Absorption, Distribution and Excretion
Most diethyltoluamide (DEET) formulations employ the agent as a liquid to be applied onto human skin in an effort to repel mosquitoes from feeding on the skin. Topical application and absorption is consequently the most common route of absorption. When used appropriately, DEET formulations are generally not indicated for too many other routes of absorption or administration, like parenterally or orally. DEET is absorbed quickly through intact skin; 48% of the applied dose is totally absorbed within 6 hours. Topical absorption is the usual route of entry as DEET is normally applied to the skin as a mosquito repellent. DEET applied to the skin has also been shown to accumulate in the dermis. DEET is rapidly absorbed after oral ingestion. Additionally, animal experiments demonstrate that DEET can cross the placenta. DEET is efficiently absorbed across the skin and by the gut. Blood concentrations of about 3 mg/L have been reported several hours after dermal application in the prescribed fashion. Between 9% and 56% of dermally applied DEET is absorbed through the skin with peak blood levels being attained within 1 hour. Absorption through the skin varies according to the site exposed to the DEET. In animal model surfaces corresponding to the human palmar surface (an area that is typically heavily exposed during the application of liquid DEET), 68% of administered topical DEET was absorbed. As a consequence, small children are at increased risk of excessive absorption of DEET applied to the skin because of their relatively higher surface to volume ratio compared to adults.
Diethyltoluamide (DEET) is principally excreted via the kidneys, where the initial phase is initially rapid but not more than 50% of the absorbed dose is excreted during the first 5 days. In a study with a human volunteer weighing 65.8 kg and having been treated with 15 g of 95% DEET, urinary levels of DEET and a metabolite were measurable 4 hours after the initial exposure and persisted 48 hours later. Maximum urinary levels of DEET observed were 207 mg/L at 8 hours.
After dermal application, about 17% of the absorbed diethyltoluamide (DEET) dose enters the bloodstream. DEET accumulates in the skin, contributing to local irritation and possibly even bullous dermatitis. Accumulation within the body, however, has not been reported and experimentally there have been no cumulative effects of subtoxic doses of DEET; but various case reports of toxicity in man suggests that accumulation of the repellent could occur, and with deleterious effects.
Readily accessible data regarding the clearance of diethyltoluamide (DEET) is not available.
... DEET crossed the placenta and was detected in 8% (95% confidence interval = 2.6-18.2) of cord blood samples from a randomly selected subgroup of DEET users (n = 50). ...
... The focus of the present studies was to determine the effect of coexposure factors, potentially encountered in a military environment, that could modulate transdermal flux of topically applied DEET. Factors investigated were vehicle, dose, coexposure to permethrin, low-level sulfur mustard, occlusion, and simultaneous systemic exposure to pyridostigmine bromide and the nerve agent stimulant diisopropylfluorophosphate (DFP). Studies were conducted using the isolated perfused porcine skin flap (IPPSF), with a few mechanistically oriented studies conducted using in vitro porcine skin and silastic membrane diffusion cells. DEET was quantitated using high-performance liquid chromatography. The vehicle-control transdermal DEET flux in the IPPSF was approximately 2 ug/sq cm/hr for both 7.5 and 75% DEET concentrations, a value similar to that reported in humans. DEET absorption was enhanced by coinfusion of pyridostigmine bromide and DFP, by the presence of sulfur mustard, or by dosing under complete occlusion. The greatest increase in baseline flux was fivefold. In vitro diffusion cell studies indicated that silastic membranes had two orders of magnitude greater permeability than porcine skin, and showed vehicle effects on flux that were not detected in the IPPSF. These results suggest that coexposure to a number of chemicals that potentially could be encountered in a military environment may modulate the percutaneous absorption of topically applied DEET beyond that seen for normal vehicles at typically applied concentrations.
