Absorption, Distribution and Excretion
Most DEET formulations are applied to human skin in liquid form to repel mosquito bites. Therefore, topical application and absorption are the most common routes of absorption. DEET formulations are generally not suitable for other routes of absorption or administration, such as parenteral or oral administration, if used properly. DEET can be rapidly absorbed through intact skin; 48% of the applied dose is completely absorbed within 6 hours. Since DEET is typically applied to the skin as a mosquito repellent, topical absorption is its most common route of entry. Studies have shown that DEET applied to the skin can also accumulate in the dermis. Orally administered DEET is also rapidly absorbed. Furthermore, animal studies have shown that DEET can cross the placenta. DEET can be effectively absorbed by the skin and intestines. It has been reported that several hours after skin application according to the prescribed method, the blood concentration of DEET is approximately 3 mg/L. The absorption rate of DEET applied through the skin ranges from 9% to 56%, with peak blood concentrations reached within 1 hour. Skin absorption rates vary depending on the site of DEET contact. In animal models corresponding to the human palm surface (the area typically in extensive contact when applying liquid DEET), 68% of topical DEET was absorbed. Therefore, young children are more prone to excessive absorption after skin application of DEET due to their higher surface area to volume ratio compared to adults. DEET is primarily excreted via the kidneys, initially rapidly, but within the first 5 days, the excreted dose does not exceed 50% of the absorbed dose. In a study of 65.8 kg volunteers, subjects received 15 g of 95% DEET. DEET and its metabolites were detectable in urine 4 hours after the first exposure and persisted for 48 hours. The highest observed concentration of DEET in urine was 207 mg/L (8 hours). Approximately 17% of the absorbed dose of DEET enters the bloodstream after skin application. DEET can accumulate in the skin, causing local irritation and potentially bullous dermatitis. However, there have been no reports of accumulation in the body, and experiments have not found a cumulative effect of subtoxic doses of DEET; however, some case reports of human poisoning suggest that this repellent may accumulate and produce harmful effects. Currently, there is no readily available data on the clearance rate of DEET. …DEET can cross the placenta, and 8% (95% confidence interval = 2.6–18.2) of DEET was detected in umbilical cord blood samples from a randomly selected subgroup of DEET users (n = 50). This study aimed to determine the effects of co-exposure factors that may be encountered in military settings on the percutaneous absorption of topical DEET. Factors studied included excipients, dosage, co-exposure with permethrin, low concentrations of mustard gas, occlusion, and simultaneous systemic exposure to pyridostigmine bromide and the nerve agent stimulant diisopropyl fluorophosphate (DFP). The study was conducted using an ex vivo perfused porcine skin flap (IPPSF), and some mechanistic studies were conducted using in vitro porcine skin and silicone membrane diffusion pools. Quantitative analysis of DEET was performed using high-performance liquid chromatography (HPLC). In the IPPSF, the transdermal DEET absorption in the excipient control group was approximately 2 μg/cm²/hr at both 7.5% and 75% DEET concentrations, similar to reported values in humans. DEET absorption was enhanced by co-infusion of pyridostigmine bromide and DFP, the presence of mustard gas, or administration under completely closed conditions. The maximum increase in baseline flux was five-fold. In vitro diffusion cell studies showed that the silicone membrane was two orders of magnitude more permeable than porcine skin and exhibited a carrier effect on flux that was not detected in the IPPSF. These results suggest that co-exposure to multiple chemicals that may be encountered in military environments can modulate the transdermal absorption of locally applied DEET, exceeding the absorption of normal carriers at typical application concentrations. To develop a novel non-scrotal matrix-based transdermal testosterone (TS) delivery system, we investigated the synergistic effect of N,N-diethyl-m-toluamide (DEET) and dodecylamine on in vitro skin penetration enhancement. When DEET was loaded into DuroTak 87-2510 with 2% TS and 3% dodecylamine, the in vitro skin permeability of TS in rats increased synergistically with increasing DEET concentration until the DEET concentration reached 