The research was conducted by Dr. Selmer, who has a professional medical background and has worked in the pharmaceutical industry for more than 40 years. He has been a Head of Research and Development in several international pharmaceutical companies and has written numerous papers and patents.
Short chains alcohols with relatively low polarity are popular solvents for extracting plant oils, including cannabinoids and terpenes. Considering the high toxicity of methanol, the choice of alcohol as a solvent, in practice, is a choice between ethanol or isopropyl alcohol (IPA). While working with extracting plant oils, Drizzle has experienced that the discussion of the pros and cons of these two solvents is often very emotional. More often than not the discussions are founded on beliefs and rumors instead of facts. For this reason, Drizzle has found it necessary to present a thorough review of scientific literature focusing on the safety of these two compounds.
Evaluation of safety includes assessment of the short and long-term toxicity, including genotoxicity (ability to damage genetic information), carcinogenicity (ability to promote cancer), and teratogenicity (causing congenital disabilities in the fetus). Notably, there will also be an evaluation of whether potential safety issues are a problem when the concentrations of the two solvents in the final extracts are taken into account. Finally, this review ends by summarizing the pros and cons of the two alcohols as solvents for the extraction of herbal oil with particular reference to cannabis oils. For those not inclined to te read the whole review, the conclusions are presented below:
Conclusions
◉ The acute toxicity of ethanol and IPA is surprisingly similar, and based on data from rodents and man, the doses of solvents causing acute lethality does not differ significantly
◉ Studies in man have shown that ethanol is both genotoxic, carcinogenic, and teratogenic. Furthermore it has been established that there are no lower limits of ethanol intake that can protect you from these harmful effects. In contrast, IPA is neither genotoxic, carcinogenic or teratogenic.
◉ Regardless of the inferior safety profile of ethanol compared to IPA, the doses of solvent in the final extracted cannabis are extremely low. The concentration of IPA is several orders of magnitude lower that what has been accepted as safe doses in man. Therefore, the discussions of the safety of ethanol versus IPA are probably not of relevance when it comes to choosing a solvent for eluting cannabis
◉ IPA is more polar than ethanol. The higher polarity means that cannabis extracted with IPA is of higher purity than cannabis extracted with ethanol. The increased concentration of chlorophyll and other ingredients in ethanol-purified cannabis may affect the taste and smell of the final product
◉ Accessibility and price of the two solvents may be important parameters in the choice of solvent
◉ For both solvents, it is crucial to ensure that they are pure according to U.S., European, or British pharmacopeia (USP, B.P., or Ph. Eur) grading.
Physical and chemical properties of the two solvents
IPA is a colorless liquid with a pungent, characteristic odor that is detectable at very low concentrations (22 parts per million). IPA has the chemical formula of (CH3)2CHOH) and a molar weight of 60.1. The flash point is 11.70C, and the explosive limit in the air is between 2 and 12 vol%. The vapor pressure at 200C is 33 mm Hg.
Ethanol is also a colorless liquid, almost without smell. Ethanol has the chemical formula of Ch3COOH and a molar weight of 46.1. The flash point is 120C, and the explosive limit in the air is between 2.5 and 12 vol%. The vapor pressure at 200C is 44 mm Hg.
Acute toxicity of isopropyl alcohol and ethanol
Isopropyl alcohol is a sedative-hypnotic agent whose toxicity closely resembles that of ethanol. Like ethanol, isopropyl alcohol has a sedative and depressive effect on the central nervous system (CNS), but the precise mechanism of action in the brain remains uncertain. In addition, there is a linear relationship between the molecular weight of alcohols and their sedative effects: as size increases, so does sedation. Thus, isopropyl alcohol is marginally more potent in sedating CNS functions than ethanol at comparable concentrations (1).
For both solvents, the acute toxicity is due to the depressive effect on the CNS, but it may be challenging to get precise information on the levels that result in death. Furthermore, data – especially for humans – suggest that the lethal dose of ethanol varies widely.
It is easier to get more precise information on lethal doses in animal studies than in man. Toxicity studies in rats have demonstrated an LD50 (dose where half of the animal die) of isopropanol to be 5.8 g/kg (2). For ethanol, the LD50 for rats is between 5.1 and 6.7 g/kg, depending on the age of the animals (3).