The synergic in vitro skin permeation enhancing-effect of N,N-diethyl-m-toluamide (DEET) and dodecylamine was investigated in order to develop a novel non-scrotal matrix-type transdermal delivery system of testosterone (TS). When DEET was loaded in DuroTak 87-2510 together with 2% TS and 3% dodecylamine, the in vitro rat skin permeation rate of TS synergistically increased as DEET concentration increased up to 0.5%. No further increase in permeation was observed thereafter and a plateau was observed up to 3.8% DEET. Moreover, compared to 0.5% DEET concentration, the addition of 3.8% of DEET in combination with 3% dodecylamine and 6% TS further increased the permeation rate of TS, and the maximum permeation rate of 11.21 ug/sq cm/hr was achieved. The in vitro skin permeation rates of TS from a transdermal delivery system of DuroTak 87-2510 containing 6% TS, 3% dodecyamine, and 3.8% DEET were in the following order: hairless mouse skin > rat skin > human cadaver skin. Assuming that a system with a surface area of 60 sq cm is applied, the human cadaver skin permeation rate of 5.74 ug/sq cm/hr achieved in this study can be interpreted as being equivalent to delivering approximately 8.27 mg of TS per day. Considering that the commercially available product (Testoderm TTS) for non-scrotal skin of the same surface area is designed to administer 5 mg of TS per day, the new formulation could maintain therapeutic plasma concentration of TS at a smaller surface area of 40 sq cm.
Urinary metabolites of DEET of 17 children (5-7 years of age) and 9 adults (23-25 years of age) were examined in the study described in this article. Urine samples were collected from each subject within eight hours after a single dermal application of 10 mL 12% DEET-containing insect repellent. Two metabolites, m-diethylaminocarbonyl benzoic acid (R3N0) and N-ethyl-m-toluamide (RON1), with unchanged DEET, were identified in the urine. The major metabolite was R3NO, which was 78.2% and 46.1% of the total DEET metabolites from children and adults, respectively, indicating that the pathway of ring methyl oxidation predominated. The recovered DEET metabolites were observed significantly more from children (1,116 pg) than from adults (446.2 pg) (p < .001). The difference in dermal absorption, albeit primarily attributed to DEET loading, was found to be related to height by regression analysis. The inverse association between height and dermal absorption of DEET suggests that shorter individuals (i.e., children) are subjected to dermal uptake of DEET. To avoid unnecessary exposure, parents need to be cautious when applying DEET-containing insect repellent on children.
For more Absorption, Distribution and Excretion (Complete) data for DEET (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Diethyltoluamide (DEET) is metabolized in humans by cytochrome P450 enzymes into the primary metabolites N,N-diethyl-m-hydroxymethylbenzamide (BALC) and Nethyl-m-toluamide (ET). Although several P450 isoenzymes have elicited activity in DEET metabolism, it appears that the CYP2B6 and CYP2C19 enzymes are the principal P450s responsible for the transformation of DEET to BALC and ET, respectively. Most of the body load is metabolized by such hepatic P450 enzymes, with only 10%–14% recovered unchanged in the urine.
DEET is metabolized by hepatic microsomes via oxidation, hydroxylation, dealkylation, and glucuronidation. Within 12 hours of application, the majority of DEET is excreted in the urine, mainly as metabolites. The amount of the parent compound excreted probably depends on the applied dose. Skin and fatty tissues may serve as a reservoir for DEET after repeated excessive dermal applications.
Urinary metabolites of DEET of 17 children (5-7 years of age) and 9 adults (23-25 years of age) were examined in the study described in this article. Urine samples were collected from each subject within eight hours after a single dermal application of 10 mL 12% DEET-containing insect repellent. Two metabolites, m-diethylaminocarbonyl benzoic acid (R3N0) and N-ethyl-m-toluamide (RON1), with unchanged DEET, were identified in the urine. The major metabolite was R3NO, which was 78.2% and 46.1% of the total DEET metabolites from children and adults, respectively, indicating that the pathway of ring methyl oxidation predominated. The recovered DEET metabolites were observed significantly more from children (1,116 pg) than from adults (446.2 pg) (p < .001). The difference in dermal absorption, albeit primarily attributed to DEET loading, was found to be related to height by regression analysis. The inverse association between height and dermal absorption of DEET suggests that shorter individuals (i.e., children) are subjected to dermal uptake of DEET. To avoid unnecessary exposure, parents need to be cautious when applying DEET-containing insect repellent on children.
Oxidation of the benzylic moiety and hydroxylation of side-chain of DEET molecules appeared to be predominant routes of metabolism in man.
DEET has known human metabolites that include acetaldehyde, N-ethyl-m-toluamide, N,N-diethyl-m-hydroxymethylbenzamide, and N-Ethyl-N-(2-hydroxyethyl)-3-methylbenzamide.

