S2 CQ tuO g t-fJ P=I cs be o «—• •*- id® % * ca r-H 3 o O 1 1 1 1 0 1 1 a> 3 I 1 l 1 1 0 0 *23 T3 *o *o "0 *o w CO • rl 1 • 1 d 1 CO 1 S 1 1 1 1 1 1 I 1 1 0 m 1 1 1 1 1 1 0 0 0 1 a> 33 •r-i cn -do_ .do_ op- 1 <0 S d op- 1 » r 2 3 0 CO op- ◄ s 1 1 1 1 1 1 t 1 1 i 1 0 CO 1 1 1 1 • r-4 § 1 1 1 1 1 1 1 1 1 1 1 © 1 1 1 1 1 1 1 I 1 1 1 32 1 1 1 i ! 3 1 1 1 1 a> 4-» N d 1 1 O w 1 1 1 1 1 1 1 1 1 03 0 1 O >» 1 • 0 1 1 0 1 1 O 1 1 O (N 1 32 T3 T3 *23 CD pH tuo 1 !>. CO w 1 1 f CS T-H 4-2 CO CO 00 *o T-H i-H 00 CO H y—i *-H 1 1 1 1 1 1 1 05 CO 1 1 » • 1 1 kO 1 1 1 1 1 rH 1 » O 1 rH 1 1 1 4H 1 1 1 I 1 1 1 CM 1 1 1 1 1 1 1 1 1 kO 1 • 1 •* # O 0 O D 0 O 1 0 O IO 0 |o O lo 0 |o 0 In 0 lo 1 0 Irt 0 00 0 ^ 05 | O »o 2* 0 1 O °H Cd 1 O Q, > >. as §-g .i S d ^ Boo 'C’P P a o o a> .2 a *0 co aaa 000 3 m a p-T 5 ^ o § +» 3 a« < 3 - 33 0^32 3 o ® © o a o 3 g ® ri 03 3 j_ u3 >» p-,G'3„33 *>> ^ rt a 32 33 a ® • > o 05 IO >5 (-• o 03 -t-a O (-« o > 0 o . o S'S £*03 3 ® T3 0 3 OT a.a— (30 “ aj 55 3 a 05 a 3 H B +J cC 03 CO 3 3 ® S p S-3 i •p 130 Chemical identification. —The primary isobutyl carbinol (No. 3) may be oxidized with potassium permanganate (1:1000) with the formation of iso-valerianic acid aldehyde and iso-valerianic acid iso¬ amyl esters which may be identified by their odor. If heated with sulfuric and acetic acid it yields iso-amylacetate. According to Hollander (1910) this can be identified by adding 1 drop of phenyl- hydrazine and boiling. After cooling, the mixture is underlaid with concentrated hydrochloric acid. In the presence of amyl acetate a green color is formed at the zone of contact of the 2 layers. The phenyl-iso-amyl-urethane (CeHsHNCOOCsHu) melts at 57° to 58° C. and the corresponding a-naphthyl compound (CioH 7 HNCOOC 5 H 1:l ) forms leaflets which melt at 67° to 68° C. The iso-amy 1-iodide boils at 152° C. (Kosenthaler, 1923). Upon oxidation, the active d-amyl alcohol (No. 8) yields d-methyl- ethyl-acetic acid. The phenyl urethane derivative melts at 30° C. whereas the a-naphthyl-urethane compound forms fine needles which melt at 82° C. (Rosenthaler, 1923). The tertiary amyl alcohol , amylene hydrate (No. 6) yields a ruby red color with y 2 cc. of a 1 percent solution of vanilline and 10 cc. of sulfuric acid, and upon oxidation it yields acetone, acetic acid, and carbon dioxide. The a-naphthyl-urethane derivative forms coarse needles which melt at 70° to 72° C. For the detection of tertiary amyl alcohol in the presence of second¬ ary amyl alcohol , Michael and Zeidler (1911) (quoted from Rosen¬ thaler, 1923) heated the mixture with 3N hydrobromic acid in a sealed tube in a boiling water bath for 5 minutes, resulting in the formation of trimethyl ethylene from tertiary amyl alcohol. If after the sepa¬ ration of this hydrocarbon sufficient hydrobromic acid is added to the remaining alcohol to bring its concentration up to 4.5N and it is heated again in the same way for 1% hours, the secondary amyl alcohol is also changed to trimethyl ethylene. For the detection of secondary isoamyl alcohol in the presence of the primary isoamyl alcohol , the same authors dissolved the alcohol mixture in 30 parts of 4.5N hydrobromic acid and heated it as above for 1 hour. The presence of the secondary isoamyl alcohol is indi¬ cated by the formation of trimethyl ethylene. Determination. —Basset (1910) determined amyl alcohol (fusel oil) in liquids by the pink or red color*produced with furfural and sulfuric acid. Korenman (1932) utilized the same reaction for the determination of amyl alcohol in air. In this procedure the air is collected in a dry flask of known volume. Twenty cc. of ethyl alcohol and the same amount of water are added and shaken for 2 or 3 hours. To 1 cc. of this solution 0.1 cc. of a 1 percent alcoholic solution of fur¬ fural and, while cooling, 1.5 cc. concentrated sulfuric acid are added, heated for 3 minutes in boiling water, and, after cooling, the pink to 131 red color is matched against standards of known strength prepared in the same way. Absorption, fate , and excretion. —Amyl alcohol is absorbed through the gastro-intestinal tract, the lungs, and the skin (Schwenkenbecher, 1904, and Sander, 1933). Neubauer (1901) claimed that a small fraction of the amount of amyl alcohol administered is excreted in conjugation with glucuronic acid, and he refers to Binz, Bodlander, and Strassmann as having found that only 5 to 10 percent of the total dose administered is excreted through the lungs and kidneys, the rest being completely oxidized in the body. According to Hockendorf (1909-10) amyl alcohol increases the sugar and decreases the nitrogen excretion in phloridzin diabetic dogs. This may indicate that amyl alcohol may be utilized as sugar. Pohl (1908) claimed that only traces of isoamyl alcohol are excreted through the lungs. Effect on the nervous system. —Strauss (1887) found that in rabbits doses of 5 to 6 gm. given orally cause, within a few minutes, deep coma and loss of corneal reflexes lasting for 5 to 6 hours. Lendle (1928) determined in rats, with intraperitoneal injection, the minimal nar¬ cotic dose as 0.36 cc. per kg. (given in 10 percent solution), recovery following after 35 to 50 minutes, and the minimal fatal dose as 0.6 cc. per kg., so that the margin of safety is 1.7. As pointed out by Lendle (1928), both doses are probably 25 percent smaller since the amyl alco¬ hol was in 33 percent ethyl alcoholic solution. Hufferd (1932) gave the narcotic dose with oral administration for guinea pigs as 0.00067 mole per 100 gm. (0.72 cc. per kg.) body weight. Isoamyl alcohol causes narcosis in rats with intraperitoneal injection of 0.5 cc. per kg., according to Lendle (1928), and since the minimal fatal dose w