0.5%. Thereafter, the permeability no longer increased and tended to stabilize at a DEET concentration of 3.8%. Furthermore, compared to a 0.5% DEET concentration, the combination of 3.8% DEET with 3% dodecylamine and 6% TS further improved the TS permeability, reaching a maximum permeability of 11.21 μg/cm²/h. The in vitro skin permeability of TS in the DuroTak 87-2510 transdermal drug delivery system containing 6% TS, 3% dodecylamine, and 3.8% DEET followed the order: hairless mouse skin > rat skin > human cadaver skin. Assuming a system with a surface area of 60 cm², the cadaveric skin permeability obtained in this study was 5.74 μg/cm²/h, which can be interpreted as equivalent to a daily delivery of approximately 8.27 mg TS. Considering that commercially available products for non-scrotal skin of the same surface area (Testoderm TTS) are designed to deliver 5 mg TS daily, the new formulation can maintain therapeutic plasma concentrations of TS on a smaller surface area (40 cm²). The study described in this article examined DEET metabolites in the urine of 17 children (5–7 years old) and 9 adults (23–25 years old). Urine samples were collected from each subject within 8 hours after a single skin application of 10 mL of 12% DEET repellent. Two metabolites were detected in the urine: m-diethylaminocarbonylbenzoic acid (R3NO) and N-ethyl-m-toluamide (RON1), as well as unmetabolized DEET. The primary metabolite was R3NO, accounting for 78.2% and 46.1% of total DEET metabolites in children and adults, respectively, indicating that the cyclomethyl oxidation pathway is dominant. The amount of DEET metabolites recovered in children's urine (1116 pg) was significantly higher than that in adults (446.2 pg) (p < .001). Although the difference in skin absorption was mainly attributed to DEET load, regression analysis revealed a correlation with height. Height was negatively correlated with DEET skin absorption, suggesting that shorter individuals (e.g., children) are more likely to absorb DEET through the skin. To avoid unnecessary exposure, parents should exercise caution when using DEET-containing insect repellents on children. For more complete data on the absorption, distribution, and excretion of DEET (12 items), please visit the HSDB record page. Metabolites/Metabolites
DEET is metabolized in the human body by cytochrome P450 enzymes to the major metabolites N,N-diethyl-m-hydroxymethylbenzamide (BALC) and N-ethyl-m-toluamide (ET). Although multiple P450 isoenzymes are involved in the metabolism of DEET, CYP2B6 and CYP2C19 enzymes appear to be the main P450 enzymes responsible for converting DEET to BALC and ET, respectively. Most DEET in the body is metabolized by hepatic P450 enzymes, with only 10%–14% excreted unchanged in the urine.
DEET is metabolized in hepatic microsomes via oxidation, hydroxylation, dealkylation, and glucuronidation. Within 12 hours of application, most DEET is excreted in the urine primarily as metabolites. The amount of parent compound excreted may depend on the dosage applied. Repeated excessive skin application may lead to the skin and adipose tissue becoming a reservoir for DEET. This study examined DEET metabolites in the urine of 17 children (5–7 years old) and 9 adults (23–25 years old). Urine samples were collected from each subject within 8 hours after a single skin application of 10 mL of 12% DEET repellent. Two metabolites were detected in the urine: m-diethylaminocarbonylbenzoic acid (R3NO) and N-ethyl-m-toluamide (RON1), as well as unmetabolized DEET. R3NO was the dominant metabolite, accounting for 78.2% and 46.1% of total DEET metabolites in children and adults, respectively, indicating that the cyclomethyl oxidation pathway is dominant. The amount of DEET metabolites recovered in children's urine (1116 pg) was significantly higher than that in adults (446.2 pg) (p < .001). Although the difference in skin absorption was mainly attributed to DEET load, regression analysis revealed a correlation with height. Height was negatively correlated with DEET skin absorption, suggesting that shorter individuals (e.g., children) are more likely to absorb DEET through the skin. To avoid unnecessary exposure, parents should exercise caution when using mosquito repellents containing DEET on children. In the human body, benzyl oxidation and side-chain hydroxylation of the DEET molecule appear to be the main metabolic pathways. Known DEET metabolites in the human body include acetaldehyde, N-ethyl-m-toluamide, N,N-diethyl-m-hydroxymethylbenzamide, and N-ethyl-N-(2-hydroxyethyl)-3-methylbenzamide. The elimination half-life of diethyltoluamide (DEET) is approximately 2.5 hours.

