|Butyl acetate||Methylethyl ketone|
|tert-Butylmethyl ether||Methylisobutyl ketone|
|Ethyl formate||Propyl acetate|
|*Should Be limited by GMP or Other Quality-Based Requirements|
Dimethyl Sulfoxide (DMSO). DMSO is an unusually nontoxic organic solvent that is finding increased use in pharmaceutical synthesis, the manufacture of electronics, and drug delivery in the body. Its use is supported by over 50 years of industrial and academic experience.
A great number of toxicological, environmental and medical studies have been performed with DMSO to determine the safety of this chemical. Many of these studies have been published as references at the end of this bulletin. This summary only lists some of the results found, but in-depth details are reported in the original publications. A substantial dossier of data was submitted to the EPA for the HPV “High Production Volume” program by a consortium of producers including Gaylord Chemical. In addition, Gaylord Chemical’s extensive database of over 23,000 articles on applications and safe process use with DMSO is available for use by those who request it.
DMSO is a commercially manufactured dipolar aprotic solvent which is also a naturally occurring substance. It is apparently a part of earth’s complex sulfur cycle. DMSO is created in the atmosphere at a rate of 20-60 billion pounds per year from dimethyl sulfide, which is produced by metabolic processes in soil and sediments. DMSO is also found in natural waters and soil. Metabolism of DMSO in soil by microorganisms results in the formation of sulfur and dimethyl sulfide. DMSO is also reported to be present at low concentrations (<0.05-3.7 ppm) in food products such as sauerkraut, tomato paste, milk, beer, coffee, tea and in forage crops such as alfalfa and corn silage.
DMSO has low acute and chronic toxicity for animal, plant and aquatic life. Exposure to test organisms at high concentrations by contact, ingestion or inhalation consistently show low toxicity. DMSO is not listed as a carcinogen by regulatory authorities and is actually used as a neutral solvent in the Ames mutagenicity tests. DMSO is not a teratogen in mice, rats or rabbits. Because of this low potential for toxicity, the EPA has approved DMSO as a solvent or a cosolvent, in pesticides which are applied before crop emergence or prior to the formation of edible parts of food plants.
In 1978, the FDA approved the use of DMSO in a 50/50 mixture with water as an effective treatment for the symptoms of interstitial cystitis. Since then, a large number of people have received this treatment. The product is marketed today by Edwards Life Sciences under the trade name of Rimso-50™. DMSO has been approved for use in other pharmaceutical formulations in the U.S. and other countries. In addition, in 1998, the FDA endorsed the recommendation of the expert working group of the International Conference on Harmonization relative to the residual solvents in pharmaceuticals. DMSO was placed in the safest category, class 3 solvents, with low toxic potential. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. Solvents in Class 3 (Table 1) may be regarded as less toxic and of lower risk to human health. Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5,000 ppm or 0.5 percent under Option 1) would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice (GMP).
When handling or using DMSO, a potential for exposure exists. Therefore, the following information should be considered regarding possible exposure routes. Skin contact, the most likely exposure, has been extensively studied with humans and animals. Large dosages over prolonged periods showed only minor toxic effects such as minor skin irritation, itching and burning Although DMSO is absorbed rapidly through the skin, it has a low degree of toxicity via dermal route of administration. Also, it has been found that the molecular weight of chemical compounds can preclude their transdermal penetration by DMSO. For instance, DMSO enhances the penetration of butyl acetate in solution, while octyl acetate is a “nonpermeator.”
DMSO is not alone in its ability to penetrate human skin, and proper industrial hygiene should be practiced when working with all solvents. Table 2 provides relative permeability data for some common solvents.
Class 3 Solvents International Conference
on Harmonization Endorsed by the FDA*
DMSO reacts very rapidly and vigorously with a number of materials, particularly with those that also react rapidly with water. The reactions are highly exothermic, with rapid steam or gas evolution. In most cases these reactions can be controlled by rate or order of addition or by arranging adequate heat removal. The following types of compounds require care to prevent extremely rapid reactions.
- Strong oxidizing agents such as perchlorates, permanganates, iodine pentafluoride, silver fluoride and others react very rapidly.
- Acid chlorides react with DMSO at about the same rate as with ethyl alcohol.
- Carboxylic acid anhydrides react rapidly.
- Alkali hydrides used for making DMSO anion require adequate heat removal. (A technical bulletin on reactions of the dimsyl anion is available.)
- DMSO cannot be used with Ziegler-Natta catalysts or in Friedel-Crafts reactions.
- Methyl bromide can react to form HBr and Br2. Uncontrolled reactions have resulted.