T as determined as 1.0 cc. per kg. the margin of safety is 2.0. According to Lehman and Newman (1937b) the minimal nar¬ cotic dose for rabbits with intravenous injection is 0.85 gm. per kg., isoamyl alcohol being, therefore, 6.5 times as potent as ethylalcohol. Hufferd (1932) determined the narcotic dose for guinea pigs with oral administration as 0.00063 mole per 100 gm. body weight (0.69 gm. per kg-)- .... The secondary amyl alcohol causes narcosis in rats with intraperi¬ toneal injection of 0.65 cc. per kg., the minimal fatal dose being 1.0 cc. per kg. and the margin of safety 1.5 (Lendle, 1928). With oral ad¬ ministration to guinea pigs, narcosis is produced by doses of 0.00052 mole per 100 gm. body weight (0.56 gm. kg.) (Hufferd, 1932). With regard to the irritant action of amyl alcohol, Cole and Allison (1930b). found that concentrations of 0.022 mole per liter cause irri¬ tation of the skin of frogs, and, according to Muller-Lobeck (1935), concentrations of 2.7 mg. per liter cause neither turbidity of the cornea 132 nor irritation of the conjunctiva of rabbits as observed with compar¬ able concentrations of amyl acetate. Effect on the circulatory system. —Salant (1909) found that the intravenous injection of amyl alcohol in 2 percent solution causes a more severe and more lasting fall of the blood pressure than observed with corresponding doses of ethyl alcohol. Heide and Schilf (1929) found that in dogs anesthetized with morphine, chloroform, or ether, even small doses of isoamyl alcohol (less than 0.5 cc. of a 2 percent solution) cause a considerable fall of the blood pressure and moderate vasodilatation. Kuno (1913) determined the minimal depressant con¬ centration for the isolated mammalian heart as 1/1500 to 1/2000 mole (0.059 to 0.044 gm.) per liter and the paralyzant concentration as l/50mole (1.76 gm.) per liter. Fiihner (1921) determined the minimal depressant concentration for isoamyl alcohol as 0.039 mole (3.4 gm.) per liter. Buchner, Fuchs, and Megele (1901) found that the vasodilatation produced by direct application to the peritoneum is more marked than that observed with propyl and butyl alcohol. Effect on other organs. —Kuno (1914) found that concentrations of 0.0125, 0.015, and 0.02 percent cause a moderate depression of the pendular movements of the isolated intestine and that 0.2 to 0.25 percent solutions rapidly cause complete paralysis. Macht (1920) y a cohol causes depression of the isolated ureter of the pig. The toxicity of amyl alcohol. —According to Salant (1909) the mini¬ mal fatal dose for frogs is 1/8 to 1/7 that of ethyl alcohol, and for rabbits it is from 2 to 4 times as toxic as the latter. Baer (1898) found that in rabbits the oral administration of 0.83 to 1.08 gm. per kg. causes a moderate reduction of the sensitivity; within 20 to 30 minutes it causes slight paralysis without distinct impairment of the corneal, pupillary, and ciliary reflexes and of the pulse rate and respiration. Doses of 1.25 to 1.66 gm. per kg. were found to cause, after 5 to 10 minutes, slight and, after 15 minutes, deep narcosis with impairment of the corneal, ciliary, and pupillary reflexes, reduction of the body tem¬ perature, and reduction of the respiration. With administration of 1.7 to 1.95 .gm. per kg. the paralysis was rapid and complete, the pupillary, ciliary, and corneal reflexes became rapidly weaker, the pupils were constricted, and body temperature and narcosis were materially lowered. Starrek (1938) ) (quoted from Lehmann and Flury, 1938) found that in mice the subcutaneous injection of 5 mg. per gram of normal amyl alcohol caused staggering, toleration of side position, dyspnea, motoric irritation, and finally deep narcosis. Isoamyl alcohol in doses of 6 mg. per gram body weight causes staggering, toleration of side position in 20 minutes, and narcosis in 133 30 minutes. Table 18 gives a summary of the minimal fatal doses as determined by various investigators in different species. With regard to 'pathological changes resulting from the absorption of amyl alcohol, Strauss (1887) found that the repeated oral adminis¬ tration of amyl alcohol to rabbits caused organ damage, especially of the liver. Table 18 .—Toxicity of amyl alcohol for different animal species with different routes of administration ORAL ADMINISTRATION Type of amyl alcohol Species Minimal fatal dose cc./kg. Author • Dog_ -- 1. 7 to 1.9 Dujardin-Beaumetz and Audig6 (1875). Sollmann and Hanzlik (1928). Rabbit_ 2. 0 to 2. 4 - SUBCUTANEOUS INJECTION Dog_ 2. 2 to 2. 8 • Dujardin-Beaumetz and Audiga (1875). Starrek (1938) (Lehmann and Flury, 1938). Starrek (1938) (Lehmann and Flury, 1938). Normal .. _ Mouse_ 13 Iso... . Mouse__ 9.2 INTRAPERITONEAL INJECTION Normal. .. Rat.. 0.6 Lendle (1928). Lendle (1928). Iso___ Rat.- 1.0 INTRAVENOUS INJECTION Normal..,.. .. Cat.. _ 0.15 Macht (1920). Macht (1920). Lehman and Newman (1937b). Iso_ .- _ Cat__ 0.26 Iso_____ Rabbit_ 1.9 With regal’d to toxic effects from industrial exposure there is very little definite information. According to Lewin (1927) ingestion of . 