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Biological Half-Life
The elimination half-life of diethyltoluamide (DEET) is observed to be about 2.5 hours.

Toxicity Summary
IDENTIFICATION AND USE: DEET is nearly colorless to amber-like liquid. It is broad-spectrum insect repellant registered for use on the human body, clothing, and on horses to repel biting flies, biting midges, black flies, chiggers, deer flies, fleas, gnats, horse flies, mosquitoes, no-see-ums, sand flies, stable flies, and ticks. HUMAN EXPOSURE AND TOXICITY: Most reports of adverse events following DEET exposure are skin-related findings. These include mild skin irritation, contact dermatitis, exacerbation of preexisting skin disease as well as generalized urticaria. DEET is very irritating to the eyes but not corrosive. Serious adverse cutaneous effects have occurred in tropical conditions, when applied to areas of skin that were occluded during sleep (mainly the antecubital and popliteal fossae). Under these conditions, the skin became red and tender and then exhibited blistering and erosion, leaving painful, weeping, denuded areas that were slow to heal. Severe scarring occasionally resulted from some of these severe reactions. Toxic encephalopathic reactions have been reported in rare instances following ingestion or dermal application. Manifestations of toxic encephalopathy have been headache, restlessness, irritability, ataxia, rapid loss of consciousness, hypotension and seizures. Some cases have shown flaccid paralysis and areflexia. Deaths have occurred following very large doses. Human primary nasal mucosa cells were exposed to 0.5-1.0 mM concentrations of DEET for 60 min. Genotoxic effects were detected by the alkaline microgel electrophoresis assay ("comet assay"). No significant cytotoxic effects were observed, but DEET showed a significant genotoxic response. ANIMAL STUDIES: Application of pure DEET to rabbit eyes has caused edema of the conjunctiva, lacrimation, discharge, and slight transient cloudiness of the corneas. Injury of the epithelium, indicated by staining with fluorescein, persisted for two days, but the eyes returned to normal in five days. DEET was applied to the shaven backs ot castrated rats at dose levels of 0 or 1000 mg/kg/day. In addition, noncastrated rats were administered DEET dermally at a dose level of 1000 mg/kg/day. Microscopic examination of the kidney revealed renal lesions in DEET-treated rats, These lesions included hyaline and granular cast formation, chronic inflammation, regenerative tubular epithelium, and hyaline droplets. The incidence and severity of these lesions was greater in the noncastrated treated group. Immunocytochemical techniques confirmed the presence of hyaline droplets containing alpha2 microglobulin in the kidneys of the noncastrated and castrated treated animals, but not in controls. In dogs, emesis, ptyalism, abnormal biting and scratching, and abnormal head movements were observed. Ataxia and ptosis also were observed in some dogs. In addition, convulsions were observed in a male dog. Clinical signs occurred shortly after dosing, after which recovery was observed. In developmental study in rats, DEET produced maternal toxicity in the form of mortality, decreased body weights, decreased food consumption, hypoactivity, ataxia, prostration, unkempt appearance, urine stains, and perioral wetness at 1000 mg/kg/day. No maternal effects were observed at levels below 1000 mg/kg/day and no evidence of developmental toxicity was observed at any dose. Five strains of Salmonella typhimurium, TA98, TA100, TA1535, TA1537, and TA1538, were used for a genotoxicity assay with and without metabolic activation. The concentrations of DEET evaluated in these studies ranged from 278 to 8333 ug/plate. Mutagenic frequency did not increase in any of the tester strains. ECOTOXICITY STUDIES: Fish (common carp) were exposed for 28 days to three concentrations of DEET (1.0 ug/L, 0.1 mg/L, and 1.0 mg/L) where 1 ug/L is corresponding to the concentration found in the environment. DEET had a significant effect on increased RBC, decreased mean corpuscular volume (MCV), and mean corpuscular hemoglobin value (MCH) compared to control groups in the concentration of 1 mg/L. A significant decline in triacylglycerols in plasma was found in the concentration of 1 mg/L compared to the control groups.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of diethyltoluamide (DEET) during breastfeeding. However, the Centers for Disease Control and Prevention and U.S. Environmental Protection Agency consider DEET to be safe and effective during breastfeeding when used as directed. It should be used by breastfeeding women to avoid exposure to mosquito-borne viruses. Avoid application directly to the nipple and other areas where the infant might directly ingest the product.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Readily accessible data regarding the protein binding of diethyltoluamide (DEET) is not available.

