Regulatory Toxicology and Pharmacology 56 (2010) 93–99

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Regulatory Toxicology and Pharmacology

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Adverse events associated with the use of insect repellents containing

N,N-diethyl-m-toluamide (DEET)
T.G. Osimitz a,*, J.V. Murphy b, L.A. Fell c, B. Page d
a
Science Strategies, LLC, Charlottesville, VA, USA
b
Neurology Section Children’s Mercy Hospital, Kansas City, MO, USA
c
ARCADIS, Racine, WI, USA
d
PEGUS Research, Inc., Salt Lake City, UT, USA

a r t i c l e i n f o a b s t r a c t

Article history: DEET is the major component of most topically applied insect repellents used in the US. The DEET Reg-
Received 29 April 2009 istry is a post-marketing surveillance system to provide systematic and detailed information about med-
Available online 12 September 2009 ical events temporally associated with DEET use.
From 1995 to 2001, 296 moderate and major severity cases were included in the DEET Registry. Of
Keywords: these, 36 (14.5%) cases were deemed to be probably and 157 (65%) cases possibly related to DEET expo-
Seizures sure. Insufficient data prevented determination of causality in the remaining 49 (20.2%) cases. Forty-one
Pesticide
percent of the cases were in children 19 or younger. Forty-two percent of children experienced a seizure
DEET
Neurological events
of moderate or major severity.
Causality The widely variable spectrum of other neurological symptoms reported in the Registry makes it unli-
Repellent kely they were due to one agent. People with an underlying neurological disorder were not dispropor-
tionately represented in the DEET Registry. Data showed no clear relationship between case severity
and DEET concentration or concurrent use of common medicines.
Recognizing the extensive use of DEET in the US and considering the information about the more seri-
ous adverse events described in the Registry, the risk of serious neurological events following the use of
DEET repellents is quite low.
Ó 2009 Elsevier Inc. All rights reserved.

1. Introduction mends these repellents as a means to help protect against certain

N,N-diethyl-m-toluamide (DEET, CAS #134-62-3, EINECS #207-
149-7) is the major component of most topically applied consumer
insect repellents. First developed by the US Department of Agricul-
ture for use by military personnel in 1946, DEET was registered for
use in the general population in 1957. Clinical studies have demon-
strated that DEET is the most effective repellent for biting insects,
mosquitoes, and arthropods such as ticks (Fradin and Day, 2002).
DEET concentrations in insect repellents range from 5 to 100%.
Product forms include pressurized aerosols, aerosol pump sprays,
lotions and creams, liquids, roll-ons and towelettes. In addition,
DEET has been detected at ng/L to lg/L levels in surface waters
in various locations around the world (Costanzo et al., 2007).
The American Academy of Pediatrics currently recommends
using insect repellents with concentrations of DEET up to 30% on
children over 2 months of age to repel mosquitoes and ticks (Weil,
2001). The Centers for Disease Control and Prevention also recom-
* Corresponding author. Address: Science Strategies, LLC, 600 E Water Street,
Suite C, Charlottesville, VA 22902, USA. Fax: +1 434 964 9398.
E-mail address: tom@sciencestrategies.com (T.G. Osimitz).
vector-borne diseases (CDCP, 2008a–c). The Canadian government
agency, Health Canada, recommends using a maximum of 10%
DEET in children (Health Canada, 2002).
Estimates show that approximately 30% of adults and children in
the US (more than 75 million people) use an insect repellent contain-
ing DEET annually (Boomsma and Parthasarathy, 1990). During the
months of June and July, adults reportedly apply repellents an aver-
age of approximately nine times, while children’s average use was
six times (Boomsma and Parthasarathy, 1990). Thus, several billion
applications of DEET were made by US consumers during the seven
years (1995–2001) that the data was collected as a part of the Na-
tional Registry of Human Exposure to DEET (DEET Registry).1
In a previous publication, we summarized published associa-
tions between use of DEET and a subsequent neurological adver-
sity, most commonly a seizure (Osimitz and Murphy, 1997).
1
Abbreviations used: AAPCC, American Association of Poison Control Centers; CDCP,
Centers for Disease Control and Prevention; CSPA, Consumer Specialty Products
Association; DEET, N,N-diethyl-m-toluamide; DEET Registry, National Registry of
Human Exposure to DEET; PCC, Poison Control Center; USEPA, United States
Environmental Protection Agency.