0.5 gm. of fusel oil causes somnolence, headache, and irritation of the throat of several hours duration. He refers to a publication of Hil¬ bert (1899) in which the exposure to the vapors of fermenting mash which contained, among other constituents, amyl alcohol caused ex¬ citement, insomnia, and colored vision. Eyquern (1905) observed in workers in an explosives plant who were exposed to the vapors of amyl alcohol and ether, irritation of the mucous membranes of the eyes and of the respiratory tract, digestive disturbances, loss of appetite, anemia, muscular weakness, and nervous disturbances. Several cases ol: fatal amyl alcohol poisoning in an explosives plant were reported by Robert (1907), as stated by Rambousek (1911). The victims suffered from nausea, vomiting, headache, vertigo and, in the more severe cases, the patients developed twitchings, loss of consciousness and delirium before death. Other industrial poison¬ ings in which amyl alcohol was one of the constituents to which the victims were exposed were reported by Burger and Stockmann (1932) 134 and by Baader (1933). Two other fatalities reported by Zangger •(1933) may have had exposure to tetrachlorethane in addition to amyl alcohol. The tertiary amyl alcohol, amylene hydrate, is of little industrial importance but it has been used as a hypnotic. With regard to its absorption, fate, and excretion, it is mainly ab¬ sorbed from the gastrointestinal tract, having a boiling point of 102° C. According to Pohl (1908) appreciable quantities are excreted through the lungs following its intravenous administration to dogs. It is questionable wdiether it is excreted in conjugation with glucuronic acid (Thierfelder and von Mering, 1885) and is said to be partly excreted unchanged (Frankel, 1927). With respect to its effect on the nervous system, Thierfelder and von Mering (1885) found it more effective than the tertiary butyl alcohol, doses of 3 cc. given orally causing in a large rabbit, in 10 to 15 minutes, deep sleep lasting for 12 to 24 hours. Lendle (1928) de¬ termined the minimal narcotic dose with intraperitoneal injection in rats as 0.9 cc. per kg. and the minimal fatal dose as 1.6 cc. per kg., so that the margin of safety is 1.8. According to Fuhner (1921) the minimal depressant concentra¬ tion for the isolated frog heart is 0.184 mole (16.2 gm.) per liter. Bock (1898) found in the isolated mammalian heart that tertiary amyl alcohol had little effect on the output and the rate, and he assumed that the reduction of the blood pressure observed by earlier investiga¬ tors was due to peripheral vasodilatation. With regard to its toxic action, Flury and Zangger (1928) stated that with sufficiently large doses it may cause circulatory disturbances characterized by vasodilatation and small and slow pqlse. Jacobi and Speer (1920) published a case of medicinal poisoning resulting from the rectal administration of 35 gm. or as pointed out by Loewe (quoted from Jacobi and Speer, 1920) probably more correctly 28 to 29 gm. of amylene hydrate. This resulted in deep sleep, loss of reflexes, collapse, and circulatory failure. Since the patient showed signs of improvement during the first 24 hours after the poisoning, and because he was found to have also suffered from pneumonia, it appears questionable whether death resulted from amylene hydrate poisoning. A similar case of amylene hydrate poisoning was reported by Anker (1892) resulting from the ingestion of 27 gm. of amylene hydrate. In this patient unconsciousness lasted 24 hours, somnolence persisted for 6 days, and for several weeks there was an excessive secretion of mucus from the respiratory tract. During the first 24 hours after ingestion, the respiration was impaired and the heart action weak. Large thera¬ peutic doses (4 gm. in water) may cause sleep readily, but are liable to cause also headache, nausea, and impairment of circulation and respiration more readily than observed with paraldehyde. j. Higher Aliphatic Alcohols The higher aliphatic alcohols—hexyl, heptyl, octyl, nonyl, decyl, undecyl, and cetyl alcohol (hexadecanol)—are of very limited prac¬ tical importance. Some of these have been studied in serial experi¬ ments covering a number of alcohols with a limited objective, and these experiments will be discussed in another chapter dealing with the rela¬ tion between the chemical structure and the physiological action of alcohols. Of the higher aliphatic alcohols, only octyl alcohol (capryl alcohol) is of any practical importance. This is used as an antifoaming agent, as a dehydrating agent for lubricating oils, in the printing of textiles, in air conditioning, in the manufacture of paper, in photographic work, and in insecticide sprays. Macht and Leach (1930) studied the toxic action of 23 of the 89 pos¬ sible isomers of octyl alcohol on goldfish. They found that they caused paralysis of the respiratory center and the neuromuscular ap¬ paratus, the primary alcohols being more toxic than the secondary alcohols, and these, in turn, being more effective than the tertiary alcohols. In some instances these workers also determined toxicity in cats with intravenous injection of 0.1 percent solutions. Such in¬ jections caused depression of the respiratory center, but no definite relation between their toxicity and their chemical structure could be established. Schroeder and Macht (1930) found that nearly all pri¬ mary octyl alcohols show some local anesthetic action in concentrations of 1:1000. With the tertiary alcohols this anesthetic action is of shorter duration and requires higher concentrations. With regard to the effect of octyl alcohol on the circulation , Clerc, Paris, and Sterne (1932) found that in rabbits and dogs it produces a lowering of the blood pressure and the surface tension of the blood which is of fairly long duration, and they suggested its use for the treatment of certain forms of hypertension in man. Similarly, Paris (1937) found that in rabbits, doses of 2 to 4 mg. per kg. cause a marked fall of the blood pressure, paralleled by lowering of the surface tension of the blood, increased clotting time, increased viscosity of the blood, and an increase of the red blood cells. According to Cavalli (1940) octyl alcohol causes no vasodilatation nor vasoconstriction; however, it lowers the surface tension in concentrations of 