Evaluation of the degree of hazard due to contact with a chemical is usually by its single-dose LD-50. The LD-50 is the Lethal Dose in number of grams of DMSO per kilogram of body weight which results in 50% mortality of the test animals under standardized conditions. Dozens of test data reports are available from many laboratories throughout the world. The reported LD-50 may vary but the data confirm a low level of toxicity. One published summary is the following:
Single-Dose Toxicity of DMSO as LD50 (1) (g/kg)
|Species||Mode of Treatment|
|Applied to Skin||Taken by Mouth||Into Blood Stream||Beneath Skin||Into Body Cavity|
|Mouse||50||16.5 – 24.6||3.8 – 8.9||13.9 – 20.5||14.7 – 17.0|
|Rat||40||17.4 – 28.3||5.2 – 8.1||12.0 – 20.5||13.0|
Using the monkey as an example, it would take more than 1.6 pounds applied to the skin or 0.6 pounds taken by mouth or injected directly into the blood stream, to have a 50% mortality rate in a group weighing 150 pounds each.
Other studies have shown that DMSO has low acute toxicity and is practically non-toxic (LD50>5 g/kg) by ingestion or dermal application. Rat oral LD50 are reported from 17.4 to 28.3 g/kg, whereas LD50 for mice have been reported from 16.5 to 24.6 g/kg. The acute dermal LD50 is 40 g/kg for the rat and 50 g/kg for the mouse, while dermal LD50 > 11 g/kg are reported for both dogs (beagles) and primates (rhesus monkeys). Although DMSO can cause skin and eye irritation, it is not a skin sensitizer.
In addition to LD50 explained above, another unit LD50 is used to evaluate the hazard from inhalation. LD50 is the Lethal Concentration that kills 50% of the test animals. The acute rat inhalation LD50 is greater than 1.6 mg /l, the only dose level tested, and which is also a No-Observed-Effect-Level (NOEL).10
The subchronic rat inhalation NOEL of 200 mg/m³(0.2 mg/I) was determined from a single concentration study. Extensive monitoring of human patients have shown that DMSO does not affect human renal function. DMSO is a diuretic but no sign of kidney damage has been found in humans or laboratory animals after repeated DMSO treatment. Hemolysis has been reported in animals that received DMSO intravenously.
DMSO easily penetrates the skin (176 ± 42 g/m2/hr) compared to, for example, water (14.8 ± 0.1 g/m2/hr), but because of DMSO’s low toxicity (see previous section) and the fact that this same permeability test showed DMSO does not carry less-permeable substances with it through the skin, it can be concluded that DMSO does not pose a significant threat by skin absorption. The penetration rate of DMSO in solutions is a direct function of the mole fraction of DMSO. (Ursin, et. al. 1995)14. Although DMSO readily penetrates human skin in concentrations of 70-100%, at concentrations of 67% or less, DMSO molecules are hydrated, which greatly reduces dermal penetration (Sulzberger et. al., 1966; Brayton, 1986: Woodford and Barry, 1986).
No significant abnormalities were found in extensive physical examinations or analyses of blood and urine during repeated applications of large amounts of DMSO to the skin of humans over a long period of time. This was reported by Dr. Richard Brobyn2 to the New York Academy of Sciences. DMSO was used in two human studies lasting 14 and 90 days. In each case, one gram of DMSO per kilogram of body weight was applied each day by each subject to his own skin. In an (80 kg = 176 lb) individual, it was 80 grams or 2.7 fl. oz. This amount required up to 2 hours for complete absorption from the 90% DMSO gel.
No conclusive evidence of intolerance resulted from dermal application of 9 grams/kilogram of 90% DMSO to Rhesus monkeys daily for 18 months. In a small (50 kg = 110 lb.) individual, this would amount to daily applications of 15.2 fluid ounces or nearly a pint of 90% DMSO.
Observation has indicated that skin application, particularly if frequent with large amounts of DMSO, may result in reddening, itching and burning at the application site. Exposure to large amounts of DMSO by skin or elsewhere may result in sedation, headache, nausea or dizziness.
DMSO is not listed as a carcinogen by regulatory agencies such as IARC, NTP, OSHA or ACGIH, based on reviews of numerous studies. An 18-month study with rhesus monkeys established an oral NOEL of 3300 mg/kg/day. No tumors were observed and bone marrow smears from the monkeys that received oral or topical doses of DMSO at up to 9g/kg/day.12 This is comparable to an average human (70 kg or 154 lbs) consuming approximately 210 g (or nearly 1/2 pound) DMSO per day, i.e., 3g/kg/day. In fact, 84 humans that have received daily topical treatment of 2.8 g DMSO/kg/day (equivalent to nearly 1/2 pound/day/person) for up to three months showed no DMSO-related effects beyond occasional skin irritation, garlic breath and body odor. Additionally, (Hull et al. 1969)7 found no DMSO-related effects in any of the 38 humans, age 21-55, who received a topical application of an 80% DMSO gel in a single daily dose of 1 g/kg for 12 weeks.