0273-2300/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.yrtph.2009.09.004
94 T.G. Osimitz et al. / Regulatory Toxicology and Pharmacology 56 (2010) 93–99
Most of these reports were anecdotal; e.g., the day after using
DEET the child had a seizure.
During the past decade, the safety issues surrounding of DEET
have been of great interest and, occasionally, the source of contro-
versy. A detailed discussion of these issues is beyond the intent of
this paper. The reader is directed to the United States Environmen-
tal Protection Agency’s (USEPA) Reregistration Eligibility Decision
(USEPA, 1998) and a recent review by Sudakin and Trevathan for
an update of the available toxicology, pharmacokinetic, and epide-
miology information about DEET (Sudakin and Trevathan, 2003).
In the past, the medical literature regarding the safety of DEET
was primarily centered on laboratory studies involving animals,
occasional individual case reports (or in a few instances, small
clusters of case reports) and, more recently, information from the
Poison Control Center (PCC) system in the US. The first analysis
and review of extensive human exposure to DEET was from PCC
data in the United States and included over 9000 calls to PCC
reporting DEET exposures from 1985 to 1989 (Veltri et al., 1994).
Approximately two-thirds of the exposures involved either no
symptoms or only minor symptoms, such as skin or eye irritation
that resolved rapidly and without medical treatment. The authors
concluded that the ‘‘risk of serious medical effects with the labeled
use of DEET-containing insect repellents appears quite low. . .” A la-
ter publication which examined more than 20,000 reported expo-
sures to DEET in the PCC system during 1993–1997 led to similar
conclusions (Bell et al., 2002).
Information routinely collected by PCC is very useful as an indi-
cator of potential safety issues for pharmaceutical or consumer
products (Sudakin and Trevathan, 2003). However, there are limi-
tations to these data, as indicated in Veltri et al. (1994) and Bell
et al. (2002). The PCC databases, while very useful as an early indi-
cator of possible safety problems, suffer from the general problems
associated with passive reporting systems. Additionally, exposures
with relatively minor or trivial consequences may also be overrep-
resented in the databases and exposures associated with severe
outcomes may be underrepresented.
Most important, because details about the temporal association,
prior medical history, and alternate etiologies are frequently lacking
in PCC data, it is difficult to accurately infer causality. For this reason,
the DEET Registry was created to help understand the nature of the
more serious adverse events associated with the use of repellents
containing DEET. It was a descriptive study that consisted of a series
of several hundred case studies where the data were collected in a
systematic and standardized manner. The value of the DEET Registry
is its expanded reporting base, the detail of data collected, and the
fact that most data were collected soon after (and occasionally dur-
ing) the occurrence and resolution of the adverse symptoms. The in-
tent of this extended study was to collect sufficient medical
information to be able to reasonably describe the events and to eval-
uate the causal relationship between the use of DEET and the subse-
quent occurrence of serious medical consequences.
The DEET Registry employed an informal but very broad report-
ing base. Nearly all PCC in the United States were vigilant in look-
ing for, identifying, and reporting appropriate cases to the DEET
Registry. In addition to the notification by PCC, information about
the DEET Registry was placed in professional journals and newslet-
ters encouraging physicians to report possible events.
The DEET Registry focused primarily on neurological or systemic
events. The objective was to identify individuals who had serious
neurological or systemic symptoms as soon after the event as possi-
ble. This allowed detailed information about the most recent expo-
sure, exposure history, information about the specific adverse
symptoms, and a brief but relevant medical and drug history to be
collected.
The DEET Registry was a voluntary effort by the DEET Task Force
and operated as part of the Consumer Specialty Products Associa-
tion (CSPA). It consisted of more than a dozen companies that pro-
duce DEET or formulate and market DEET-based insect repellents
for consumer use. PEGUS Research, Inc. (Salt Lake City, UT), an
independent research company specializing in the collection and
evaluation of post-marketing health related data, designed and
maintained the DEET Registry. The more serious adverse events,
according to USEPA guidelines, were reported to USEPA by CSPA.
An annual report containing all of the data was submitted to the
USEPA each year.
2. Methods
2.1. Identification and enrollment of participants
The methods for identifying and enrolling patients into the
DEET Registry were developed in collaboration with the USEPA
and the DEET Task Force (see Fig. 1). Once a DEET exposure with
adverse symptoms was identified2, follow-up telephone interviews
were conducted with the subject (or parent of a minor) and the
treating physician, where necessary. Detailed information was col-
lected regarding the most recent exposure, history of exposure to
DEET, details of the nature and development of the adverse symp-
toms, treatment of the adverse symptoms, and a brief but relevant
medical and drug history.
If subjects received medical treatment, medical records were
obtained where possible. Clinicians (primarily registered nurses)
skilled in identifying and evaluating adverse events conducted
the telephone follow-up interviews. The intent was to collect this
information as soon as possible after the exposure and occurrence
of symptoms. This study was reviewed and approved by the Wes-
tern Institutional Review Board (Olympia, WA).
The existence of the DEET Registry was publicized widely pri-
marily in the early spring, just prior to the onset of the mosquito
season, and cases were solicited from PCC and other health care
professionals. Notices were placed in the American Academy of
Pediatric News, Annals of Emergency Medicine, Child Neurological
Society Newsletter, Journal of Toxicology—Clinical Toxicology, Journal
of Family Practice, Mayo Clinical Proceedings, New England Journal of
Medicine, and Pediatrics. Direct mailings to neurologists, family
practice physicians, and emergency room physicians occurred dur-
ing 1998 and 1999. Referring sources were compensated to cover
the time required to refer a case.
Most of the DEET Registry cases were referred by PCC. The PCC
covered more than 90% of the US population and was receiving
more than one million exposure calls from all substances and
chemicals annually. Data from PCC under contract to handle partic-
ipating company-specific DEET calls were also evaluated for inclu-
sion in the DEET Registry.
The criteria for referring a case to the DEET Registry were
broadly defined to minimize the likelihood of missing a serious
case. The criteria were:
(1) Exposure to a DEET-containing product;
(2) The presence of at least one neurological or systemic
symptom;
(3) The likely severity of symptoms was at least minor for neu-
rological symptoms or moderate for other types of symptoms3;
(4) The presence of an unusual symptom or, in the judgment of
the health professional, the case warranted further investigation.
2
In the interest of ‘‘over-inclusion,” some cases showing interesting dermal-only
effects were included in the DEET Registry.
3
As defined by the American Association of Poison Control Centers (AAPCC)
guidelines (American Association of Poison Control Centers Toxic Exposure Surveil-
lance System (TESS) Field Definitions. Published by the American Association of
Poison Control Centers, January 1, 1993).
 T.G. Osimitz et al. / Regulatory Toxicology and Pharmacology 56 (2010) 93–99 95