Deaths from acute ethanol poisoning are common, with more than 2200 yearly fatalities in the U.S. alone. In humans it is accepted that individuals with a blood level of ethanol above 4 ‰ have a significant risk for death (4). With a water volume of 60%, a potentially lethal dose of an 80 kg person (176 lb) is 250 ml of 96% alcohol. Young and healthy subjects accustomed to ethanol intake can consume higher amounts without risking death. However, the 4 ‰ limit is a generally accepted level that may alert hospital staff to subjects in danger of fatal alcohol intoxication.
IPA intake in man is rare, and data on acute toxicity are unreliable. It has been proposed that in an adult, a “probable lethal dose” was presented 240 ml 99% IPA, although no supportive data were provided (5), and most believe the toxic dose to be higher. There are a several examples where subjects have survived ingestion of considerably larger quantities of IPA. For example, two persons recovered with supportive medical care after each ingested approximately 1000 ml of a 70% IPA solution (6, 7, 8).
Patients surviving large quantities of ethanol or IPA almost always survive without sequela, meaning apart from the CNS depressive effect, acute ethanol or IPA ingestion is not toxic to the body.
Chronic toxicity of isopropyl alcohol and ethanol
Chronic toxicity of ethanol
Ethanol is considered both genotoxic, carcinogenic, and teratogenic. The main reason for these effects is a consequence of the metabolism of ethanol. At low ethanol concentrations, ethanol is mainly metabolized by the enzyme alcohol dehydrogenase (ADH), resulting in the formation of acetaldehyde. Subjects with regular ethanol consumption induce a specific enzyme system “microsomal ethanol oxidizing system” (MEOS), which is also capable of metabolizing ethanol. The initial products of the MEOS system are acetaldehyde and reactive oxygen species.
The European Chemicals Agency (ECHA) has evaluated the chronic toxicity of ethanol in rodents. A study has reported on the subchronic (90 days) oral toxicity of ethanol (administered by gavage) in rats. In this study, the no observed adverse level (NOAEL) was 1.7 g/kg (9).
Chronic ingestion of ethanol in men is associated with very high mortality. The harmful use of alcohol resulted in some 3 million deaths or 5.3% of all deaths worldwide (2016) (10). Among the many diseases associated with chronic ingestion of ethanol, alcoholic liver disease (ALD) is one of the most frequent and severe complications of chronic ethanol intake. Approximately 50% of all European liver cirrhosis is due to alcohol (11). Until recently, the prevailing notion was that ethanol was non-toxic and that ALD and other ethanol-related diseases resulted from malnutrition rather than being causally related to ethanol ingestion. However, research within the last 40 years has, in detail, unraveled the molecular mechanism behind the toxic effect of ethanol. The development of ethanol-related diseases, including ALD, is closely linked to the formation of acetaldehyde and reactive oxygen species derived from ethanol metabolism. For a recent review, see (12). Most national health authorities have recommendations on maximal weekly levels of alcohol intake to reduce levels of alcohol-related diseases. The recommended maximal levels have in most guidelines decreased with time reflecting that it is difficult or impossible to define a level of ethanol consumption that is not associated with a health risk.
Acetaldehyde is quite toxic and can lead to irreversible DNA damage, i.e., it is genotoxic (13). In addition, the reactive oxygen species formed by ethanol metabolism can also cause DNA damage (14). These ethanol metabolites are probably the main reason that ethanol can cause cancer(15). The International Agency for Research on Cancer has, in several publications, e.g. (16), based on a wealth of epidemiological data, concluded that ethanol is a Group 1 carcinogen (i.e. there is sufficient evidence of carcinogenicity in humans), a conclusion supported by the latest epidemiological studies, e.g. (17, 18). Almost all health organizations have acknowledged this association between cancer and ethanol consumption. Available data suggest that approximately 4% of cancers worldwide are caused by alcohol (14). Cancer risk increases with the daily intake of ethanol, but recently several publications have stressed that no safe amount of alcohol consumption for cancers and health can be established (19, 20, 21). For completeness’ sake, it should be mentioned that FDA has not labeled ethanol as a cancer risk – a viewpoint they do not share with many.
Ethanol is a well-documented human developmental teratogen that can cause a spectrum of physical and mental dysfunctions following prenatal exposure. Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in persons exposed to alcohol before birth. The harmful effects of ethanol on pregnant women include physical problems and problems with behavior and learning. Ethanol can cause problems for a fetus throughout the pregnancy including before the pregnancy is established (22). There is no safe amount of alcohol during pregnancy (23).
