al. / Regulatory Toxicology and Pharmacology 51 (2008) 31–36 The oral NOEL was converted to a dermal equivalent NOEL by using pharmaco- kinetic data from rats. The conversion factor of 5 was derived from measured levels Percent concentration of repellents compatible with an MOE of at least 100 for each of parent DEET in rat plasma or blood following oral and dermal dosing. Also, stud- ies estimating human dermal absorption of DEET showed an approximately 5-folddifference in dermal absorption in rats (38.5%) and humans (7.5%) (Health Canada, 2002). When using a dermal NOEL as our endpoint, we corrected only for rat-to-hu- man dermal absorption. Margins of exposures less than 100 (i.e., the exposure is greater than 1% of the NOEL) often are considered to exceed a regulatory level ofconcern (LOC) (Whitford et al., 1999). In this study, we characterized risk by com- paring our estimated exposures to NOEL, and estimated MOEs to an MOE LOC of a concentration range of 6.8% to 21.3% compatible with an MOE of Daily exposure estimates ranged from 2 to 59 mg/kg BW/day at least 100 for all subgroups (Table 4).
for DEET and 2 to 22 mg/kg BW/day for picaridin (Table 3). Poten-tial acute MOEs for DEET ranged from 85 to 2127 (Table 3). For picaridin, acute MOEs ranged from 451 to 4254. The maximumDEET concentrations compatible with an MOE of at least 100 ran- The MOEs for DEET chronic exposure ranged from 42 to 1064 ged from 33.8 to >100% for children and adults (Table 4). For picar- (Table 3). At 25% DEET, children (612 years of age), and at 40% idin, the concentrations ranged from 67.6 to >100% for all DEET, children (612 and 13–17 years) had MOEs below 100 (Table population subgroups (Table 4). At a concentration of 40% DEET, 3). For an MOE of 100, DEET concentrations were 45.3 and 53.2% children at 612 years had an MOE below 100 (Table 3). For picar- for adult females and males, and 16.9 and 34.2% for children 612 idin, the MOEs were >100 at 5% and 15% concentrations for all pop- years and children 13–17 years, respectively (Table 4).
Picaridin MOEs ranged from 45 to 425. Children (612 and 13– 17 years) were the only subgroups with MOEs below 100 at 15% picaridin (Table 3). For picaridin, concentrations compatible withan MOE of at least 100 was 21.3% for adult males, 18.1% for adult For DEET, subchronic MOEs ranged from 25 to 638. At 25% females, 13.7% for children 13–17 years, and 6.8% for children DEET, children (612 and 13–17 years) had MOEs below 100 and at 40% DEET, all population subgroups had MOEs below 100 (Table3). The maximum DEET concentrations compatible with an MOE of at least 100 ranged from 10.1% to 31.9% for all population sub-groups (Table 4).
None of our estimated exposures equaled or exceeded the Picaridin had subchronic MOEs ranging from 45 to 425 (Table NOELs for DEET or picaridin (i.e., MOEs 61). However, acute MOEs 3). At 15% picaridin, children (612 and 13–17 years) had MOEs were below 100 for children (612 years) at 40% DEET. For picari- of 45–91 which were below the level of concern. Picaridin required din, all of the population subgroups had margins of exposures Table 3Margins of exposure for the active ingredients for each population subgroup a Values in column are margins of exposure per application per day.
Author's personal copy
F.B. Antwi et al. / Regulatory Toxicology and Pharmacology 51 (2008) 31–36 greater than 100. For subchronic exposure, MOEs for children (612 well known are the risks from the arthropod bites. Mosquito and 13–17 years) were below 100 at P25% DEET. At 40% DEET, all and arthropod bite exposure results in a variety of cutaneous population subgroups had MOEs below 100. Picaridin application reactions and other complications, and may be attributed to resulted in MOEs below 100 for children 612 and 13–17 years) antigenic, non-antigenic irritating substances or both (Feingold at 15% concentration. For chronic exposures, children (612 and et al., 1968). Mosquito salivary secretions contain proteins that 13–17 years) had MOEs below 100 at 25% and 40% DEET. For picar- are responsible for skin reactions to mosquito bites (Peng and idin, MOEs were below 100 for children (612 and 13–17 years) at Simons, 2004a,b). Skin response to mosquito bites consists of 15%. The lowest MOE (highest risk) indicated that the exposure an immediate wheal and flare ups, and a delayed indurated pap- was 25- and 45-fold lower than the NOEL for DEET and picaridin, ule or nodule (Peng and Simons, 1997). Other symptoms include respectively, for children 612 years. Children had the lowest MOEs ‘‘Skeeter Syndrome”, a mosquito bite-induced large local inflam- primarily because DEET is applied to the skin, and hence a higher matory reactions accompanied by fever in young children (Peng surface area of skin relative to body weight in children will result and Simons, 2004a,b). The immediate reaction is compatible in a larger exposure per kg body weight.