0.000087 gm. percent and-more. McLain (1940) found that caprylic alcohol causes hemo¬ lysis and that in this respect it is 50 times as effective as ethyl alcohol and 200 times as effective as distilled water. Cavalli (1940) found that concentrations of 0.5 mg. per 80 cc. Ringer’s solution cause, in the isolated intestine, immediate loss of tone and inhibition of the contractions, whereas concentrations one- tenth as strong have no constant effect. Similarly, Macht and Leach (1930) found that octyl alcohols depress smooth muscle structures 136 such as the vas deferens of the rat and the isolated uterus of the guinea pig, but they were unable to establish a relation between the intensity of this action and the chemical structure of the different isomeric alcohols. Paris (1937) stated that octyl alcohol has distinct diuretic properties. According to Clerc, Paris, and Sterne (1932), pure octyl alcohol is toxic for rabbits in doses of 2 cc. in contrast to a saturated aqueous solution which is only slightly toxic. No information appears to be available with regard to the toxicity of the vapors of octyl alcohol aside from the fact that they cause irritation of the mucous membranes of the eyes and the upper respiratory tract. II. THE UNSATURATED MONOVALENT ALCOHOLS The lowest member of the unsaturated alcohols is allyl alcohol propene-l-ol-3, 0112 = 011 — 0112011, which has the molecular weight • _ 20 ° 58.08. It is a colorless liquid of the specific gravity 0.854 at C. which solidifies at —129° C., boils at 96.6° C., and is miscible with water, alcohol, and ether. According to Jones (1938) the upper limit of its inflammability is 2.40 percent. It is prepared by heating glycerol and oxalic acid to 200° C., and may be obtained from crude wood alcohol by fractional distillation (Flury and Zernik, 1931). Allyl alcohol is absorbed through the gastro-intestinal tract, the lungs, and, according to Sander (1933), readily through the skin of mice. Evidently nothing is known with regard to its fate in the organism or in respect to its excretion. Miessner (1891) found that, in rabbits, doses of 0.15 to 0.1 cc. are slowly fatal, and doses of 0.2 cc. rapidly prove fatal, causing marked irritation of the mucous membranes, marked vasodilatation, lowering of the blood pressure, and considerable irritation of the kidneys as indicated by the presence of albumen in the urine. Piazza (1915) noted lowering of the body temperature, diarrhea, irritation of the kidneys, fibrillary twitcl lings, and paresis. According to Carlier (1911) the intravenous injection of saline saturated with allyl alco¬ hol causes a primary rise and a subsequent fall of the blood pressure, first shallow and later dyspneic respiration, and, finally, convulsions. Similarly, Atkinson (1925) noted in dogs, vomiting, marked irrita¬ tion of the gastric mucosa, convulsive movements, and coma; and in 1 dog he noted, following the administration of a sublethal dose, temporary opacity of the cornea and blindness. Miessner (1891) noted irritation of the mucous membranes, red¬ dening of the skin, increasing dyspnea, paralysis of the hind legs, and irritation of the kidneys in mice exposed to vapors of allyl alcohol. McCord (1932) exposed rabbits, rats, and 1 monkey to concentrations of 50,200, and 1,000 p. p. m. of allyl alcohol in air. The monkey, which was exposed to 1,000 p. p. m., showed vomiting, diarrhea, and severe pain, and died after 4 hours of exposure. At autopsy the intestinal tract was markedly inflamed and showed petechial hemorrhages which were also found in kidneys and spleen, and similar inflammatory reactions were also seen in the brain and the meninges. Of 2 rabbits exposed to the same concentration, 1 died 314 hours after the begin¬ ning of the exposure and the other died after 314 hours. Both de¬ veloped severe dyspnea and discharged an exudate from nose and mouth. Rats exposed to this concentration died after 3 hours. Three rabbits and 4 rats exposed to 200 p. p. m. showed, after 1 hour, obvious discomfort, noisy respiration, and discharge from nose and mouth, but tolerated from 3 to 18 exposures for 7 hours each. 555178—43-10 (137) 138 Of 2 rabbits and 5 rats exposed for 7 hours daily to 50 p. p. m. in air, each 1 of the former died or was killed after either the 14th or the 28th exposure, whereas the rats died after an average of 30 exposures. These experiments show that allyl alcohol causes considerable irri¬ tation, characterized by pulmonary edema, hemorrhages, gastroenteri¬ tis, diarrhea, and nephritis with hematuria, and that the dangerous concentration of allyl alcohol in air may be well below 50 p. p. m.; and, according to McCord (1932), even 5 p. p. m. will cause some irritation. According to Lewin and Guillery (1913), exposure to vapors of allyl alcohol may not only cause lacrimation, irritation of the conjunctiva, and pain in the eyes, but also disturbances of accommodation. Oettel (1936) stated that direct contact of allyl alcohol with the skin will cause, after 70 minutes, moderately sharp pain, and moderate erythema and hyperemia. According to Miessner (1891), allyl alcohol is 50 times more toxic than propyl alcohol, and Atkinson (1925) considers it to be 150 times more toxic than methanol. With regard to cases of human poisoning from exposure to allyl alcohol vapors, Flury and Zernik (1931) refer to the case of a chemist who suffered from irritation of the mucous membranes of nose and eyes, pain in eyes and head, difficult respiration, general malaise, and disturbances of accommodation as a result of exposure to this material. The corresponding alcohol with a triple bond is propargylic alcohol , propin-l-ol-3, CH C —CH 2 OH. It has the molecular weight 