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Toxicity Data
LC50 (rat) = 5950 mg/m3

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Interactions
DEET and permethrin were implicated in the development of illnesses in some veterans of the Persian Gulf War. This study was designed to investigate the effects of daily dermal application of these chemicals, alone or in combination, on the permeability of the blood-brain barrier (BBB) and blood-testes barrier (BTB) and on sensorimotor performance in male Sprague-Dawley rats. Groups of five rats were treated with a dermal daily dose of 4, 40, or 400 mg/kg DEET in ethanol or 0.013, 0.13, or 1.3 mg/kg permethrin in ethanol for 60 d. A group of 10 rats received a daily dermal dose of ethanol and served as controls. BBB permeability was assessed by injection of an iv dose of the quaternary ammonium compound [(3)H]hexamethonium iodide. While permethrin produced no effect on BBB permeability, DEET alone caused a decrease in BBB permeability in brainstem. A combination of DEET and permethrin significantly decreased the BBB permeability in the cortex. BTB permeability was decreased by treatment with DEET alone and in combination with permethrin. The same animals underwent a battery of functional behavior tests 30, 45, and 60 d after exposure to evaluate their sensorimotor abilities. All treatments caused a significant decline in sensorimotor performance in a dose- and time-dependent manner. These results show that daily dermal exposure to DEET, alone or in combination with permethrin, decreased BBB permeability in certain brain regions, and impaired sensorimotor performance.
In this study, the ratio of 6beta-hydroxycortisol (6beta-OHF) to free cortisol (F) was determined in urine following a single dermal dose of 400 mg/kg of DEET (N,N-diethyl-m-toluamide), and 1.3 mg/kg of permethrin, alone and in combination, in rats. Urine samples were collected at 2, 4, 8, 16, 24, 48, and 72 hr after application. Recoveries of 6beta-OHF and cortisol (F) from control urine samples were between 75 and 85%, with limits of detection at 30 and 10 ng/mL for cortisol and 6beta-OHF, respectively. A single dermal dose of DEET alone and in combination with permethrin significantly increased urinary excretion of 6beta-hydroxycortisol 24 hr after dosing. Permethrin did not significantly alter the urinary excretion of 6beta-hydroxycortisol. These results indicate that DEET, alone and in combination with permethrin, increased urinary excretion of 6beta-OHF in rats following a single dermal dose application.
The acute lethal interaction that occurs in rodents when high doses of a peripherally restricted cholinesterase inhibitor, pyridostigmine bromide (PB), and the insect repellent N, N-diethyl-m-toluamide (DEET) are combined was first described during studies of chemical mixtures that were targeted as potential causative agents of Gulf War illnesses. This study was intended to provide insight into possible mechanisms of that lethal interaction. Following a single intraperitoneal injection of PB (2 mg/kg) and/or DEET (300 or 500 mg/kg), respiratory activity was measured in conscious freely moving rats using whole-body plethysmography. Cardiovascular function was also monitored simultaneously through an arterial catheter. PB (2 mg/kg) given alone stimulated respiration and increased blood pressure. Arterial pH levels were decreased, whereas pO(2) and pCO(2) remained at control levels. Administration of DEET (300 mg/kg) alone increased tidal volume and decreased blood pressure. Blood gases and pH levels were unaltered. A higher dose of DEET (500 mg/kg) also decreased respiratory and heart rate. Coadministration of PB (2 mg/kg) and DEET (300 mg/kg) increased tidal volume, decreased arterial pH, and elevated pCO(2). Heart rate and blood pressure declined progressively after drug coadministration. Pretreatment with atropine methyl nitrate (AMN), a peripherally selective competitive antagonist at nicotinic and muscarinic receptor sites, reduced the individual effects of PB or DEET, and significantly increased survival after coexposure to these agents. Although changes in respiratory function may have contributed to the lethal interaction, it was concluded that the primary cause of death was circulatory failure.
... The focus of the present studies was to determine the effect of coexposure factors, potentially encountered in a military environment, that could modulate transdermal flux of topically applied DEET. Factors investigated were vehicle, dose, coexposure to permethrin, low-level sulfur mustard, occlusion, and simultaneous systemic exposure to pyridostigmine bromide and the nerve agent stimulant diisopropylfluorophosphate (DFP). Studies were conducted using the isolated perfused porcine skin flap (IPPSF), with a few mechanistically oriented studies conducted using in vitro porcine skin and silastic membrane diffusion cells. DEET was quantitated using high-performance liquid chromatography. The vehicle-control transdermal DEET flux in the IPPSF was approximately 2 ug/sq cm/hr for both 7.5 and 75% DEET concentrations, a value similar to that reported in humans. DEET absorption was enhanced by coinfusion of pyridostigmine bromide and DFP, by the presence of sulfur mustard, or by dosing under complete occlusion. The greatest increase in baseline flux was fivefold. In vitro diffusion cell studies indicated that silastic membranes had two orders of magnitude greater permeability than porcine skin, and showed vehicle effects on flux that were not detected in the IPPSF. These results suggest that coexposure to a number of chemicals that potentially could be encountered in a military environment may modulate the percutaneous absorption of topically applied DEET beyond that seen for normal vehicles at typically applied concentrations.
For more Interactions (Complete) data for DEET (16 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LC50 Rat inhalation >4100 mg/cu m/4 hr
LD50 Rat oral 1892 mg/kg
LD50 Rat dermal >5000 mg/kg
LC50 Rat inhalation >2.0 mg/L/4 hr
For more Non-Human Toxicity Values (Complete) data for DEET (8 total), please visit the HSDB record page.