with that of an IgE-mediated hypersensitivity, is usually pruritic, Another route of exposure to DEET and picaridin includes inges- and consists of erythema and edema. The delayed reaction is tion, although it would be much less than dermal exposures. Blan- consistent with lymphocyte-mediated hypersensitivity, and an set et al. (2007) estimated that ingestion of DEET in drinking water IgE-mediated late phase reaction (Peng and Simons, 1997). It is for specific populations was 8.2 Â 10À5 mg/kg BW/day, which was characterized by erythema and papule and may persist for sev- 720-fold less than our maximum dermal exposure estimate. The eral days. The skin reactivity sequences occur due to repeated authors concluded that DEET in drinking water is unlikely to result insect bites. This includes a period of induction of hypersensitiv- in significant human health effects in the general population.
ity (i.e. no observable skin reactions), delayed skin reaction, The major uncertainties in our risk assessments are associated immediate skin reactions followed by delayed reactions, immedi- with dermal exposure of the active ingredients. Data for actual der- ate reactions only, and no reactivity.
mal exposures and the variability in the amount of active ingredi- Allergic reactions to mosquito bites are common. Compared ent absorbed dermally need to be generated to accurately to older children, infants and younger children have higher lev- characterize risk. Even though we had access only to information els of mosquito saliva specific IgE and IgG antibodies, and are at reporting the estimated mean amount of product applied (Health high risk of having allergic reactions to mosquito bites (Peng Canada, 2002), there undoubtedly is variability in the amount of et al., 2004). However, there are few epidemiologic data regard- product used within and among subgroups. Future work should ing the prevalence of mosquito allergies (Peng et al., 2004). Anti- be directed towards reducing the uncertainties associated with bodies IgE and IgG are associated with mosquito allergy exposure and absorption of the active ingredients in insect repel- development. Peng et al. (2002) measured antibodies (IgE and IgG), and observed that 18% of 1059 adult blood donors living As with any technology, the risks must be considered with in an environment with a high summer mosquito population concomitant benefits. Fradin and Day (2002) observed that a for- are sensitized to mosquito saliva. Peng et al. (2004) found that mulation containing 24% DEET provided bite protection for an levels of IgE peaked in infants aged 6 months to 1 year and ear- average of 5 h. In laboratory studies for mosquito species on lier for IgG, and levels of both antibodies gradually declined after forearms, Frances et al. (2005) found that 10% and 80% DEET the age of 5. In individuals aged 16 to 18, mean levels of IgE and at a rate of 2.24 and 2.92 mg/cm2 provided protection of 5 and IgG antibodies were low and similar to those reported previously greater than 8 h, respectively. For picaridin (9% and 19%) optimal in adults (Peng et al., 2004). Population subgroups with a high protection time was 3–4 h at a rate of 3.23 and 3.39 mg/cm2 level of exposure (i.e., civilian or military personnel outdoor (Frances et al., 2005). This agrees with Health Canada (2002) workers), children, immune-deficient persons, and visitors to that 15% DEET formulations resulted in mean complete protec- areas with indigenous mosquitoes to which they have not been exposed to previously are at greater risk for severe reactions to Although we present only estimated exposures and MOEs for the exposure scenario of one application per day, it is possible that Our assessment reveals that exposures to DEET and picaridin people will apply repellents two or three times per day. In these are unlikely to exceed NOELs. Health Canada (2002) estimated cases, the MOEs, and therefore the risks, are linearly proportional acceptable MOEs greater than 100 for acute risks for products up to the increase in exposures (i.e., two applications would double to 35% DEET for children. For acute risks, we estimated an MOE the exposure per day and reduce the MOE by half). We summarize of 195 for children 13–17 years, and an MOE of 97 for children the MOEs for these high-end use scenarios here. MOEs varied from 612 years for 35% DEET although we have presented analysis only 169 to 532 and 113 to 355 for two and three applications per day, for 5%, 25%, and 40% DEET. Health Canada (2002) estimated sub- respectively, for acute 10% DEET exposures. For acute exposures at chronic MOEs greater than 100 for products containing 30% DEET 80% DEET MOEs ranged from 21 to 67 and 14 to 44 for two and or less for adults, and 10% or less DEET for children. Our data show three applications, respectively. The MOEs for 9% picaridin ranged that MOEs greater than 100 for subchronic exposures ranged from from 225 to 709 and 150 to 473 for two and three applications per less than 10% to 32% DEET and 7% to 21% picaridin for all day, respectively. At 19% picaridin the MOEs ranged from 178 to 560 for two applications, and 119 to 373 for three applications.