Toxicity Summary
Identification and Uses: DEET is a nearly colorless to amber liquid. It is a broad-spectrum insect repellent registered for use on humans, clothing, and horses to repel biting flies, midges, blackflies, chiggers, deer flies, fleas, blackflies, horseflies, mosquitoes, midges, sandflies, stable flies, and ticks. Human Exposure and Toxicity: Most reports of adverse reactions following DEET exposure are skin-related. These adverse reactions include mild skin irritation, contact dermatitis, exacerbation of pre-existing skin conditions, and generalized urticaria. DEET is highly irritating to the eyes but not corrosive. In tropical regions, severe skin adverse reactions can occur when applied to covered skin areas (primarily the elbows and knees) during sleep. In these cases, the skin becomes red, tender, and subsequently develops blisters and erosions, leaving painful, oozing, exposed, and slow-healing areas. Some severe reactions can lead to severe scarring. In rare cases, toxic encephalopathy has been reported after ingestion or skin application. Symptoms of toxic encephalopathy include headache, restlessness, irritability, ataxia, rapid loss of consciousness, hypotension, and seizures. Some cases have also shown flaccid paralysis and loss of reflexes. Deaths have occurred following high doses. Exposure of primary human nasal mucosal cells to 0.5–1.0 mM DEET for 60 minutes revealed genotoxic effects by alkaline microgel electrophoresis (“comet test”). No significant cytotoxic effects were observed, but DEET exhibited significant genotoxicity. Animal studies: Application of pure DEET to the rabbit eye caused conjunctival edema, lacrimation, increased secretions, and mild transient corneal opacity. Fluorescein staining showed epithelial damage lasting for two days, but the eyes returned to normal after five days. DEET was applied to the shaved backs of castrated rats at doses of 0 or 1000 mg/kg/day. In addition, DEET was administered percutaneously to uncastrated rats at a dose of 1000 mg/kg/day. Kidney microscopy revealed renal lesions in the DEET-treated rats, including hyaline and granular casts, chronic inflammation, regenerative tubular epithelium, and hyaline droplets. The incidence and severity of lesions were higher in the uncastrated group than in the castrated group. Immunohistochemistry confirmed the presence of hyaline droplets containing α2-microglobulin in the kidneys of both uncastrated and castrated animals, but not in the control group. In dogs, vomiting, salivation, abnormal biting and scratching, and abnormal head movements were observed. Ataxia and ptosis were also observed in some dogs. Additionally, one male dog experienced seizures. Clinical symptoms appeared shortly after administration and subsequently resolved. In rat developmental studies, DEET at a dose of 1000 mg/kg/day produced maternal toxicity, manifested as death, weight loss, decreased food intake, reduced activity, ataxia, weakness, disheveled fur, urine stains, and perioral wetting. No maternal toxicity was observed at doses below 1000 mg/kg/day, and no developmental toxicity was observed at any dose. Genotoxicity tests were performed using five Salmonella typhimurium strains (TA98, TA100, TA1535, TA1537, and TA1538) under both metabolically activated and non-metabolic conditions. The DEET concentrations evaluated in this study ranged from 278 to 8333 μg/plate. No increase in mutagenicity was observed in any of the tested strains. Ecotoxicity studies: Carp were exposed to three different concentrations of DEET (1.0 μg/L, 0.1 mg/L, and 1.0 mg/L) for 28 days, with the 1 μg/L concentration being comparable to environmental concentrations. At a concentration of 1 mg/L, DEET significantly increased red blood cell count and decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) compared to the control group. Compared to the control group, plasma triglyceride concentrations were significantly decreased at 1 mg/L.