Continuing research has demonstrated that the ocular effects reported from DMSO treatment of dogs, rabbits, guinea pigs and swine are species-specific and not reproducible in primates, including humans. Even though ocular toxicity, specifically lenticular refractive changes, have been reported in some animal studies with dogs, rabbits and swine (Rubin and Barnett, 1967; Smith et al. 1969)3and in guinea pigs (Rengstarff et al.,1972)4, it was subsequently demonstrated that the ocular effect was species-specific and was not
reproducible in primates, including humans (Smith et al., 1969)3 (de la Torre et al. 1981)5. Furthermore, full ophthalmologic examinations revealed no DMSO-related lenticular changes in any of 84 patients treated three times daily for three months with topical 70% DMSO, topical 2% DMSO or 0.85% normal saline (maximum theoretical dosage of 2.6 g DMSO/kg/day), which is comparable to dosages used in the animal studies (Shirley et al.,1988)6.
Human and Animal Metabolism
DMSO is metabolized in humans by oxidation to dimethyl sulfone, DMSO2 or by reduction to dimethyl sulfide, DMS. DMSO and DMSO2 are excreted in the urine and feces. DMS is eliminated through the breath and skin with a characteristic “garlic” or “oyster-like” odor. Human excretion of orally administered DMSO is complete within 120 hours, with urinary excretion being the primary pathway. The rate of renal clearance has been shown to be similar for chronic and singly administered doses regardless of dose concentration. No residual accumulation of DMSO has been reported in humans or lower animals who have received DMSO treatment for protracted periods of time, regardless of route of dose administration.
The metabolites of DMSO are DMSO2, which naturally occurs at low levels in human urine (PDR, 1994)8, and DMS, which naturally occurs in plants, the atmosphere, and lakes and oceans (Pearson et al., 1981)9. Both of these metabolites are readily excreted from the body. Based on their widespread natural occurrence and ready degradation and/or excretion, the production of these metabolites from the proposed use of DMSO on food producing plants is not expected to pose any toxicological concern.
Fishman and coworkers at the Naval Medical Center (10) performed many toxicological measurements on the exposure of rats to DMSO vapors. The following single and repeated exposures were made:
|DMSO Concentration||Length of Exposure|
|1600 mg/m3||4 hours|
|2900 mg/m3||24 hours|
|2000 mg/m3||40 hours|
|200 mg/m3||210 hours7 hrs/day, 5 days/week for 30 exposures|
Extensive blood and tissue samples were examined. No evidence of toxicity was demonstrated. No significant changes were noted during or following repeated exposure. We suggest, as a good hygiene practice, avoiding exposure to DMSO sprays or mists and very high doses of DMSO vapors.
Effects on Other Organisms
- Effects on Plants. DMSO by itself and DMSO with antibiotics, minerals, nutrients, pesticides and other materials have been sprayed on, injected into, painted on, and fed to a variety of plants. It has a low order of phytotoxicity in these applications.
- Effects on Fish.Wilford11investigated the toxicity of DMSO in water to 9 species of fish. At 96 hours, the LC-50 was 32,000 to 43,000 ppm DMSO (3•4%). This is far less toxic than acetone (fingernail polish remover) and other widely used solvents.
- Effects on Sewage Plants. DMSO is biodegradable in biological systems. It is converted in part to methyl sulfone and to dimethyl sulfide. The sulfone is stable and inert and degraded only slowly by microorganisms or physical factors. At high concentrations, some DMS may escape, producing its characteristic odor.
Natural Occurrences in Food
The occurrence of DMSO and its metabolites, dimethyl sulfide and methyl sulfone (DMSO2), have been widely reported in a variety of foods. Pearson9 and coworkers reported finding 0.07 to 16 ppm DMSO, along with DMSO2, in 14 fruits, vegetables or beverages. This natural occurrence insures that the body can dispose of DMSO by well-established metabolic processes. Naturally-occurring DMSO has been identified in alfalfa, asparagus, barley, beans, beets, cabbage, corn, cucumbers, oats, onions, Swiss chard, tomatoes, apples, raspberries, spearmint, beer, milk, coffee and tea. DMSO concentrations in fresh fruits, vegetables and grains ranged from undetectable (<0.05 parts per million) to 1.8 ppm.