Call to Poison Center or other

Health Practitioner Reporting
Exposure to DEET

Call Screened for

Referral to Pegus
Exposure and Symptom Data Collected

Evaluation – Is case Consent Obtained for PEGUS Follow-up Interview

appropriate for Registry?

Enrollment
in DEET
Registry

One-Year
Initial If Patient Received Medical Records Follow-Up
Medical Treatment, Obtained Interview
Interview Obtain Consent to
Release Medical
Records

Data Collection Points

Fig. 1. Flow chart for DEET Registry.

The criteria for inclusion in the DEET Registry were the
following:
(1) The presence of neurologic or systemic clinical manifesta-
tion(s) that resulted in a severity rating of moderate or major based
on definitions used by the American Association of Poison Control
Centers (AAPC).
(2) The subject experienced an unusual clinical manifestation,
regardless of medical outcome. This type of case was included to
capture as many cases with neurological symptoms as possible.
by other referrers (for example, physicians). The exposure was con-
firmed by staff interviews. For those individuals who could not be
interviewed, the information provided by the referring party was
allowed to stand. Occasionally, it was later determined that a per-
son in fact was not exposed to DEET. Two cases illustrate this: one
was an exposure to a young child, where the mother later deter-
mined (believed to be reliably so) that the child had lied to her
about the exposure. In another instance, the product involved in
the exposure turned out to not contain DEET.