56.06, 20 ° and is a colorless liquid of the specific gravity 0.972 at C. which solidifies at —17° C. and boils at 114° to 115° C. It is soluble in water, and it mixes freely with alcohol and ether. Tietze (1926) found that in. rabbits the subcutaneous injection of 0.2 cc. per kg. diluted with 10 cc. of saline causes, at first, light nar¬ cosis, diarrhea, and paresis; after 2 hours, lowering of the body tem¬ perature and slowing of the respiration; later, increasing depression of the respiration; and, finally, death due to respiratory paralysis. In another rabbit twice this dose (0.4 cc. per kg. diluted with 20 cc.) caused no distinct effect in 3 hours, but when 0.8 cc. per kg. was given on the next day the animal died in 6 hours. Of the higher homologues of propargylic alcohol, diethyl-ethenyl- carbinol, (C 2 H 5 ) 2 — C— (C = CH)OH, was studied by Bock (1930) who found, in dogs, that doses of 0.2 gm. per kg. cause sleep and narcosis from which the animals do not recover, but smaller doses of 0.16 gm. per kg. have no effect. According to the same author, the methyl-tertiary-butyl-ethenyl-car- binol, (CH 3 )s — C — C— CH 3 (C = CH) OH, in doses of 0.25 gm, per kg. causes sleep. III. ACETONE SUBSTITUTED ALIPHATIC ALCOHOLS Diacetone alcohol, dimethyl-acetonyl-carbinol, pyranton A, (CH 3 ) 2 - COHCH 2 —COCH 3 , is a colorless liquid of the molecular weight 116.16 and the specific gravity 0.931 at 25° C., which boils at 165° to 166° C., and which is miscible with water, alcohol, and ether. Its flash point is 45° to 46° C. (Lehmann and Flury, 1938). According to Browning (1937) diacetone alcohol is a good solvent for nitrocellulose, cellulose acetate, cellulose ethers, and many resins, and it is, therefore, met with in the lacquer industry, in the textile and dyeing industries, and in the manufacture of quick-drying ink. According to Walton, Kehr and Loevenhart (1928), the intravenous injection causes, in rabbits, fall of the blood pressure, depression and narcosis, the onset, depth, and duration of the latter varying with the dose. The fall of the blood pressure is said to be due to reduction of the cardiac output and not to vasodilatation, and it is not affected by dissection of the vagus. I 11 rats the intravenous injection of even relatively small doses is said to produce sleep. With intravenous injection in rabbits the narcotic dose ranges from 1.0 to 1.5 cc. per kg. body weight, whereas the minimal fatal dose is 3.25 cc. per kg. With intramuscular injection the minimal fatal dose is slightly higher, namely 3 to 4 cc. per kg, and the somniferous doses 2.0 cc. per kg., whereas with oral administration the minimal fatal dose is 5 cc. per kg. and the narcotic dose is 2.4 to 4 cc. per kg. These data indicate that diacetone alcohol is about twice as toxic as acetone, for which the corresponding minimal fatal doses were determined as 6 to 8 cc. per kg., 5.0 cc. per kg., and 10 cc. per kg. According to Gros (quoted from Lehmann and Flury, 1938) the repeated subcutaneous injection of 0.08 cc. causes in rats somnolence followed by recovery. In rabbits, oral doses of 2 cc. given 12 times daily caused moderate narcosis, injury of the kidney—as indicated by the presence of albumen and sugar in the urine—and death in three-fourths of the animals. Inhalation of concentrations of 10 mg. per liter ( 2,100 p. p. m.) caused, in mice, rats, rabbits, and cats, restlessness, irritation of the mucous membranes, excitement and, later, somnolence. In rabbits kidney injury was observed. Keith (1932) noted temporary changes of the liver follow¬ ing the oral administration of 2 cc. per kg. to rats. These developed 6 hours after the administration, reached their maximum after 24 hours, but were, after this, retrogressive. These animals showed also a temporary reduction of the red blood cells and of the hemoglobin. There appear to be no records with regard to toxic effects observed with industrial exposure, but the results from animal experiments indicate that diacetone alcohol is about twice as toxic as acetone and that it may cause injury of the kidney, liver, and blood. ( 139 ) IV. PHENYL SUBSTITUTED ALIPHATIC ALCOHOLS Among the phenyl substituted aliphatic alcohols, "benzyl alcohol , phenyl carbinol, C 6 H 5 CH 2 OH, is of some importance. It is a colorless liquid of the molecular weight 108.13 and the specific gravity 1.043 at 20 ° which solidifies at —15.3° C. and boils at 204.7° C. It is soluble in 100 parts of water to the extent of 4 parts at 12° C. and mixes freely with alcohol and ether. Its flash point is, according to Leh¬ mann and Flury (1938), 96° C. Benzyl alcohol is used in the manufacture of carbon paper, as dope in the airplane industry, and in the perfume industry. With regard to the absorption , fate and excretion of benzyl alcohol in the organism, Battelli and Stern (1909) refer to Jaquet as having found that liver and kidneys oxidize benzyl alcohol to benzoic acid. The latter is conjugated with glycine and excreted as hippuric acid (Macht, 1918). Diack and Lewis (1928) found that after the oral administration of benzyl alcohol the excretion of hippuric acid is only slightly less prompt than after the administration of sodium benzoate, illustrating the rapidity of the oxidation to benzoic acid. The effect of benzyl alcohol on the central nervous system is not very marked. Macht (1918) found that in rabbits and dogs intra¬ venous doses of 5 to 10 cc. per kg. of a 1 percent solution may have some sedative effect without affecting the respiration or the respira¬ tory center; large doses may, however, cause paralysis of the respira- tion. Starrek (1938) (quoted from Lehmann and Flury, 1938) found that in mice the subcutaneous injection