DMSO is not mutagenic to Salmonella, Drosophila, and fish cell cultures. Because DMSO is so non-reactive as a mutagen, it is widely used as a solvent in mutagenicity testing. Although DMSO is bacteriostatic or bactericidal at concentrations of 5-50%, there is no evidence that DMSO causes chromosomal aberrations at levels that are not directly toxic to cells. Bone marrow smears from primates (rhesus monkeys) that received oral or topical doses of DMSO for 18 months showed no DMSO effects (Vogin et al., 1970)12. An in vivo cytogenetics study of DMSO administered by intraperitoneal injection to male rats found a significant increase in aberrant femoral bone marrow cells when compared to controls (Kapp and Eventoff, 1980)13. However, evidence from the Salmonella studies and other toxicology data, especially the teratology data, suggests that the increase in aberrant femoral cells likely resulted from direct toxicity of DMSO injected into an animal instead of a classic “mutagenic” response.
According to Brayton (1986), there are no documented adverse genetic effects reported as a result of medicinal DMSO uses (including quasi-medicinal uses for treatment of arthritis or sprains and strains). Additionally, no adverse genetic effects have been reported from occupational exposure to DMSO in over 40 years of industrial use (Brayton, 1986). There is no evidence that DMSO causes chromosomal aberrations at levels that are not directly toxic to cells.
Reproductive and Developmental Toxicity
A mouse teratology NOEL of 12g/kg/day has been established based on research with a 50% DMSO solution administered orally. Additional teratogenicity studies of orally administered DMSO to pregnant mice, rats, rabbits and guinea pigs have demonstrated that DMSO is not a teratogen in mammals except at high levels that cause overt maternal toxicity and are coincident with the maximum tolerated dose. The data suggest that DMSO is not teratogenic at low levels regardless of the route of administration. Finally, the teratogenic potential of DMSO is dependent on the route of administration, the dose level and gestation stage at exposure.
The one study (Robens, 1968) that did show evidence of teratogenic effects (in hamsters, one of three animal species tested) from oral administration of DMSO is inappropriate to use for a teratologic evaluation of DMSO for the following reasons:
- DMSO was not the compound of interest but was used only as a solvent control at two very high dose levels which precluded establishing a NOEL.
- One of the DMSO levels tested resulted in maternal death and was clearly beyond the maximum tolerated dose (MTD).
DMSO is not considered to be directly embryotoxic and has been shown to be a successful cryoprotectant for mammalian semen and embryos (Brayton, 1986).
In summary, the evidence of the above teratology data suggests that:
- DMSO is not a teratogen to mammals when administered via oral and dermal routes at dose levels that do not produce overt maternal toxicity.
- DMSO is not a teratogen at low dose levels regardless of the route of administration.
- The teratogenic potential of DMSO is dependent on route of administration, the dose level and the gestational time of exposure.
DMSO Solutions From Gaylord Chemical
The high polarity and low toxicity of DMSO makes it an ideal solvent for numerous industrical applications including pharmaceutical syntheses. Gaylord Chemical’s Procipient® is the only grade of DMSO suitable for healthcare and drug delivery applications. As the preeminent manufacturer of DMS and DMSO we pride ourselves on the quality of our products and world-class customer service. If you would like more information about our products, we would love to hear from you.
The data cited are from published papers in the medical and scientific literature.
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- Tox C. Jacob, S. W. and Wood, D.C. “Dimethyl Sulfoxide (DMSO) – A Status Report,” Clinical Medicine, 78, 21-34, (1971).
- Tox D. Mason, M.M. “Toxicology of DMSO in Animals,” Basic Concepts of DMSO, Vol. 1, Chpt. 3, 113-131, Marcel Dekker, New York (1971).
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- Rengstorff, R.H., J.P. Petrali and V.M. Sim. “Cataracts Induced in Guinea Pigs by Acetone, Cyclohexanone and Dimethyl Sulfoxide,” American Journal Optometry, 49: 308-319, (1972).
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Caujolle, F.M.E., D.H. Caujolle, S.B. Cros and M.M.J. Calvet. “Limits of Toxic and Teratogenic Tolerance of Dimethyl Sulfoxide,” Ann. N.Y. Acad. Sci., 141: 110-125, (1967).
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The information in this bulletin is based on information available to us and on our observations and experiences. However, no warranty is expressed or implied regarding the accuracy of this data, the results to be obtained from the use thereof, or that any use will not infringe any patent. Each user must establish appropriate procedures for off-loading, handling, and use of the product(s). Since conditions for use are beyond our control, we will make no guarantee of results, and assume no liability for damages incurred by off-loading, handling, or use of the product(s). Nothing herein constitutes permission, or recommendation to practice any invention covered by any patent without license from the owner of the patent.