For subchronic 10% DEET exposures, MOEs ranged from 3 to 34 and 34 to 107 for two and three applications, respectively. At 80%DEET, MOEs varied from 6 to 20 for two applications, and 4 to 13 We thank M. Debboun (US Army Medical Department Center for three applications per day. Picaridin at 9% had MOEs of 38 to and School), D. Strickman (USDA-ARS), G. White (University of 118, and 32 to 101 for two and three applications per day, respec- Florida), and J. Schleier, R. Davis, and M. Schat (Montana State Uni- tively. At 19% picaridin, MOEs ranged from 18 to 56 for two appli- versity) for reviewing an earlier version of this paper. This study cations per day and 12 to 37 for three applications.
was funded by a grant from the U.S. Armed Forces Pest Manage- It is commonly understood that insect repellents are impor- ment Board’s Deployed War Fighter Protection Research Program, tant personal protective measures to help prevent disease from Montana State University, and the Montana Agricultural Experi- vector-borne pathogens (e.g., West Nile virus). However, less Author's personal copy
F.B. Antwi et al. / Regulatory Toxicology and Pharmacology 51 (2008) 31–36 McGready, R., Hamilton, K.A., Simpson, J.A., CHO, T., Luxemburger, C., Edwards, R., Looaresuwan, S., White, N.J., Nosten, F., Lindsay, S.W., 2001. Safety of the insectrepellent N,N-diethyl-m-toluamide (DEET) in pregnancy. Am. J. Trop. Med. Hyg.
Abdel-Rahman, A., Shetty, A.K., Abou-Donia, M.B., 2001. Subchronic dermal application of N,N-diethyl-m-toluamide (DEET) and permethrin to adult rats, Moody, R.P., 1989. The safety of diethyltoluamide insect repellents. J. Am. Med.
alone or in combination, causes diffuse neuronal cell death and cystoskeletal abnormalities in the cerebral cortex and the hippocampus, and purkinje neuron Mount, M.E., Moller, G., Cook, J., Holstege, D.M., Richardson, E.R., Ardans, A., 1991.
loss in the cerebellum. Exp. Neurol. 172, 153–171.
Clinical illness associated with a commercial tick and flea product in dogs and Abou-Donia, M.B., Goldstein, L.B., Dechovskaia, A., Bullman, S., Jones, K.H., Herrick, cats. Vet. Hum. Toxicol. 33, 19–27.
E.A., Abdel-Rahman, A.A., Khan, W.A., 2001. Effects of daily dermal application Osimitz, T.G., Grothaus, R.H., 1995. The present safety assessment of DEET. J. Am.
of DEET and permethrin, alone and in combination, on sensorimotor performance, blood–brain barrier, and blood–testis barrier in rats. J. Toxicol.
Osimitz, T.G., Murphy, J.V., 1997. Neurological effects associated with use of the Environ. Health Part A 62, 523–541.
insect repellent N,N-diethyl-m-toluamide (DEET). J. Toxicol.: Clin. Toxicol. 35, Blanset, D.L., Zhang, J., Robson, M.G., 2007. Probabilistic estimates of lifetime daily doses from consumption of drinking water containing trace levels of N,N- Peng, Z., Simons, F.E.R., 1997. Cross-reactivity of skin and serum specific IgE diethyl-meta-toluamide (DEET), triclosan, or acetaminophen and the associated responses and allergen analysis for three mosquito species with worldwide risk to human health. Hum. Ecol. Risk Assess. 13, 615–631.
distribution. J. Allergy Clin. Immunol. 101, 498–505.