The incidence of FASD is very high, with prevalences in the U.S. between 1 and 5%, but in some geographic locations, the prevalence can reach 20% (24). Also, the prevalence of FASD is probably severely underestimated because of diagnostic difficulties and the reluctance of clinicians to stigmatize children and mothers (22). All available evidence suggests that acetaldehyde-mediated reduction in the level of retinoic acid in the fetus causes FASD. (25). Numerous animal can, after exposure to alcohol or acetaldehyde, reproduces features of FASD (26).
Chronic toxicity of IPA
Studies in animal studies have demonstrated that isopropanol is neither genotoxic, carcinogenic, nor teratogenic (27)
The carcinogenicity of isopropanol was evaluated in a long-term study with rats and mice. The rodents were exposed to isopropanol vapor at 0, 500, 2500, or 5000 ppm for 6 hr/day, five consecutive days/week for at least 78 weeks for the mice or 104 weeks for the rats. At the end of the study, there were minor histopathological changes in the animals given the two highest doses. The no-observed-effect-level (NOEL) in rats and mice was 500 ppm. As no tumors existed in any groups, the NOEL for carcinogenicity was determined to be greater than 5000 ppm (28).
Similarly, a two-generation reproductive toxicity study in rats has demonstrated that isopropyl alcohol is not teratogenic (29). In this study, dosing was once daily by oral gavage with 0, 100, 500, or 1000 mg isopropanol/kg. Compared to the controls, a statistically significant reduction was observed in the male mating index (no. of females mated/no. of females placed with males) of the high-dose, second-generation males. However, regardless of dose, no treatment-related post-mortem findings were observed in the offspring from either generation. Therefore, the NOEL for reproductive effects in this study, only based on the reduced male mating index of the high-dose second-generation males, was 500 mg/kg. In a similar study (30) where maternal and development toxicity were evaluated, the NOAL for both toxicities was 400 mg/kg/day.
It is not customary for people to drink IPA, and therefore there is limited information on the chronic toxicity in man. In an epidemiological study with 60 women exposed to IPA for up to 17 years (median 4.5 years), there were no signs or symptoms suggesting toxicity of IPA. In another study, daily ingestion of IPA in doses of 2.6 and 6.4 mg/kg over a period of 6 weeks did not lead to adverse effects in 8 healthy volunteers (31)
Epidemiological data from people involved in the production of IPA has suggested an increased incidence of cancer in the upper respiratory tract (32, 33). However, these epidemiological data were generated when isopropyl alcohol was produced by a strong acid method. This production process resulting in a high concentration of the intermediary diisopropyl sulfate. Diisopropyl sulfate is a known carcinogen in animals (34), and it is generally accepted that the high concentration of this compound explains the slight increase in cancer among factory workers. The strong-acid process for producing IPA has been replaced by a new process that eliminates the formation of diisopropyl sulfate. This new IPA production method has not been associated with the development of cancer (35).
Exposure limits of inhaled IPA according to US Occupational Safety and Health Administration
(OSHA) health standards (36) for exposure to air contaminants require that an employee’s exposure to isopropyl alcohol not exceed an 8-h time weighted average (TWA) of 400 ppm in the working atmosphere in any 8-h shift of a 40-h workweek. In addition, the American Conference of Governmental Industrial Hygienists and the Japan Association of Industrial Health has adopted the same exposure limit for inhaled isopropyl alcohol.
Levels of IPA in cannabis oil
Preliminary evaluations have demonstrated that cannabis oil produced by the Merlin400 contains less than 1% IPA. The concentration of CBD and THC in the final cannabis oil is higher than 50%, but if the purity is as low as 50%, you will ingest less than 0.5 mg IPA. If you use cannabis oil in a vape pen (0.5 ml), the conservative estimate is that the air will contain IPA in a concentration of less than 8 ppm during inhalation. To put this in perspective, an oral safe dose of IPA is 6.4 mg/kg and exposure limit for 8-h shift in a 40-h workweek is 400 ppm. This means that the IPA dose injested is several orders of magnitudes lower than what has been found safe. If you use ethanol as a solvent, the ethanol concentration is most likely in the same range.
Choosing between IPA and ethanol as solvents
99% isopropanol and 96% ethanol can be used in the Merlin400 to extract cannabis oil. For several reasons, however, Drizzle prefers and recommends using IPA over ethanol. Regardless of your chosen solvent, you should only use a solvent with guaranteed purity according to the U.S., European, or British pharmacopeia (the commonly used abbreviations are USP, Ph.Eur, and B.P. grade, respectively.