Drug Warnings
/DEET/ should not be applied to any skin area that is likely to be opposed to another skin surface for a significant period of time (antecubital and popliteal fossae, inguinal areas).
Serious adverse cutaneous effects have occurred in tropical conditions, when applied to areas of skin that were occluded during sleep (mainly the antecubital and popliteal fossae). Under these conditions, the skin became red and tender and then exhibited blistering and erosion, leaving painful, weeping, denuded areas that were slow to heal. Severe scarring occasionally resulted from some of these severe reactions.

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Pharmacodynamics
When used appropriately, diethyltoluamide (DEET) containing products are designed to be applied directly to people's skin as a means to elicit a repelling action to keep insects from targeting human skin. At the amounts and doses recommended for use on human children and adults, noticeable absorption or systemic exposure is not expected. Owing to the proportional difference in size between humans and insects, however, the exposure of insects to the applied DEET (whether topically or via inhalation of DEET) is expected to be enough to interfere with the insects' sensory attraction to human skin.

C12H17NO

191.27

191.131

134-62-3

Diethyltoluamide-d10;1215576-01-4;Diethyltoluamide-d7;1219799-37-7

4284

Nearly colorless to amberlike liquid

1.0±0.1 g/cm3

297.5±0.0 °C at 760 mmHg

-45ºC

141.7±13.3 °C

0.0±0.6 mmHg at 25°C

1.517

1.96

0

1

3

14

187

0

O=C(C1=C([H])C([H])=C([H])C(C([H])([H])[H])=C1[H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])[H]

MMOXZBCLCQITDF-UHFFFAOYSA-N

InChI=1S/C12H17NO/c1-4-13(5-2)12(14)11-8-6-7-10(3)9-11/h6-9H,4-5H2,1-3H3

N,N-diethyl-3-methylbenzamide

NSC33840; NSC-33840; NSC 33840

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~522.82 mM)
H2O : ~2 mg/mL (~10.46 mM)

Solubility in Formulation 1: 100 mg/mL (522.82 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)