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Pharmacokinetics/Toxicokinetics

DEET (N,N-Diethyl-meta-toluamide)
Chemical Technical Summary for Public Health
and Public Safety Professionals

Agency for Toxic Substances and Disease Registry
Atlanta, Georgia
December 6, 2004

Absorption

Studies have found that the dermal absorption of DEET in intact human adult skin is between 5% and 17% of the applied dose (Robbins and Cherniack 1986; Feldmann and Maibach 1970; Selim et al. 1995).

Percutaneous penetration of DEET in humans was studied by Feldmann and Maibach (1970). A treatment of 4 µg/cm2 containing 1 µCi of 14C was applied to a 13 cm2 area of the forearm in four subjects. The site was not washed for 24 hours, and the subjects' urine was collected for 5 days. Percutaneous penetration was quantified by the amount of radioactivity recovered in the urine. By this method, the total absorption of DEET was found to be 16.71% (S.D.=5.1) of the applied dose. The peak absorption rate was noted to be approximately 0.77% of the dose per hour in the period 0-12 hours after administration.

Dermal absorption of DEET in 12 adult male volunteers was studied under controlled laboratory conditions by Selim et al. (1995). The subjects received single applications of radiolabeled DEET to a 4 x 6 cm2 area of the forearm, where it was left for 8 hours: 5.6% of the applied dose of technical grade (98.9%) DEET was absorbed; 8.4% of the applied dose of 15% DEET in alcohol was absorbed.

When excised human abdominal skin was treated with 10 µL DEET at a dose of 0.3 mg/cm2 dissolved in an ethanol solution in vitro, a mean recovery from the skin of 77.8% ±2.6 DEET was recorded (with evaporation loss included). An average of 6.6% ± 2.2 of the applied radioactive dose was recovered from percutaneous penetration, with an average of 16.7% ± 3.7 recovered from evaporation into the vapor trap (Reifenrath and Robinson 1982).

Due to the differences in skin type and inherent permeability, dermal absorption of DEET by animals does not necessarily accurately reflect human dermal absorption (Robbins and Cherniack; Moody et al. 1995; Qiu et al. 1997, 1998; Schoenig et al. 1996).

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Distribution

Limited human data exist on the distribution of absorbed DEET within the human body. Results from animal studies might not mimic human distribution, and it is unclear which animal model, if any, could be used to predict human distribution.

In mice, results from whole-body radiography by Blomquist and Thorsell (1977) showed that a high concentration of radiolabeled [14C] DEET was found in the lacrimal gland, liver, kidney, and nasal mucosa following dermal treatment with a 10 µCi of [14C] DEET. High activity was also detected in the bile and in parts of the intestines, as well as in the urine. These detections were taken as an indication of biliary and urinary excretion. Six days after the application, DEET was found only in the skin of the treated area, and persisted in that area at 36 days post-treatment. The evidence also suggests that persistence of the chemical could be due to depot formation below the cutaneous layer, which could contribute to the slow release evidenced by the urinary excretion rate in mice. In humans, tape stripping of the skin revealed that less than 0.1% of the applied dose was recovered from the skin surface, whereas most of the radioactivity was recovered in the skin rinse (Selim et al. 1995).

In a study to determine the distribution and fate of DEET, Blomquist et al. (1975) studied the effects of the insect repellent in male mice and pregnant mice by whole-body autoradiography. After the dose was given via injection, high tissue concentrations of DEET were found in the liver, kidney, lacrimal gland and nasal mucosa. The thyroid and brown fat exhibited concentrations above the blood level a short time after injection, but the highest uptake measured was present in the lacrimal gland, where the radioactivity was also retained the longest. The mean concentrations of the kidney and lacrimal gland peaked after the other tissues were measured, with their peak times at 5 minutes and 20 minutes, respectively. This could be an indication that metabolism of DEET occurred in the mouse. In the experiments with pregnant mice, it was noted that some radioactivity did pass through the placenta to the fetus, but the average radioactivity concentration was far below the concentration found in the mother. Excretion of DEET was found to take place almost exclusively through the kidney, with most tissues losing their maximum radioactivity by 1 hour post-injection.

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Metabolism

Most of the information on DEET metabolism has been derived from animal studies. Using these studies, two major pathways of metabolism have been determined. One pathway involves oxidative hydroxylation of the aromatic methyl group in the meta position, yielding N,N-diethyl-m-hydroxymethylbenzamide (BALC). The second pathway involves dealkylation of an N-ethyl group, producing N-ethyl-m-toluamide (ET). Subsequent oxidation or hydroxylation can then yield additional metabolites (Sudakin and Trevathan 2003; Constantino and Iley 1999). These pathways are shown in Figure 1.

Wu et al. (1979) evaluated urine samples of a 30-year-old man who had applied 10.4 g of DEET in a commercial product to approximately 75% of his skin. Urine samples were taken over a 36-hour period and evaluated by high resolution gas chromatography/mass spectrometry. A blood sample was also taken 8 hours after the exposure. The metabolites detected from N-deethylation of the DEET side-chain molecules were N-ethyl-m-toluamide (ET) and m-carboxyl-N,N-diethylbenzoylamide.

