Dimethyl sulfoxide

Endpoint summary

Description of key information

No data are available on the absorption of DMSO by inhalation exposure. However, its physico-chemical properties (low molecular size, high polarity and water solubility) suggest that DMSO is significantly absorbed by the inhalation route.
DMSO is also well absorbed after oral exposure. Peak plasma concentration of DMSO was attained at 4 hours after oral dosing in humans and at 0.5 hours in rats. DMSO is widely distributed to all body tissues. Higher concentrations of DMSO were found in the kidney, spleen, lung, heart and testes of rats given an oral dose, while higher levels were noted in the spleen, liver and lungs following a dermal dose. In humans, the plasma DMSO clearance half-life was about 11 to 14 hours, and 20 hours after dermal and oral dosing, respectively. A shorter clearance half-life of 6 hours was observed in rats after both routes of exposure. Metabolism of DMSO takes place primarily in the liver and kidneys. The principal metabolite is dimethyl sulfone (DMSO2). Peak plasma levels of DMSO2 in humans were observed at 72 to 96 hours after dosing, and then declined with a half-life of about 60 to 72 hours. DMSO is excreted unchanged or as the metabolite DMSO2 in the urine. In the human, about 13 and 18% of a dermal dose, and 51% and 10% of an oral dose were accounted for by urinary excretion of DMSO and DMSO2, respectively.
Short description of key information on absorption rate: 
DMSO appears to be readily absorbed through the human and rat skin, however the dermal absorption is 2-fold higher in rats than in humans. An in vitro permeability rate of 176 g/m2.hour has been reported for human skin. Maximal serum concentration of DMSO occurred at 4 to 8 hours following skin contact in humans, and at 2 hours in rats.

Key value for chemical safety assessment

Absorption rate - oral (%):

70

Absorption rate - dermal (%):

31

Absorption rate - inhalation (%):

50

Additional information

The following absorption factors have been retained for risk assessment:

Absorption factor (%)	Oral	Dermal	Inhalation
Rat	ca.70	ca.66	50 (default value)
Human	ca.70	ca.31	50 (default value)

Discussion on bioaccumulation potential result:

Metabolism

In many mammalian species, DMSO is quickly biotransformed from an essentially odorless liquid to a highly volatile smelly metabolite, dimethyl sulfide (DMS). DMSO metabolism to DMS is mediated by sulfoxide reductases, primarily in the liver and kidneys, and then DMS is rapidly reoxidized to DMSO by mixed-function oxidases. Irreversible oxidation of DMSO to DMSO₂is extensive (Swanson, 1985).

Absorption and excretion

Dermal administration

A dose level of 1 g/kg bw of radiolabelled S³⁵-DMSO (as a 70% solution in water) was applied over the entire body surface of 2 human subjects (Hucker et al., 1967). DMSO levels in the serum became maximal after 4 (504 µg/ml) to 8 (560 µg/ml) hrs and then declined, with a half-life of approximately 11 to 14 hrs, until after 36 to 48 hrs, when DMSO could no longer be detected. Serum levels of DMSO₂, however, did not become maximal until after about 36 (333 µg/ml) to 72 (514 µg/ml) hrs. The DMSO₂concentration then declined, with a half-life of approximately 60 to 70 hrs. After 312 hrs, the levels were quite low but still detectable. Urinary excretion of DMSO began shortly after administration and continued for 48 hrs, after which very little, if any, more DMSO was excreted. Total DMSO excretion averaged 13.0% of the dose for both subjects. Urinary excretion of DMSO₂, became significant approximately 8 hrs after dosing and continued for 456 hrs, the average total amount excreted being equivalent to 17.8% of the dose of DMSO. Thus, in this experiment, an average of 30.8% of the dose was accounted for by urinary excretion of DMSO and DMSO2.