of 3 mg. per gram body weight causes, in 8 minutes, toleration of side position, and, in 20 minutes, deep narcosis, labored respiration and paralysis of the hind legs. As shown by Macht (1918), benzyl alcohol has local anesthetic properties. When applied to the tongue it causes first, slight irrita¬ tion, and, later, numbness. One percent solutions cause complete anesthesia of the frog’s skin and of the cornea of rabbits and dogs, preceded by a slight irritation. According to Sollmann (1919) it is a fairly efficient local anesthetic for mucous membranes, being, in this respect,'superior to procaine but somewhat less effective than holocaine and cocaine, especially with regard to the duration of the anesthesia. He pointed out that even 1 percent solutions of benzyl alcohol cause considerable smarting. As shown by Macht (1918), 1 percent solutions of benzyl alcohol may cause complete paralysis of the isolated sciatic nerve of the frog. ( 140 ) 141 With regard to the effect of benzyl alcohol on the circulation , Macht (1918) found that the intravenous injection of 5 to 10 cc. per kg. of a 10 percent solution causes, in rabbits and dogs, a fall of the blood pressure which is due to vasodilation and not to a direct toxic effect on the heart. As stated by Gruber (1923a), Mason and Pick, and Nelson and Higgins noted lowering of the blood pressure following parenteral administration of benzyl alcohol, but Gruber (1923a) did not see any such effect after the oral administration. He stated that the intravenous injection of large doses may paralyze the heart muscle prior to the respiratory center. As shown by Macht (1918), benzyl alcohol depresses smooth muscle structures, and Gruber (1924) showed that it has some diuretic action. The minimal fatal dose of benzyl alcohol is: For mice, 1 cc. per kg.; for rats, 1 to 3 cc. per kg.; for guinea pigs, 1 to 2.5 cc. per kg.; and for rabbits, 2 cc. per kg. (Macht, 1918). Lehmann and Flury (1938) quote Starrek (1938) as having determined the minimal fatal dose with subcutaneous injection for mice as 2 mg. per gram body weight, and stated that in this species benzyl alcohol is twice as toxic as butyl alcohol and 3 times as toxic as isopropyl and amyl alcohol. It has evidently not given rise to industrial poisoning. Macht (1918) showed that benzyl alcohol has antiseptic properties, 0.5 percent solutions killing bacillus Friedlander in 19 hours, bacillus pyocyaneous in 24 hours, and bacillus coli in 72 hours. Macht and Hill (1923) showed that its solutions in oil also have distinct bacteri¬ cidal action. Of the higher homologues of benzyl alcohol only tolyl-methyl- carbinol , h 3 c^ ^-c-ch 3 , has been studied, and according to Schoene (1938) it has cholagogic properties. It is a constituent of the ethereal oil from curcuma domestica and has no industrial importance. V. RELATION BETWEEN THE CHEMICAL STRUCTURE AND THE PHYSIOLOGICAL ACTION OF MONOVALENT ALCOHOLS Table 19 gives a resume of the physico-chemical data of some of the aliphatic alcohols. It shows that with normal alcohols the specific gravity increases with the molecular weight, and that the specific gravity of the iso compounds and, evidently to a greater degree, the specific gravity of the secondary and tertiary compounds is lower than that of the normal alcohols. Similarly, the boiling point increases with the molecular weight of the normal alcohols, and the boiling point of the iso, secondary, and tertiary alcohols is lower. Corresponding to the changes of the boiling point, the vapor pres¬ sure at a given temperature decreases with the molecular w T eight. But it should be pointed out that the vapor pressure of isopropyl and iso¬ butyl alcohol is greater than that of the corresponding normal alcohols and that the vapor pressure of the secondary and, especially, the ter¬ tiary alcohols (tertiary butyl alcohol) is considerably higher. The flash point increases with the molecular weight, and the lower limit of inflammability decreases with the molecular weight. The available data indicate that the surface tension of normal alco¬ hols increases with the molecular weight and the surface tension of the iso, secondary, and tertiary alcohols is lower than that of the normal compounds. Whereas the solubility in water decreases with the molecular weight, the*solubility in oil increases so that the partition coefficient oil/water increases with the increase of molecular weight. The available data do not show whether or not, or to what extent, the iso, secondary, and tertiary alcohols differ from the normal compounds. The toxicological properties of aliphatic alcohols increase with the molecular weight, as was already shown by Richardson (1869), and it has generally been found that the iso compounds are less effective than the normal alcohols. It has been shown by several investigators, such as Fulmer (1904 and 1905) on sea urchin eggs, by Fiihner and Neubauer (1907) with the hemolytic action on red blood cells, by Fiihner (1921) in the isolated frog heart, by Kamm (1921) in para- mecia, and by Morgan and Cooper (1912) and Tilley and Schaffer (1926) on bacteria, that the effectiveness of the various normal alco¬ hols from one member to the next higher homologue increases ap¬ proximately 3.3 times. According to Tilley and Schaffer (1926) for secondary alcohols this ratio is slightly lower, namely, 3.0, and for tertiary alcohols it is 2.7. In contrast to these findings with comparatively primitive test ob- ( 142 ) Alcohol Methyl- Ethyl.. C.) C.) P } Normal propyl (propam ' Isopropyl (propanol-2)-J ' Normal butyl (butanol- ^ Secondary butyl (butan ^ Isobutyl (2-methyl-prc ^ D- Tertiary butyl (2-meth panol-2). Normal amyl (pentane! C.) Secondary normal amy| tanol-2). Primary isoamyl (2-nj butanol-4). Secondary isoamyl (2-ir butanol-3). Amyl (pentanol-3) —.. O.) Tertiary amyl (2-metl tanol-2). Tertiary amyl (2,2-din- propanol-1). Active amyl. Normal hexyl (hexanol-i-- Normal hexyl (hexanol^. Normal hexyl (hexanob-. Normal heptyl (heptao-- Normal octyl (octanol-f. Octyl (octanol-2; capryf Normal nonyl (nonanoj-. Normal nonyl (nonanol- Normal nonyl (nonanol-. Normal primary decy anol-1). Normal undecyl (unde<|- Normalundecyl (under Normal dodecyl (doder Solubility in 100 parts of- Water 9 15° C... 12.5 20° C. 10 15° C__. 