2.2. Data collection procedures 2.3. Severity and causality determination

Upon receiving a referral, the case was reviewed by a research
nurse or physician at PEGUS Research, Inc. The nurses had exten-
sive clinical experience, were skilled in interviewing and in patient
work-ups, and were specially trained to participate in the DEET
Registry. If the patient gave verbal consent, the nurse conducted
a telephone interview with the patient to collect information about
their exposure, symptoms, previous experience with this or similar
products, medical and drug histories, occupational, social and fam-
ily histories, and any other relevant information. An initial evalua-
tion was made to determine if the case met the criteria for
inclusion in the DEET Registry. If the symptoms were ongoing,
additional follow-up telephone calls were made until the symp-
toms resolved or it was clear they had stabilized and were unlikely
to return to baseline. If the patient received medical treatment and
gave written consent for release of their records, the medical re-
cords were obtained for further evaluation of the case.
In determining whether a person was exposed to DEET, the Reg-
istry staff relied first on the PCC report or the information collected
Severity was assessed by the research nurse and conformed to
the standard AAPCC definitions (Litovitz, 1998). One of the reasons
for conducting the DEET Registry was to better understand related-
ness of the more substantial adverse events to DEET exposure.
Among the principles used in this causality assessment were those
similar to the Bradford Hill Criteria (Hill, 1965): temporal relation-
ship between exposure and reported effect, plausible etiological
alternatives, consistency with previously reported symptoms, pre-
vious experience with exposure to DEET, and result of subsequent
use of the product. Also considered was the exposure pattern such
as estimates of extent and frequency of use prior to the adverse
event. The causality rating categories are detailed in Table 1.
Once all data were collected for a case, two research nurses
independently reviewed all the information available on each case
and completed a causality assessment using a standardized work-
sheet. The two assessments were then compared. If the two
reviewing clinicians did not agree, a third party (either the re-
search nurse supervisor or physician) independently reviewed
96 T.G. Osimitz et al. / Regulatory Toxicology and Pharmacology 56 (2010) 93–99

Table 1
Causality rating categories.

Relationship undetermined—there is insufficient information or contradictory information that makes it impossible to make a reasonable judgment about the causal
relationship
Unrelated—clinical manifestations (CM) preceded exposure and did not worsen following exposure to DEET, or there is an alternative etiology that provides a more
compelling explanation of the symptoms than does the exposure to DEET
Unlikely related—the temporal relationship between the exposure and the onset of CM is weak, and there is a plausible alternative explanation, although not
compelling. If there was prior or subsequent use of DEET, with approximately the same exposure, the CM did not occur with either previous or subsequent use
Possibly related—the temporal relationship is appropriate and alternative explanations are no more or less compelling than DEET, and if there was prior or
subsequent use, with approximately the same exposure, there were no similar CMs
Probably related—there is a strong correlation between the onset of the CM and the exposure. There are no plausible alternative explanations, and there was either
previous or subsequent similar exposure to DEET with the occurrence of similar CM, and the clinical manifestation was similar to previously reported symptoms

Table 2
Causality ratings of cases in the DEET Registry 1995–2001.a

Unrelated Unlikely related Possibly related Probably related Relationship undetermined Total
Total cases 14 (4.7%) 40 (13.5%) 157 (53.0%) 36 (12.2%) 49 (16.6%) 296
Neurological cases 9 (5.9%) 24 (16.4%) 85 (55.9%) 13 (8.5%) 21 (13.7%) 152
a
Includes cases with a severity rating of moderate, major, insufficient information, but excludes 20 minor cases included in the DEET Registry.

the case and assigned a rating. The three reviewers then discussed Table 3
the case to reach a consensus rating. DEET Registry cases by age.a

Age (years) Probably related Possibly related Undetermined Total

2.4. One-year follow-up interview 0–2 2 (.08%) 14 (56%) 9 (13%) 25
3–5 4 (16%) 15 (6%) 6 (24%) 25
For those patients who were included in the DEET Registry, a fi- 6–12 6 (16.2%) 26 (70.3%) 5 (13.5%) 37
13–19 1 (7.7%) 10 (77%) 2 (15.4%) 13
nal follow-up interview was conducted approximately one year
Adult 23 (17.2%) 90 (67.2%) 21 (15.7%) 134
after their report of the exposure to determine if there were any Unknown 0 (0%) 2 (25%) 6 (75%) 8
long-term effects, recurring symptoms, or subsequent product use. Total 36 (14.9%) 157 (65%) 49 (20.2%) 242
a
Table excludes the 54 cases admitted to the Registry that were determined to be
3. Results not related to DEET exposure.