Male Sprague-Dawley rats received 0.55 g/kg (0.5-11 µCi) of S³⁵-DMSO dermally (Hucker et al., 1966). There were appreciable concentrations of radioactivity in the plasma 0.5 hr after dosing (c. a. 300 µEq DMSO/ml). The concentration was highest (ca. 600 µEq DMSO/kg) at 2 hrs after administration. The levels thereafter declined, with an average half-life of approximately 6 hrs. After 24 hrs, the levels had declined to about 5 to 10% of the peak concentration. Approximately 66% of the dose was excreted in rat urine within 24 hrs and 4% in the faeces. The rate of passage of dermally applied S³⁵-DMSO through the skin was also estimated in rats. Eight rats were dosed dermally with 0.55 g/kg of S³⁵-DMSO. Two animals each were sacrificed after 30 min, 1 hr, 2 hrs and 24 hrs. After 30 min, 63% (average) of the dose remained at the site of application; after 1 hr, 19% (average) of the dose remained; and, after 2 hrs, 14% (average) was left. After 24 hrs, the radioactivity at the site of application was the same as that of the surrounding skin.

Oral administration

Single administration

A single dose level of 1 g/kg bw of radiolabelled S³⁵-DMSO (as a 70% solution in water) was administered by oral route to 6 human subjects (Hucker et al., 1967). Peak levels of DMSO were seen within approximately 4 hrs after administration; the levels then decreased fairly rapidly, with an estimated half-life of about 20 hrs. DMSO could no longer be detected in the serum after 120 hrs. Serum levels of DMSO₂reached a maximum after approximately 72 to 96 hrs and then decreased slowly, the half-life being about 72 hrs in most cases. Only traces of DMSO₂could be detected after 400 hrs. Urinary excretion of DMSO began almost immediately after administration and continued at a fairly even rate for about 120 hrs, when excretion ceased. At this time, an average of 50.8% of the dose had been excreted as DMSO (30.7-68.5%). Excretion of DMSO₂did not commence, except for trace amounts, until about 20 hrs after dosing, and it then proceeded until, after 120 hrs, an average of 9.6% of the dose had been excreted as DMSO₂. In two subjects followed for 480 hrs, an average of 22% of the dose was excreted as DMSO₂. Thus, in six subjects an average of 60.4% of the dose was accounted for after 120 hrs; in two subjects, 89.5% and 53.6% of the dose were accounted for after 480 hrs (Hucker et al., 1967).

Male Sprague-Dawley rats received 0.55 g/kg (0.5-11 µCi) of S³⁵-DMSO orally (Hucker et al., 1966). There were appreciable concentrations (ca. 600 µEq DMSO/ml) of radioactivity in the plasma 0.5 hr after dosing. The levels thereafter declined, with an average half-life of approximately 6 hrs. After 24 hrs, the levels had declined to about 5 to 10% of the peak concentration. Approximately 67% of the dose was excreted in rat urine within 24 hrs and 10% in the faeces.

Repeated administrations

A single human subject received 0.5 g/kg p. o. of radiolabelled S³⁵-DMSO (as a 70% solution in water) daily for 14 days (Hucker et al., 1967). Serum and urine were collected and assayed for DMSO and DMSO₂, beginning at 1 hour after the first dose and then at regular intervals for 24 days thereafter. Serum levels of DMSO reached a maximal value of 1850 µg/ml after 196 hrs, when a total of nine doses had been administered. The levels then declined until on the day of the final dose the DMSO level was 1275 µg/ml. When dosing was stopped, after 14 days, the DMSO concentration fell until after 72 hrs when it could no longer be detected in the serum. Levels of DMSO₂were also maximal (1040 µg/ml) after 196 hrs.The levels then slowly declined, with daily fluctuation, until 48 hrs after the final dose when the fall in concentration became more abrupt, to a level of 170 µg/ml after 556 hrs. Urinary excretion of DMSO proceeded linearly throughout the dosing period, until on the day of the last dose (312 hrs) a total of 317.2 g, or 49.3% of the total dose administered, had been excreted as DMSO.After 368 hrs, excretion totalled 346 g, or 53.7% of the dose, and was completed.Excretion of DMSO₂proceeded exponentially, so that on the day of the last dose, 86.1 g, equivalent to 11.1% of the total drug administered, had been excreted.After 560 hrs, a total of 132.7 g, equivalent to 17.2% of the total dose, was excreted as DMSO₂.Thus, in this experiment, 70.9% of the administered dose was accounted for by urinary excretion.