2. ? 22° 0.. 16.6. 2 14° O. Slightly soluble... -do..... -do.___ -do... .do. 0.59 20° C. Slight¬ ly soluble. Slightly soluble... -do__ 0.1 18° O. Very slightly soluble. Slightly soluble... 0.13 25° C. Insoluble... -do. -do.. Insoluble. _do_ Ether Soluble. -do.. Soluble. -do.. Soluble. Very soluble.. Alcohol Soluble. -do.. Soluble. -do.. Soluble.. Very soluble. Soluble_ .do. .do. _do. »Doolittle (1935). 2 Weese (1928). 1 Landolt and Bornst - isoamyl alcohol, international critical tables. 555178—43 (Face p. 142) Partition coef¬ ficient oil/water 8 0.03 8.13 .18 *. 47 8 1.0 Table 19.— Physico-chemical properties of aliphatic monovalent alcohols Alcohol Formula Molec¬ ular weight State Methyl.... CHsOH 32.04 Colorless liquid. Ethyl... CH 3 -CH 2 -OH 46.07 .do. Normal propyl (propanol-1)... C 2 H 6 CH 2 OH 60.09 .do. Isopropyl (propanol-2).. (CH3)2CHOH 60.09 _do.. Normal butyl (butanol-1). C 2 H 5 CH 2 CH 20 H 74.12 .do. Secondary butyl (butanol-2)... CH 3 CHOHC 2 H 5 74.12 .do.. Isobutyl (2-methyl-propanol- (CH3) 2 CHCH20H 74.12 _do.. Tertiary butyl (2-methyl-pro- (CHslsCOH 74.12 _do.. panol-2). nrm q1 ottittI l rvArttannl-l^ CH3(CH'>)3CH20H 88.15 _do_.._ Secondary normal amyl (pen- C 2 HjCH 2 CHOIICH3 88.15 .do.. tanol*2). Primary isoamyl (2-methyl- (CH3)2CHCH2CH 2 OH 88.15 _do.. butanol-4). Secondary isoamyl (2-m ethyl- (CHsJjCHOHCHs 88.15 .do_ butanol-3). (C 2 Hs) 2 CHOH 88.15 _do_ Tertiary amyl (2-methyl-bu- (CH3)2COHC 2 H 5 88.15 _do_ tanol-2). Tertiary amyl (2,2-dimethyl- (CH 3 )3CCH20H 88.15 Crystalline- propanol-1). Active amyl.... C 2 H5CH(CH 3 )CH20H 88.15 Colorless liquid. Normal hexyl (hexanol-1). CH3(CH2)4CH 2 OH 102.17 .do.. Normal hexyl (hexanol-2). CH 3 CHOH(CH2)2C 2 H5 102.17 _do..... Normal hexyl (hexanol-3).. C2Hs-CHOHCH 2 C 2 Ha 192.17 _do.. Normal heptyl (heptanol-1) - - - CH3(CH 2 )5CH 2 OH 116. 20 _do.. Normal octyl (octanol-1). CH3(CH2)6CH 2 OH 130. 22 .do... Octyl (octanol-2; capryl).. Cn 3 (CH 2 )6CHOHCH3 130. 22 Liquid__ Normal nonyl (nonanol-1). CH 3 (CH 2 )7CH 2 OH 144. 25 _do_ Normal nonyl (nonanol-2)- CHs(CH 2 )«CHOHCH» 144.25 .do.. Normal nonyl (nonanol-3). C 2 H 8 CHOHC6Hi 3 144.25 _do_ Normal primary decyl (dec- CH3(CH 2 )8CH 2 OH 158.28 Colorless oil- anol-1). Normal undecyl (undecanol-1). CH 3 (CH 2 )#CHjOH 172. 30 Liquid. Normal undecyl (undecanoI-2). CHa(CH 2 )8CHOHCH3 172.30 _do.. Normal dodecyl (dodecanol-1)„ CH 8 (CHj)ioCH 2 OH 186.33 Leaflets. 1 Doolittle (1935). 2 Weese (1928). . * Landolt and Bornstem (1905). Specific gravity 20 ° 0.792 c. 20 ° .789 C. 20 ° .804^ O. 20 ° . 789 gr C. 20 ° .810 gr C. . 808 ^ C. ,805 17.6° O. 20 ° 4 C 786 C. 20 ° .817 go C. 20 ° .810 2qo C. .813 ^ C. .819 19° C. 25° .815 -jr C. 20 ° .809 gs-C. .816 C. 20 ° .820 2qo O. . 818 ^ 0 . .818 O. .824 ^ 0 . .827 ^£-C. .822 ^-0. .828^ C. .823 ^0. .825 ^C. 20 ° .830 ~-C. .833 . 827 ^ O. .831 C. Melting point °C. -97.8 -112 -127 -85.8 -79.9 -108 25.0 to 25.5 -117.2 -11.9 52 to 53 -51.6 -34.6 -16 -38.6 -5 -35 -22 7 19 12 24 Boiling point d C. 64.7 78.4 97.8 82.5 117 99.5 107 to 108 82.9 137.3 toT37.9 118.5 to 119.6 132.0 113 to 114 115.6 102 113 to 114 128 155.2 to 155.7 137 to 138 135 175 756 mm. 194 to 195 179 to 180 213.5 193 to 194 194.5 750 mm. 231 131 15 mm. 228 to 229 255 to 259 Vapor pressure At 30° Flash point 8 C.i At 20° mm. C.2 Hg. 160 96 f 1 to 32 l (52) 78 44 / 9.0 to 32.0 1 (65) 29.4 15.2 22.5 to 45. 5 60 / 19.2 ill. 75 to 14.5 l 3 32. 4 (67) 11 6 35 to 35. 5 26 16.6 (88) 17 8.6 27.5 (HD 66.9 5. 54 12 4.9 / 40.6 \ 3 30. 6 2. 77 2.3 }• ( 110 ) 40 to 42 Inflammability (in percent) Upper limit * } 36.50 } 18.95 < Doolittle (1935) in 0 F., international critical tables. 5 Jones (1938). 8 Results probably 3 to 4 percent low. Lower limit» 6.72 3.28 2.55 2. 65 1.70 1.68 1.19 1.20 Surface tension 22.61 (20° 0.) 22.27 (20° C.) 23.8 (20° 0.) 21.7 ( 20 ° 0 .) 24.6 (20° C.) 8 23.5 (10° 0.) 22.8 (20° O.) 20.7 (20° C.) 7 23.8 (20° 0.) 27.63 (20° C.) Solubility in 100 parts of- Water 9 15° C... 12.5 20° C. 10 15° C... 2. 7 22° C. 16.6. 2 14° O. Slightly soluble... _do_... _do__ -do... _do.. Ether 0.59 20° C. Slight¬ ly soluble. Slightly soluble... do. 0.1 18° O. Very slightly soluble. Slightly soluble... 0.13 25° C. Insoluble... -do. -do. Insoluble. .do_ Soluble. -do.. Soluble. -do.. Soluble... Very soluble. Alcohol Soluble. _do.. Soluble. -do.. Soluble.. Very soluble. Soluble. .do. .do. .do. Partition coef¬ ficient oil/water 7 Presumably isoamyl alcohol, international critical tables. * Meyer (1899). • Seidell (1919). 