Carpenter, C.P., Weil, C.S., Smyth, H.F., 1974. Range-finding toxicity data. Toxicol.
Peng, Z., Ho, M.K., Li, C., Simons, F.E.R., 2004. Evidence for natural desensitization to mosquito salivary allergens: mosquito saliva specific IgE and IgG levels in Carpenter, S., Eyres, K., McEndrick, I., Smith, L., Turner, J., Mordue, W., Mordue Luntz, children. Ann. Allergy Asthma Immunol. 93, 553–556.
A.J., 2005. Repellent efficiency of Bayrepel against Culicoides impunctatus Peng, Z., Rasic, N., Liu, Y., Simons, F.E.R., 2002. A survey of mosquito allergy by (Diptera: Ceratopogonidae). Parasitol. Res. 95, 427–429.
measuring serum saliva-specific IgE and IgG antibodies in 1059 blood donors. J.
Davis, R.S., Peterson, R.K.D., Macedo, P.A., 2007. An ecological risk assessment for Allergy Clin. Immunol. 110, 816–817.
insecticides used in adult mosquito management. Integ. Environ. Assess.
Peng, Z., Simons, F.E.R., 2004a. Mosquito allergy: immune mechanisms and recombinant salivary allergens. Int. Arch. Allergy Immunol. 133, 198– Debboun, M., Frances, S.P., Strickman, D. (Eds.), 2006. Insect Repellents: Methods, and Uses. CRC Press Inc., Boca Raton, FL.
Peng, Z., Simons, F.E.R., 2004b. Mosquito allergy: immune mechanisms and Debboun, M., Strickman, D.A., Klun, J.A., 2005. Repellents and the military: our first recombinant salivary allergens. Int. Arch. Allergy Immunol. 133, 198–209.
line of defense. J. Am. Mosq. Cont. Assoc. 21, 4–6.
Peterson, R.K.D., Macedo, P.A., Davis, R.S., 2006. A human-health risk assessment for Feingold, B.F., Benjamini, E., Michaeli, D., 1968. The allergic responses to insect West Nile virus and insecticides used in mosquito management. Environ.
bites. Annu. Rev. Entomol. 13, 137–158.
Fradin, M.S., 1998. Mosquitoes and mosquito repellents: a clinician’s guide. Ann.
Qiu, H., Jun, H.W., Tao, J., 1997. Pharmacokinetics of insect repellent N,N-diethyl-m- toluamide in beagle dogs following intravenous and topical routes of Fradin, M.S., Day, J.F., 2002. Comparative efficacy of insect repellents against administration. J. Pharmaceut. Sci. 86, 514–516.
mosquito bites. N. Engl. J. Med. 347, 13–18.
Qiu, H., Jun, H.W., McCall, J.W., 1998. Pharmacokinetics, formulation, and safety of Frances, S.P., Auliff, A.M., Edstein, M.D., Cooper, R.D., 2003. Survey of personal insect repellent N,N-diethyl-3-methyl benzamide (DEET): a review. J. Am. Mosq.
protection measures against mosquitoes among Australian defence force personnel deployed to East Timor. Mil. Med. 168, 227–230.
Robbins, P.J., Cherniack, M.G., 1986. Review of the biodistribution and toxicity of the Frances, S.P., Waterson, D.G.E., Beebe, N.W., Cooper, R.D., 2004. Field evaluation of insect repellent N,N-diethyl-m-toluamide (DEET). J. Toxicol. Environ. Health 18, repellent formulations containing Deet and picaridin against mosquitoes in Northern Territory, Australia. J. Med. Entomol. 41, 414–417.
Scheinfeld, N., 2004. Picaridin: a new insect repellent. J. Drugs Dermatol. 3, 59–60.
Frances, S.P., Marlow, R.M., Jansen, C.C., Huggins, R.L., Cooper, R.D., 2005. Laboratory Schleier, J.J., Shama, L.M., Davis, R.S., Macedo, P.A., Peterson, R.K.D, in press. Equine and field evaluation of commercial repellent formulations against mosquitoes risk assessment for insecticides used in adult mosquito management. Hum.
(Diptera: Culicidae) in Queensland, Australia. Aust. J. Entomol. 44, 431–436.
Goodyer, L., Behrens, R.H., 1998. Short report: the safety and toxicity of insect Schoenig, G.P., Osimitz, T.G., Gabriel, K.L., Hartnagel, R., Gill, M.W., Goldenthal, E.I., repellents. Am. J. Trop. Med. 59, 323–324.