3.1. General findings

During 1995–2001, a total of 392 cases were referred to Pegus
Research for initial screening. Of these referrals, 76 cases (19.4%)
were not included because they did not meet the severity criteria
(e.g., were rated as minor severity) or included dermal symptoms
without any neurological or systemic component. Ten of the 76
(13.2%) cases were subsequently confirmed as having had no expo-
sure to DEET.
The remaining 316 (80.6%) cases met the inclusion criteria for
the DEET Registry for further investigation. This analysis focused
on those cases of major and moderate outcome and for which
the causality was ‘‘possibly” and ‘‘probably” related to DEET expo-
sure. For completeness, we also included cases for which the infor-
mation was ‘‘insufficient” to categorize severity of outcome and
cases for which the ‘‘relationship is undetermined ” Twenty of
the 316 cases mentioned above were of minor severity and thus
not considered further, leaving 296 cases for subsequent analysis
(see Table 2).
Of the 296 cases included in the DEET Registry, 54 (18.2%) cases
were judged to be unrelated or unlikely to be related to DEET expo-
sure. The remaining 242 (81.8%) cases were determined to be
either probably related (36 cases—12.2%), possibly related (157
cases—64.9%), or the causality was undetermined (49 cases—
16.6%) due to insufficient information.
3.3. Medical outcome severity and causality by symptom category
Symptoms were categorized as follows:
Seizures—convulsive activity followed by weakness and
confusion.
Other CNS and PNS—headaches, ataxia, numbness, memory
lapse, visual disturbances and delirium.
Dermal—hives, rash, itching, redness and swelling.
Other—nausea, dizziness, vomiting, fatigue, shortness of breath
and any other symptoms that do not fall within the other
categories.
A total of 59 cases with seizures were reported, with 53 (90%) of
these being of major or moderate severity (severity was not able to
be determined for the remaining six cases). There were 58 cases
with other neurological symptoms of moderate or major severity
(severity was not able to be determined for an additional two
cases). There were 113 cases with non-neurologic events (severity
was not able to be determined for an additional 10 cases) (see
Table 4).
3.4. Symptoms and age

3.2. DEET Registry cases by age group
A majority of the cases in the DEET Registry (134, 55.4%) were
adults. There were 100 (41%) children 19 years of age and younger
and 87 (36%) under the age of 13 (see Table 3).
In the Registry data, seizures were a more common symptom in
children than they were in adults. Forty-two of the 59 subjects
(71%) experiencing seizures were 19 years old and younger,
whereas, the large majority of patients (49/60, 82%) with other
neurological symptoms were older than 19 years old (see Table 5).
 T.G. Osimitz et al. / Regulatory Toxicology and Pharmacology 56 (2010) 93–99 97

Table 4
Medical outcome and causality for cases by symptom category.a

Major Moderate Insufficient information Total

Probably Possibly Undetermined Probably Possibly Undetermined Possibly Undetermined
Seizure cases 0 6 2 5 35 5 2 4 59
Other neuro cases 0 3 0 8 39 8 0 2 60
Other 1 0 3 4 15 6 2 7 38
Dermal only 0 0 0 13 36 9 0 0 58
Dermal, other 0 2 0 5 17 2 0 1 27
Total cases 1 11 5 35 142 30 4 14 242
a
Table excludes the 54 cases admitted to the Registry that were determined to be not related to DEET exposure.

Table 5
Symptom category for DEET Registry cases by age.a

Symptom category Age (years)

0–2 3–5 6–12 13–19 Adult Unknown Total
Seizure cases 14 (23.7%) 11 (18.6%) 13 (22%) 4 (6.8%) 16 (27.1%) 1 (1.7%) 59
Other neuro cases 2 (3.3%) 1 (1.7%) 4 (6.7%) 2 (3.3%) 49 (81.7%) 2 (3.3%) 60
Other only 4 (10.5%) 2 (5.3%) 9 (23.7%) 3 (7.9%) 15 (39.5%) 5 (13.1%) 38
Dermal only 5 (8.6%) 8 (13.8%) 7 (12.1% 3 (5.2%) 35 (60.3%) 0 (0%) 58
Dermal, other 0 (0%) 3 (11.1%) 4 (14.8%) 1 (3.7%) 19 (70.4%) 0 (0%) 27
Total all cases 25 (10.3%) 25 (10.3%) 37 (15.3%) 13 (6.0%) 134 (61.8%) 8 (3.3%) 242
a
Table excludes the 54 cases admitted to the Registry that were determined to be not related to DEET exposure.

Table 6
Seizure cases by age and medical outcome.