---

Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no clinical information regarding the use of DEET during lactation. However, the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Environmental Protection Agency consider DEET safe and effective when used as directed during lactation. Breastfeeding women should use DEET to avoid exposure to mosquito-borne viruses. Avoid direct application to the nipples and other areas where the infant may ingest the substance.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

---

Protein binding
There is currently no readily available data on the protein binding of DEET.

---

Toxicity Data
LC50 (Rat) = 5950 mg/m3
Interactions
DEET and permethrin are associated with some Gulf War veterans. This study aimed to investigate the effects of daily transdermal application of these chemicals, alone or in combination, on the permeability of the blood-brain barrier (BBB) and blood-testis barrier (BTB) and sensorimotor function in male Sprague-Dawley rats. Rats were divided into five groups and transdermally applied daily with 4, 40, or 400 mg/kg of DEET ethanol solution or 0.013, 0.13, or 1.3 mg/kg of permethrin ethanol solution for 60 days. Another group of ten rats served as a control group and transdermally applied ethanol daily. BBB permeability was assessed by intravenous injection of the quaternary ammonium compound [(3)H]hexamethylammonium iodide. The results showed that permethrin had no effect on BBB permeability, while DEET alone reduced brainstem BBB permeability. The combined use of DEET and permethrin significantly reduced the permeability of the cortical blood-brain barrier (BBB). DEET alone or in combination with permethrin also reduced the permeability of the blood-testis barrier (BTB). A series of functional behavioral tests were performed on the same group of animals at 30, 45, and 60 days post-exposure to assess their sensorimotor abilities. All treatments resulted in a significant, dose- and time-dependent decrease in sensorimotor abilities. These results indicate that daily percutaneous exposure to DEET (alone or in combination with permethrin) reduces BBB permeability in certain brain regions and impairs sensorimotor abilities. This study determined the ratio of 6β-hydroxycorticosteroid (6β-OHF) to free cortisol (F) in the urine of rats after a single percutaneous administration of 400 mg/kg DEET (N,N-diethyl-m-toluamide) and 1.3 mg/kg permethrin (alone or in combination). Urine samples were collected at 2, 4, 8, 16, 24, 48, and 72 hours post-administration. The recoveries of 6β-hydroxycorticosteroids (6β-OHF) and cortisol (F) in urine samples from the control group ranged from 75% to 85%, with detection limits of 30 ng/mL and 10 ng/mL for cortisol and 6β-OHF, respectively. Single transdermal administration of DEET (alone) and its combination with permethrin significantly increased urinary excretion of 6β-hydroxycorticosteroids 24 hours post-administration. Permethrin had no significant effect on urinary excretion of 6β-hydroxycorticosteroids. These results indicate that single transdermal administration, alone or in combination with permethrin, increases urinary excretion of 6β-hydroxysteroids (6β-OHF) in rats. In rodents, an acutely lethal interaction occurred when high doses of the peripheral cholinesterase inhibitor pyridostigmine bromide (PB) were used in combination with the anthelmintic N,N-diethyl-m-toluamide (DEET). This phenomenon was initially discovered during research on a chemical mixture considered a potential causative factor of Gulf War syndrome. This study aimed to further understand the possible mechanisms of this lethal interaction. Respiratory activity was measured using whole-body plethysmography after a single intraperitoneal injection of PB (2 mg/kg) and/or DEET (300 or 500 mg/kg) into conscious, freely moving rats. Cardiovascular function was monitored simultaneously via catheter artery. PB alone (2 mg/kg) stimulated respiration and increased blood pressure. Arterial blood pH decreased, while pO₂ and pCO₂ remained at control levels. DEET alone (300 mg/kg) increased tidal volume and decreased blood pressure. Blood gases and pH remained unchanged. Higher doses of DEET (500 mg/kg) also decreased respiratory rate and heart rate. Concomitant use of PB (2 mg/kg) and DEET (300 mg/kg) increased tidal volume, decreased arterial blood pH, and increased pCO₂. With combined drug administration, heart rate and blood pressure gradually decreased. Pretreatment with atropine methyl nitrate (AMN, a peripherally selective competitive antagonist acting on nicotine and muscarinic receptors) mitigated the individual effects of either PB or DEET and significantly improved survival after co-exposure to both drugs. Although changes in respiratory function may have contributed to the lethal interaction, circulatory failure was the leading cause of death. This study focused on determining the effects of co-exposure factors likely encountered in military settings on the percutaneous absorption of topical DEET. Factors studied included excipients, dosage, co-exposure with permethrin, low concentrations of mustard gas, skin occlusion, and simultaneous systemic exposure to pyridostigmine bromide and the nerve agent stimulant diisopropyl fluorophosphate (DFP). The study was conducted using an in vitro perfused porcine skin flap (IPPSF), and some mechanistic studies were performed using in vitro porcine skin and a silica membrane diffusion cell. Quantitative analysis of DEET was performed using high-performance liquid chromatography. In IPPSF, transdermal DEET uptake in the excipient control group was approximately 2 μg/cm²/hr at both 7.5% and 75% DEET concentrations, similar to reported values in humans. DEET uptake was enhanced by co-infusion of pyridostigmine bromide and DFP, the presence of sulfur mustard, or administration under completely closed conditions. The maximum increase in baseline flux was five-fold. In vitro diffusion cell studies showed that the silicone membrane was two orders of magnitude more permeable than porcine skin and exhibited a carrier effect on flux that was not detected in IPPSF. These results suggest that co-exposure to multiple chemicals that may be encountered in military environments can modulate the transdermal uptake of topical DEET, resulting in uptake exceeding that of conventional carriers at normal concentrations. For more complete (16) data on interactions with DEET, please visit the HSDB record page.

---

Non-human toxicity values
Rat inhalation LC50 >4100 mg/m³/4 hr
Rat oral LD50 1892 mg/kg
Rat dermal LD50 >5000 mg/kg
Rat inhalation LC50 >2.0 mg/L/4 hr
For more complete (8 data points) non-human toxicity values of DEET, please visit the HSDB record page.

Drug Warnings
DEET should not be applied to areas of skin that may be in prolonged contact with other skin surfaces (elbow fossa, popliteal fossa, groin area). Serious adverse skin reactions have occurred in tropical regions when DEET is applied to areas of skin covered during sleep (primarily the elbow fossa and popliteal fossa). In these cases, the skin becomes red and tender, followed by blisters and erosions, leaving painful, oozing, exposed, and slow-healing areas. Some severe reactions can sometimes result in severe scarring. Pharmacodynamics When used correctly, products containing DEET are intended to be applied directly to human skin to produce a repellent effect against insect bites. At the recommended dosages and amounts for children and adults, no significant absorption or systemic exposure is expected. However, due to the significant difference in body size between humans and insects, the amount of DEET applied to an insect (whether topically applied or inhaled) is expected to be sufficient to interfere with the insect's 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.

---

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