IPA is a polar organic solvent well-suited for cannabis extraction. It is more polar than ethanol, meaning it will dissolve polar cannabis oil and terpenes more quickly than the less polar ethanol (data on file). Furthermore, ethanol will extract chlorophyll and other nonpolar components more readily than IPA. That means that an ethanol extract often coelutes chlorophyll and other components that may adversely affect the taste and smell of the final product (data on file).
Another issue to consider is the availability of the two solvents. In some countries it can be very difficult to purchase ethanol that does not contain denaturing agents. Also, the price in most countries is significantly higher than IPA due to taxes and other charges. Finally, ethanol is often sold without a declaration of purity. Usually, ethanol sold as “pure ethanol” contains denaturing agents, which makes it useless as a solvent for cannabis oil. In contrast, IPA is nearly always with a declaration of purity, i.e., technical or with a purity according to USP, Ph. Eur, or B.P. For details, see a short memo about the purity of IPA in our knowledge base.
Conclusion
Comparing the safety of ethanol and IPA, data suggest that the acute and chronic toxicities in animals and man do not differ much. However, data shows that ethanol, unlike IPA, is genotoxic, carcinogenic, and teratogenic. Based on available data, health authorities cannot recommend a minimum dose that guarantees safety from ethanol’s carcinogenic and teratogenic properties. However, the levels of IPA (and probably also ethanol) are extremely low when ingesting the cannabis oil from the Merlin400. According to conservative estimates, oral ingestion of 25 mg cannabis oil will lead to ingestion of 0.5 mg IPA or – if inhaled – a concentration of less than 8 ppm. These levels are so much lower than any dose evaluated in studies that it makes no sense to choose between the two solvents based on safety arguments.
The cannabis extract produced by IPA is purer than an extract produced with ethanol. In many countries, it is easier (and often less expensive) to obtain pure IPA than pure 96% ethanol. Regardless of the choice of solvent, it is important that the solvent you use is pure according to U.S., European, or British pharmacopeia standards.
References
1. Sivilotti MLA. Isopropyl alcohol poisoning. UpToDate. 2023. Available from: https://www.uptodate.com/contents/isopropyl-alcohol-poisoning.
2. National Research Council (US) Committee on toxicology. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants. Hazards BoTaEH, editor: National Academies Press (U.S.) 1984.
3. Wiberg GS, Trenholm HL, Coldwell BB. Increased ethanol toxicity in old rats: Changes in LD50, in vivo and in vitro metabolism, and liver alcohol dehydrogenase activity. Toxicology and Applied Pharmacology. 1970;16(3):718-27.
4. Poikolainen K. Estimated lethal ethanol concentrations in relation to age, aspiration, and drugs. Alcohol Clin Exp Res. 1984;8(2):223-5.
5. Gosselin RES, R.P.; Hodge, H.C. Clinical Toxicology of Commercial products. Baltimore: Williams & Wilkins; 1984.
6. Freireich AW, Cinque TJ, Xanthaky G, Landau D. Hemodialysis for isopropanol poisoning. N Engl J Med. 1967;277(13):699-700.
7. King LH, Jr., Bradley KP, Shires DL, Jr. Hemodialysis for isopropyl alcohol poisoning. Jama. 1970;211(11):1855.
8. Trullas JC, Aguilo S, Castro P, Nogue S. Life-threatening isopropyl alcohol intoxication: is hemodialysis really necessary? Vet Hum Toxicol. 2004;46(5):282-4.
9. European Chemicals Agency . Repeated toxicity of oral dose of ethanol 1973. Available from: https://echa.europa.eu/da/registration-dossier/-/registered-dossier/16105/7/6/2
10. WHO. Global status report on alcohol and health. In: Organization WH, editor. 2018. Available from: https://www.who.int/publications/i/item/9789241565639
11. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58(3):593-608.
12. Seitz HK, Neuman MG. The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology. Journal of Clinical Medicine. 2021;10(4):858.
13. Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM). Statement on the mutagenicity of alcohol (ethanol) and its metabolite acetaldehyde 2015.Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/490582/COM_2015_S2_Alcohol_and_Mutagenicity_Statement.pdf.
14. Rumgay H, Murphy N, Ferrari P, Soerjomataram I. Alcohol and Cancer: Epidemiology and Biological Mechanisms. Nutrients. 2021;13(9).
15. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7(8):599-612.