Outcome Age (years)

0–2 3–5 6–12 13–19 Adult Unknown Total
Moderate 9 (20%) 10 (22.2%) 11 (24.4%) 3 (6.7%) 11 (24.4%) 1 (2.2%) 45
Major 3 (37.5%) 1 (12.5%) 1 (12.5%) 1 (12.5%) 2 (25%) 0 (0%) 8
Insufficient information 2 (38.3%) 0 (0%) 1 (16.7%) 0 (0%) 3 (50%) 0 (0%) 6

Table 7
DEET concentration by symptom category.a

Symptom category DEET concentration (%)

0–10 10.1–20 20.1–40 40.1–60 60.1–100 Unknown Total
Seizure cases 15 (25.4%) 6 (10.2%) 7 (11.9%) 0 (0%) 5 (8.5%) 26 (44.1%) 59
Other neuro cases 5 (8.3%) 6 (10%) 14 (23.3%) 0 (0%) 5 (8.3%) 30 (50%) 60
Other only 9 (23.6%) 5 (13.2%) 10 (26.3%) 0 (0%) 5 (13.2%) 9 (23.7%) 38
Dermal only 16 (27.1%) 9 (15.3%) 9 (15.3%) 0 (0%) 2 (3.4%) 23 (39%) 59
Dermal, other 6 (23.1%) 3 (11.5%) 4 (15.4%) 1 (3.8%) 1 (3.8%) 11 (42.3%) 26
Total all cases 51 (21.0%) 29 (12.0%) 44 (18.2%) 1 (0.4%) 18 (7.4%) 99 (40.9%) 242
a
Table excludes the 54 cases admitted to the Registry that were determined to be not related to DEET exposure.