Inter-individual variation in the metabolism of DEET could be significant. Different cytochrome P450 isoforms tend to favor one metabolic pathway versus the other. As determined by Usmani et al. (2002), microsomes from people with higher levels of the P450 isoforms CYP2B6 and CYP1A2 favored metabolism along the BALC pathway, whereas those with higher levels of isoform CYP3A4 and CYP2C19 favored higher ET production (Taylor 1986; Usmani et al. 2002). There is also evidence that DEET can induce cytochrome P450 isoforms responsible for its metabolism (Abu-Qare et al. 2001; Usmani et al. 2002).

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Excretion

Limited data exist on excretion of DEET in human volunteers, but the studies that have been done share similar conclusions. In two such studies DEET excretion, as a percentage of the applied dose, was less than 10%. In most cases, the majority of the applied dose has been recovered from the application site, and therefore was not absorbed.

Excretion of DEET in human volunteers was evaluated by Selim et al. (1995). Two groups of six male volunteers were administered either technical grade DEET (98.8% pure) or 15% DEET in ethanol over a 4- by 6-cm area on the volar surface of the forearm. Both treatments were fortified with [14C] DEET for detection purposes. Blood and urine samples were both taken before dosing from all volunteers and then at varying intervals over the 120-hour testing duration. DEET was left in contact with the skin for 8 hours, after which the application site was wiped with cotton swabs soaked in isopropyl alcohol and then rinsed with isopropyl alcohol. The average urinary excretion observed in the volunteers was 5.6% for the technical grade group and 8.33% for the 15% DEET group. The majority of the applied doses were recovered when the skin was rinsed after application.

Urinary excretion of DEET in humans was evaluated by Blomquist and Thorsell (1977). A dose of 250 µCi of [14C] DEET was applied to a single male volunteer in 0.03 mL across the forearm on an area measuring 3 cm2. The application area was washed 8 hours after application with absolute ethanol (10 ml) and urine was collected from the volunteer for 2 days following treatment. The experiment was repeated once. During the 48 hours after the treatment, 5.5% and 3.8% of the applied radioactivity, respectively, was recovered from the urine. Analysis of the urinary excretion data showed that a peak in urinary radioactivity occurs 16 hours after application of DEET. When washing the applied area of the treated man 8% and 15% of the applied dose, respectively, was recovered 8 hours after treatment (Blomquist and Thorsell 1977).

Smallwood et al. (1992) used high-performance liquid chromatography (HPLC) to test human urine and serum for the presence of DEET. The experiment was conducted with 17 human volunteers: eight were National Park Service (NPS) employees who used DEET while at work, and the other nine were 18- to 34-year-old male volunteers. Both groups applied a lotion containing 71% DEET. The NPS employees put approximately 1g of the lotion per day on their skin and clothes for 1 work week. The volunteers applied between 0.14 and 1.86 g of DEET over skin areas ranging from 1300 to 3700 cm2 in a single application. Samples were collected from the NPS employees in the middle of the work week at the end of their shifts. The volunteers gave blood specimens at 1, 2, 4 and 6 h after application, and all excreted urine was collected from the volunteers during the 24 hours following exposure. Urinary DEET concentrations for the NPS employees ranged from <0.18 and 5.69 µg/mL. In the volunteer group, only two men produced levels higher than the quantization limit of 0.18 µg/mL; their urinary DEET levels ranged from 0.31 to 2.02 µg/mL. It was concluded that there is a relationship between DEET urine concentrations and use.

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Summary of Pharmacokinetic/Toxicokinetic Data

Human studies have shown that 5% to17% of the applied dose is absorbed into the skin. In animal studies, depending on the test animal, 10% to 60% of the applied dose is absorbed percutaneously. However, animal study data have been found to inaccurately reflect human DEET absorption due to the differences in skin composition and physiology. Because human data on distribution of DEET throughout the body is lacking, animal data is presented. DEET concentrations were highest in the liver, lacrimal gland, and the kidney of the mouse. The major metabolites of DEET in humans a N-ethyl-m-toluamide (ET) and N,N-diethyl-m- hydroxymethylbenzamide (BALC). These metabolites are produced by separate cytochrome P450 isoforms, so the level of activity of these isoforms in each individual will determine how they metabolize DEET. Excretion studies using radiolabeled DEET in humans showed that 3.8% to 8.33% of the applied dose of DEET is recovered form the urine. The majority of the applied radioactivity was recovered in skin rinses.

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Figure 1: Pathways of DEET Metabolism

Figure 1: Pathways of DEET Metabolism

Horizontal lines represent N-dealkylation; the vertical direction represents ring-methyl oxidation. The pathways represent metabolism in rats that were pretreated with phenobarbital (from Constantino and Iley 1999). Metabolite 2a is m-hydroxymethylbenzamide (BALC); metabolite 1b is N-ethyl-m-toluamide (ET).


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