16. International Agency for Research on Cancer (IARC). Alcohol consumption and ethyl carbamate. IARC Monogr Eval Carcinog Risks Hum. 2010;96:3-1383.
17. Im PK, Yang L, Kartsonaki C, Chen Y, Guo Y, Du H, et al. Alcohol metabolism genes and risks of site-specific cancers in Chinese adults: An 11-year prospective study. International Journal of Cancer. 2022;150(10):1627-39.
18. Yoo JE, Han K, Shin DW, Kim D, Kim BS, Chun S, et al. Association Between Changes in Alcohol Consumption and Cancer Risk. JAMA Netw Open. 2022;5(8):e2228544.
19. WHO. No level of alcohol consumption is safe for our health. https://wwwwhoint/europe/news/item/04-01-2023-no-level-of-alcohol-consumption-is-safe-for-our-health. 2023.
20. Anderson BO, Berdzuli N, Ilbawi A, Kestel D, Kluge HP, Krech R, et al. Health and cancer risks associated with low levels of alcohol consumption. Lancet Public Health. 2023;8(1):e6-e7.
21. Rovira P, Rehm J. Estimation of cancers caused by light to moderate alcohol consumption in the European Union. European Journal of Public Health. 2020;31(3):591-6.
23. Ceccanti M, Romeo M, Fiorentino D. [Alcohol and women: clinical aspects]. Ann Ist Super Sanita. 2004;40(1):5-10.
23. National Institute on Alcohol Abuse and Alcoholism Fetal Alcohol Exposure 2023 [Available from: https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/fetal-alcohol-exposure.
24. Hoyme HE, Kalberg WO, Elliott AJ, Blankenship J, Buckley D, Marais AS, et al. Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders. Pediatrics. 2016;138(2).
25. Shabtai Y, Bendelac L, Jubran H, Hirschberg J, Fainsod A. Acetaldehyde inhibits retinoic acid biosynthesis to mediate alcohol teratogenicity. Sci Rep. 2018;8(1):347.
26. Patten AR, Fontaine CJ, Christie BR. A Comparison of the Different Animal Models of Fetal Alcohol Spectrum Disorders and Their Use in Studying Complex Behaviors. Frontiers in Pediatrics. 2014;2.
27. Forschungsgemeinschaft D. MAK value Documentations. Isopropyl alcohol 2013. Available from https://onlinelibrary.wiley.com/doi/epdf/10.1002/3527600418.mb6763e2313
28. Burleigh-Flayer H, Garman R, Neptun D, Bevan C, Gardiner T, Kapp R, et al. Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats and CD-1 mice. Fundam Appl Toxicol. 1997;36(2):95-111.
29. Bevan C, Tyler TR, Gardiner TH, Kapp Jr RW, Andrews L, Beyer BK. Two-generation reproduction toxicity study with isopropanol in rats. Journal of Applied Toxicology. 1995;15(2):117-23.
30. Tyl RW, Masten LW, Marr MC, Myers CB, Slauter RW, Gardiner TH, et al. Developmental Toxicity Evaluation of Isopropanol by Gavage in Rats and Rabbits. Fundamental and Applied Toxicology. 1994;22(1):139-51.
31. Dutch Expert Committee on Occupational Standards. 1-and 2-propanol: Health-based recommended occupational exposure limits. Publicvation No 1994/24. In: Health Council of the Netherlands DH, editor. 1994.
32. Lynch J, Hanis NM, Bird MG, Murray KJ, Walsh JP. An association of upper respiratory cancer with exposure to diethyl sulfate. J Occup Med. 1979;21(5):333-41.
33. Weil CS, Smyth HF, Jr., Nale TW. Quest for a suspected industrial carcinogen. AMA Arch Ind Hyg Occup Med. 1952;5(6):535-47.
33. International Agency for Research on Cancer (IARC). Occupational Exposures to Mists and Vapours from Strong Inorganic Acids; and Other Industrial Chemicals.1992.
34. Teta MJ, Perlman GD, Ott MG. Mortality study of ethanol and isopropanol production workers at two facilities. Scand J Work Environ Health. 1992;18(2):90-6.
35. Occupational Safety and Health Administration (OSHA). Permissible Exposure Limits – Annotated Tables. 2023. Available from: https://www.osha.gov/annotated-pels/table-z-1
36. United states Department of Labour; Occupational Safety and Health Administration. Permissible Exposure Limits – Annotated Tables. 2023. Available from: https://www.osha.gov/annotated-pels/table-z-1