When considering the severity of the seizures in the Registry
population, 42 out of the 100 children younger age 19 and younger
(42%) experienced a seizure considered to be of moderate or major
severity (see Table 6). This is compared to 13 out of 134 adults
(12%).
3.5. DEET concentration and symptoms
Subjects exposed to more than one DEET-containing product,
were counted in the category of the highest DEET concentration
used. Forty-five percent of the patients reporting seizures after
DEET had been exposed to concentrations of 10% or less.4 However,
the DEET concentration is not known for about 40% of all cases (see
Table 7).
4
Denominator includes only those cases for which the DEET concentration is
known.
3.6. Case with major outcomes
During the 7-year history of the DEET Registry, no seizure cases
of ‘‘major” severity were judged to be ‘‘probably” related to DEET
exposure. Only 12 cases (5%) had a major severity outcome rating
whose symptoms were possibly related to exposure to DEET and
only six of these cases (2.5% of the DEET Registry cases) were re-
ported seizures. An additional five cases with major outcome were
reported for which the causation could not be determined.
3.7. One year follow-up—all cases
Of the 242 cases studied, follow-up interviews were conducted
for 123 cases (50.8%). The remaining 119 (49.2%) cases were lost to
follow-up. The key questions were, in the year since the initial re-
port to the DEET Registry;
98 T.G. Osimitz et al. / Regulatory Toxicology and Pharmacology 56 (2010) 93–99
(1) Did they experience the same or similar adverse events as
they previously reported?
(2) Did they use DEET again, and was its use associated with the
same symptoms?
Of the 123 completed interviews, 109 subjects reported no fur-
ther exposure to DEET. Yet, 20 (18.3%) of these subjects reported
experiencing the same or similar symptom as reported initially.
The remaining (89, 72.4%) neither used DEET again, nor did they
experience the earlier reported symptoms again. However, 14 of
the 123 subjects reported re-exposure to DEET-based insect repel-
lent in the year following their initial report. Six of these 14 sub-
jects (42.9%) experienced the same type of symptom with the re-
use as previously reported. None of these were recurrences of sei-
zures. The remaining eight subjects (57.1%) experienced no symp-
toms upon re-exposure to DEET.
If the information discovered in the annual follow-up interview
is considered a sort of informal dechallenge or rechallenge, then
the likelihood of DEET as the causative agent increased in six cases,
is substantially reduced for 28 subjects5, and unchanged in the
remaining 109 cases.
3.8. Subjects with known prior seizure disorders
People with an underlying neurological disorder (such as epi-
lepsy) or a history of seizures prior to the first documented use
of DEET were not disproportionately represented in the DEET Reg-
istry (4/59 seizure cases—6.8%; one probably related and three pos-
sibly related).
Two of these cases had a seizure disorder that was known prior
to the first use of DEET and for which DEET exposure seems to have
resulted in an increase in frequency of the seizures. In the first case
(moderate severity, possibly related), the mother of one adult male
with cerebral palsy and an idiopathic seizure disorder reported a
seizure after DEET application, although her son had been seizure
free for six months. The mother did not seek medical evaluation
due to the infrequent nature of her son’s seizures.
In the other case (moderate severity, probably related), a 4-year
old female with prior seizure history due to encephalitis experi-
enced a cluster of nine seizures over six days two weeks following
DEET exposure. As in the previous case, the mother did not seek
treatment due to frequency of seizures in past. However, she noted
the increase of seizures more than 2 weeks after DEET exposure.
The 1-year follow-up interview reported that the child continued
to have seizures without any further DEET exposures.
Both these patients had pre-existing encephalopathies (known
prior to the first use of DEET) of cerebral palsy and encephalitis,
which can be associated with lesional epilepsy. Epilepsy is known
to randomly provoke seizures of varying frequency and severity.
3.9. DEET interaction with pharmacologically active agents
Of the 59 seizure cases reported following DEET exposure, six
cases had other concurrent medicinal exposures covering a broad
spectrum of those medicines frequently used by the general public.
These observations do not suggest any link between their use and
reactions to DEET.
3.10. One year follow-up—seizure cases
At the one-year follow-up, 24 of the 59 seizure cases (40.7%)
were lost to follow-up. Follow-up calls were made on the remain-
5
The number 28 includes the 20 subjects with no DEET exposure during the period,
yet exhibiting symptoms similar to the initial report plus the 8 subjects that were re-
exposed to DEET but experienced no symptoms.
ing 35 cases (59.3%). In five of these 35 cases (14.3%) subsequent
investigations (EEG and brain imaging), along with further medical
follow-up, revealed evidence of an underlying disorder.
Thirty-two subjects (54.2% of all cases) reported no further use
of DEET during the year following their initial report. Of these, six
subjects (18.8% of the subjects with no DEET use) continued to
experience seizures over the intervening year in the absence of
DEET. Although it is theoretically possible that DEET exposure
led to the creation of an epileptic focus, nothing in the human
safety record for DEET would suggest that these seizures are any-
thing other than idiopathic. Twenty-six of the 32 individuals
(81.2%) had no further DEET exposures and no further seizure
activity. Only three of the 35 follow-up cases (8.6%) reported use
of DEET. None of these people experienced any additional seizure
activity.
4. Discussion
The DEET Registry provided valuable information regarding the
more serious adverse experiences. Neurological toxicity, particu-
larly in children, has been postulated as a possible risk in DEET
use. Since this study focused on neurologic events and ignored
the myriad of cases that, while apparently exposed, were asymp-
tomatic or had minor symptoms that were brief and medically
insignificant, there is now additional information to consider in
evaluating the advisability of using DEET.
However, while we attempted to advertise the DEET Registry as
broadly as possible and were pro-active in following up as neces-
sary with each patient, the DEET Registry ultimately relied on a
passive reporting strategy and, therefore, is affected by the limita-
tions in such a system. The extent of the underreporting is un-
known. Moreover, misclassification errors could occur with
respect to the identity of the product as well as in the application
of the acquired data to severity and causality determinations. The
assessment of any bias in the DEET Registry due to passive report-
ing is difficult to determine or even hypothesize since we were