1999. Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m- Gujral, I.B., Zielinski-Gutierrez, E.C., LeBailly, A., Nasci, R., 2007. Behavioral risks for toluamide (DEET). Toxicol. Sci. 47, 99–109.
West Nile virus disease, Northern Colorado, 2003. Emerg. Infect. Dis. 13, 419– Sudakin, D.L., Trevathan, W.R., 2003. DEET: a review and update of safety and risk in the general population. J. Toxicol.: Clin. Toxicol. 41, 831–839.
Gupta, R.K., Rutledge, L.C., 1994. Role of repellents in vector control and disease Tice, R., Brevard, B., 1999. DEET: Review of toxicological literature. National prevention. Am. J. Trop. Med. Hyg. 50 (suppl), 82–86.
Institute of Environmental Health Sciences, Contract No. N01-ES-65402, Harvey, J.G., 1987. Topical hazard evaluation of three DEET products (N,N-diethyl- m-toluamide (m-det). U.S. Army Environmental Hygiene Agency, Study No. 75- USEPA, 1998. Reregistration Eligibility Decision (RED)-DEET. United States 51-0034-87, Aberdeen Proving Ground, MD.
Environmental Protection Agency. Available from: <http://www.epa.gov/ Health Canada, Pest Management Regulatory Agency, 2002. Re-evaluation Decision Document RRD 2002-01. 4-15-2002. Available from: <http://www.pmra- USEPA, 2005. New pesticide fact sheet-picaridin. United States Environmental arla.gc.ca/english/pdf/rrd/rrd2002-01-e.pdf>.
Protection Agency. Available from: <http://www.epa.gov/opprd001/factsheet/ Imperial College, Department of Health Toxicology Unit, 2002. Diethyl-m-toluamide (DEET) insect repellent: review of the toxicology literature for the topical insect Veltri, J.C., Osimitz, T.G., Bradford, D.C., Page, B.C., 1994. Retrospective analysis of repellent diethyl-m-toluamide (DEET). Scientific evaluation and assessment calls to poison control centers resulting from exposure to the insect repellent <http://www.advisorybodies.doh.gov.uk/pdfs/ N,N-diethyl-m-toluamide (DEET) from 1985–1989. J. Toxicol.: Clin. Toxicol. 32, Koren, G., Matsui, D., Bailey, B., 2003. DEET-based insect repellents: safety Wahle, B.S., Sangha, G.K., Lake, S.G., Sheets, L.P., Croutch, C., Christensen, W.R., 1999.
implications for children and pregnant and lactating women. Can. Med. Assoc.
Chronic toxicity and carcinogenicity testing in the Sprague–Dawley rat of a prospective insect repellent (KBR 3023) using the dermal route of exposure.
Macedo, P.A., Peterson, R.K.D., Davis, R.S., 2007. Risk assessments for exposure of deployed military personnel to insecticides and personal protective measures Whitford, F., Kronenberg, J., Lunchick, C., Driver, J., Tomerlin, R., Wolt, J., Spencer, H., used for disease-vector management. J. Toxicol. Environ. Health 70, 1758–1771.
Winter, C., Whitmyre, G., 1999. Pesticides and human health risk assessment: Macko, J.A., Bergman, J.D., 1979. Phase 4. Inhalation toxicities of N,N-diethyl-meta- policies, processes, and procedures. Purdue University West Lafayette, IN.
toluamide (m-det). U. S. Army Environmental Hygiene Agency, Study No. 75-51- WHO, 2000. Review of IR3535; KBR3023; (RS)-methoprene 20% EC; pyriproxyfen 0034-80, Aberdeen Proving Ground, MD.
0.5% GR; and lambda-cyhalothrin 2.5% CS. World Health Organization, Geneva.
McCain, W.C., Lee, R., Johnson, M.S., Whaley, J.E., Ferguson, J.W., Beall, P., Leach, G., Young, D., Evans, S., 1998. Safety and efficacy of DEET and permethrin in the 1997. Acute oral toxicity study of pyridostigmine bromide, permethrin, and prevention of arthropod attack. Mil. Med. 163, 324–330.
deet in the laboratory rat. J. Toxicol. Environ. Health 50, 113–124.

Source: http://landresources.montana.edu/WNV/Antwi%20et%20al.%202008.pdf