The pharmacokinetics of DMSO in rhesus monkeys was studied during and after a 14-day oral administration of a dose level of 3 g/kg bw as a 50% solution in water (Layman & Jacob, 1985). DMSO and DMSO₂were measured in serum, urine and feces by gas-liquid chromatography. The absorption of DMSO was rapid. After the first administration, an average peak serum concentration of 2.3 mg/ml was observed after about 4 hrs, which declined relatively rapidly to about 0.95 mg/ml after 24hrs. DMSO half-life was 16 hrs and its elimination rate constant was about 4% per hr. DMSO2 became detectable in serum after about 2 hrs, rose slowly and reached about 0.18 mg/ml at 24 hrs. With continued daily oral administration, serum DMSO rose slightly from 0.95 to 1.1 mg/ml on day 2. DMSO and DMSO₂reached a steady state concentration of about 0.9 mg/ml and 0.34 mg/ml after 4 days, respectively. After the last DMSO dose, serum DMSO declined rapidly and was not detected after 72 hrs. The mean DMSO₂serum concentration declined slowly over the next 96 hrs and trace amounts were detected at 120 hrs. DMSO₂half-life was calculated to be about 38 hrs and its elimination rate constant about 2% per hr.

About 60% of an orally administered dose was excreted in the urine as DMSO and about 16% as DMSO₂(Layman & Jacob, 1985). Neither DMSO nor DMSO₂could be detected in feces. The pulmonary elimination of DMS was not quantified in this study but was detectable as a sweet smell in the exhaled air.

Intravenous administration In human patients undergoing an autologous stem-cell transplant preserved with DMSO, plasma concentrations of DMSO and its metabolites (DMS and DMSO₂) remained essentially constant at 3 to 5 mmol/L troughout the 48 hours during which blood was sampled (Egorin et al., 1998).

Distribution

³⁵S-DMSO (0.55 g/kg, approximately 0.5 µCi) was administered to rats orally and dermally, the animals were killed at various times and the tissues were assayed for total radioactivity (Hucker et al., 1966). There were appreciable concentrations of radioactivity in all tissues 0.5 hr after an oral dose. Plasma, kidney, spleen, lung, heart and testes appeared to have somewhat higher levels than liver, fat, small intestine, brain, skeletal muscle and red cells. Concentrations in the testes, brain skeletal muscle and heart increased after 0.5 hr, but remained virtually constant in other tissues. Levels had declined to minimal values in all tissues after 24 hrs. The ratio of DMSO₂to DMSO in rats 4 hrs after oral administration of S³⁵-DMSO was found to be virtually constant in liver, testes, kidney, spleen, small intestine, heart and plasma, averaging about 6.5% (range of 4.1-10.6% for tissues of 2 rats). Thus, the major part, at least, of radioactivity present in tissues seems to be represented by DMSO.

After dermal administration, tissue concentrations of radioactivity were also appreciable after 0.5 hr, but were somewhat lower than after an oral dose. In this case, levels in the plasma, spleen, liver and lungs were higher than the other tissues. Concentrations in the liver, testes, kidney, spleen, brain, lungs, skeletal muscle, heart, plasma and red cells increased after 4 hrs to values comparable to those after an oral dose. Levels in the fat and small intestine remained virtually constant. All tissue concentrations had declined to minimal values after 24 hrs.

Discussion on absorption rate:

In vitro studies

The steady-state rate of permeation of commercial solvents was measured through living human skin (Ursin et al. 1995). The skin was removed from healthy females during plastic surgery of the breast. The samples were thinned by removing the dermal tissue from the epidermis and then stretched to a thickness of 300 to 600 µm. The permeability rate of DMSO was reported to be 176 g/m². hour compared to a permeability rate for water of 24 g/m². hour indicating that DMSO is readily absorbed through the skin. For comparison, N-methyl-2-pyrrolidone, dimethylformamide and methylethylketone present a permeability rate of 171, 100 and 55 g/m². hour, respectively.

No appropriatein vivo study has been performed.