specifically interested in only serious medical events of certain
types. It is important to note that in this registry the exposure
was to a product, not just to the chemical DEET. It was not possible
to isolate the effects of DEET from other ingredients that may cause
reactions in humans (e.g., fragrance, solvent, etc.).
The DEET Registry collected a number of neurological cases
showing a temporal relationship with DEET exposure. The most
common neurological symptom reported to the DEET Registry
was seizure. Of the total 59 seizure cases, 45 (76.3%) were of mod-
erate severity, 8 (13.6%) were of major severity, and 6 (10.2%) cases
had insufficient information to assess the medical outcome. Of
these 59 cases, 30 moderate (50.8%) and 5 major (8.5%) outcomes
for seizure were reported in children under the age of 13. Three
cases had insufficient information to assess the medical outcome.
This analysis focused on cases for which the effects were deter-
mined to be ‘‘possibly” or ‘‘probably” or had ‘‘insufficient informa-
tion” to determine causality related to DEET use.
Reports of seizures must be evaluated carefully. These results
are not surprising because seizures are at least twice as common
in children (Hauser, 2001). Also, because children are generally
more closely observed than adults, seizures are more likely to be
noticed. Reports suggest that about 2% of children have isolated
idiopathic, afebrile seizures by age ten (Hauser, 2001). Thus, given
the widespread use of DEET-containing repellent products among
children, it is likely that some idiopathic cases of a single seizure
will be temporally associated with such use by chance alone. About
1/3 of children with single seizures will have reoccurring seizures
in the 12 months after the first event (Camfield et al., 1985). An
analysis of the DEET Registry data shows that of 26 seizure cases
 T.G. Osimitz et al. / Regulatory Toxicology and Pharmacology 56 (2010) 93–99
in children under 13 years of age 6 (23%) had seizure reoccurrence
during the one-year follow-up period, a rate not unexpected for the
reoccurrence of seizures in general. Thus, some of these reoccur-
ring seizures could simply be the reoccurrence of seizures in the
normal population. Most of these reoccurrences are not
unexpected.
Other neurologic symptoms were reported after DEET exposure.
The spectrum of symptoms, e.g., dysesthesias, back spasms, etc.,
makes it unlikely that such variable symptoms could all be due
to one agent. Moreover, several patients with known migraine
experienced recurrences after DEET exposure. Three patients had
Bell’s palsy following DEET exposure. Given the frequency of mi-
graine and of Bell’s palsy in the general population, the DEET expo-
sure and subsequent symptoms are probably unrelated events.
Determining a relationship between case severity and DEET
concentration was difficult because we have no estimate of the
proportion of the DEET user population who use products with var-
ious DEET concentrations. Only if a proportion of our subjects were
overrepresented in a given product concentration category would
we know whether it is safer to use products with lower concentra-
tions. It is noteworthy that most cases of seizures in children were
associated with low-concentration DEET (<10%) as recommended
by the Health Canada authorities. Nonetheless, the available data
make it difficult to draw definitive conclusions about the relative
safety of lower and higher concentrations of DEET.
Another important feature of the DEET Registry was the ability
to probe the potential interaction of DEET with other products,
such as over-the-counter and prescription medications. No pattern
was apparent in these data to suggest that such interactions are
occurring. DEET is much like other products applied to the skin
or taken into the body in that the risks of its use must be carefully
balanced with the benefits. Insect-borne diseases in the United
States affect a significant number of people each year. Lyme dis-
ease is the most commonly reported insect-borne disease in the
US and is endemic in some areas of the country. One of the per-
sonal protection measures that the Centers for Disease Control
and Prevention (CDCP) recommends for Lyme disease, and now
for the West Nile virus, is the dermal application of insect repel-
lents containing DEET, applying the product according to USEPA’s
guidelines (CDCP, 2008b,c). Other significant insect-borne diseases
include Dengue Fever, Dengue Hemorrhagic Fever, Rocky Moun-
tain Spotted Fever and most recently, the West Nile Virus. It is
worth noting that illnesses such as Lyme disease and West Nile
virus often have neurologic sequelae that may include seizures.
Moreover, the fevers associated with many of these vector-borne
diseases themselves might results in seizures, especially in chil-
dren, leading to an overestimation of the frequency of neurologic
effects of DEET.
5. Conclusions
The DEET Registry approach described in this paper is a practical,
affordable post-marketing product surveillance approach that can be
used to obtain reliable information sufficient in detail to adequately
assess severity and causality. The creation of an adverse event report-
ing system that actively seeks cases and is very pro-active in follow-
ing up with sufficient data collection represents a method that can be
used to continuously monitor the safety profile of these consumer
products that are beneficial to the population’s health.
A wide variety of cases were included in the DEET Registry. The
symptoms tended to differ among ages, with seizures being
reported more frequently in children than other symptoms, and
99
nonspecific complaints representing a high percentage of the cases
in adults. Nonetheless, children did not appear to be disproportion-
ately represented in the DEET Registry; with cases spanning all age
groups. Careful investigation of the data suggests no apparent rela-
tionship between DEET concentration and severity of outcome.
Moreover, nothing in the DEET Registry suggests that DEET is inter-
acting with other chemicals in the elicitation of the reported
seizures.
Despite the limitations in the use of passively reported data and
considering the number of applications of DEET in the US (more
than 75 million people use it annually), relatively few reports of
neurological adversity (even assuming that we are underreporting
by a substantial factor) were documented in the DEET Registry.
Conflict of interest statement
Dr. Osimitz has been an occasional paid consultant to the DEET
Task Force, sponsor of the study being reported. Ms. Fell was paid
by Dr. Osimitz to assist in data compilation and analysis. Dr. Page is
employed by Pegus, the firm paid by the DEET Task Force to set-up
and operate the Registry. Dr. Murphy was not paid for any of his
efforts associated with the DEET Registry.
Acknowledgments
This project was funded by the DEET Task Force, part of the Con-
sumer Specialty Products Association in Washington, DC.
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