555178—43 (Face p. 142) «0.03 8.13 18 *.47 8 1.0 143 jects, comparative studies in higher animals gave a lower ratio of the increase of the toxic action of normal alcohols. Joffroy and Serveaux (1895a, b) and Baer (1898) found in dogs; Macht (1920), in cats; Rost and Braun (1926), in guinea pigs and rabbits; and Weese (1928), in mice, a rational increase of less than 3.0 whereas Fuhner (1912a) found in frogs an increase of 3.99 between adjoining homologues. It appears, therefore, that, whereas certain toxicological properties may be affiliated quite readily to certain physico-chemical character¬ istics, their systemic effects are the result of a combination of a number of factors, the appraisal of which shall be attempted in the following synopsis. It has been pointed out that aliphatic alcohols have more or less marked antiseptic properties. Wirgin (1904) found that this in¬ creases from methyl alcohol to amyl alcohol so that the latter is 10 times as effective as the former, and Morgan and Cooper (1912) and Christiansen (1918) found propyl alcohol more effective than ethyl and methyl alcohol. Tilley and Schaffer (1926) studied the germi¬ cidal action of alcohols by means of a modified Rideal-Walker test with Bacillus typhosus and Staphylococcus aureus. They determined the phenol coefficient and the molecular coefficient, the latter being the molecular weight of the alcohol tested divided by the molecular weight of phenol and multiplied by the phenol coefficient. Their results are summarized in table 20 which shows that the disinfectant action Table 20 .—The germicidal action of various alcohols on different organisms [Tilley and Schaffer, 1926] Alcohol t Bacillus typhosus Staphylococcus aureus Ratio Phenol coefficient * Molecular coefficient Phenol coefficient Molecular coefficient Bacillus typhosus Staphylo¬ coccus aureus Methyl. ____ 0. 026 0.009 0. 030 0.010 'I Ethyl_ # _ .040 .020 .039 .019 j 2.2 1.9 Propyl__ . 102 .065 .082 .053 | 3.25 2.8 Butyl_ _ .273 .215' .22 . 175 | 3.30 3. 30 Amyl_ .... .. .780 .73 .63 .59 } 3.39 3.37 Hexyl_ _ 2.3 2. 5 ] 3.38 Heptyl. ... .... 6. 8 8. 4 } 3.46 Octyl.. _ ... . 21.0 29. 0 }. • Secondary propyl_ . .064 .041 .054 .034 }. ------ Secondary butyl_ .152 . 120 . 131 .103 j • 2.9 3.0 Secondary amyl _ .38 .36 .32 .30 j 3.0 2.9 Secondary hexyl_ . .. 1.00 1.09 } 3.0 Tertiary butyl_ .081 .064 .064 .050 .- Tertiary amyl___ . 182 . 170 . 142 . 133 ) 2.7 2.7 Tertiary hexyl.. .45 .49 ] 2.9 ■ 144 increases with the molecular weight in the normal series from methyl to ethyl, propyl, butyl, amyl, hexyl, heptyl, to octyl alcohol; that the secondary alcohols are less active than the nor¬ mal alcohols, as illustrated by the comparison of secondary propyl, butyl, amyl, and hexyl alcohol with the corresponding normal com¬ pounds; and that the tertiary alcohols are even less effective than the latter. Similar findings with Bacillus coli and Staphylococcus aureus were published by Ivokko (1939). As illustrated by figure 10 which gives the antiseptic concentration of various alcohols which BACTERICIDAL ACTION OF ALIPHATIC ALCOHOLS FOR BACILLUS COLI BOILING POINT °C 200 - OCTYL ALCOHOL | 8Q r SEC. OCTYLALCOHOL^- HEPTYLALCOHOl/ HEXYLALCOHOL 160 amylalcohoiA ISO amylalo— SEC. AMYL ALC0H0I BUTYL ALCOHOL^ ISO BUTYL ALCOHOI l2a f“' TERT AMYLALCOHOL SEC. BUTYL ALCOHOL',qqJi; PROPYLALCOHOL TERT BUTYL ALCOHOL ISO PROPYL ALCOHOL ' ETHYL ALCOHOL / METHYL ALCOHOL bU—i i I I 11"'* ' " ■ 15 20 25 30 % CONCENTRATION Figure 10. — This figure illustrates the relation between the boiling point of primary, secondary, and tertiary alcohols and their antiseptic action against Bacillus coli. (Redrawn from the data of-Kokko, 1939.) kill Bacillus coli within a certain period of time, the germicidal action of the normal alcohols increases with the boiling point, whereas the secondary and tertiary alcohols are less potent. Lockemann, Bar, and Totzeck (1941) studied the bactericidal properties of methyl, ethyl, propyl, and isopropyl alcohol in various dilutions with differ¬ ent bacteria. They found that the maximal bactericidal action was produced by 60 to 90 percent methyl alcohol, 50 to 90 percent ethyl alcohol, 20 to 90 percent propyl alcohol, and 30 to 80 percent isopropyl alcohol. It appears, therefore, that the range of the bactericidal action increases with the molecular weight and that the iso compounds are less effective than alcohols with an equal number of carbons in a straight chain. In table 21, some physico-chemical properties of these alcohols are summarized, together with their germicidal action as determined by Tilley and Schaffer (1926). It shows that, according to the available data, the antiseptic action in the normal series in¬ creases in the same direction as the surface tension, the partition 145 Table. 21 .—The relation between the physico-chemical properties of aliphatic alcohols and, their antiseptic action against Bacillus typhosus Alcohol Formula Molec¬ ular coefi- cient Boiling point 0 C. Surface tension Solubility in water Partition coefficient oil/water 2 3 Methyl_ Ethyl_ Normal propyl— . Normal butyl_ Normal amyl CH 3 OH CH 3 CH 2 OH CH 3 (CH 2 ) 2 OH CH 3 (CHj) 3 OH CH 3 (OH 2 ) 4 OH CH 3 (CH 2 ) 6 OH CH 3 (CH 2 ) 6 0H CH 3 (CH 2 )70H (CH 3 ) 2 CHOH ch 3 chohc 2 h 5 C 2 H 5 CHOHCH 3 0.009 .020 .065 .215 .73 2.5 8.4 29.0 .041 . 120 .36 1.09 .064 .170 .49 54.7 78.4 97.8 117 137.8 to 137.9 155.-2 to 155.7 175 at 756 mm. 22.61 22. 27 23.8 24.6 Miscible_ .do_ _ _do_ 9 16°_ 91 7 22 ° 0.03 .13 Normal hexyl_ Normal heptyl.. __ Normal octyl- 27. 53 21.7 23. 5(?) Slightly soluble. Very slightly soluble. Secondary propyl._. Secondary butyl_ Secondary amyl_ Secondary hexyl 82.5 99. 5 118.5 to 119.5 Miscible . . . 12.5 2 o 0 _ 16.6_ Tertiary butyl_ Tertiary amyl... Tertiarv hc.xvl (CH 3 ) 3 CH 2 CHOHCH 3 (CH 3 ) 2 C0HC 2 H 5 82.9 102 20.7 Miscible_ Slightly soluble. .18 1.0 1 Tilley and Schaffer (1926). 2 Baum (1899). 3 Meyer and Gottleib-Billroth (1920). coefficient oil/water, and the decrease in solubility in water. In a comparative study of the antiseptic action of methyl, ethyl, and propyl alcohol, Christiansen (1918) found that the antiseptic action and the precipitant effect of these alcohols .on proteins were not strictly par¬ allel, as illuustrated by the fact that the molar concentrations of the 3 alcohols (1T.5, 9.0 and 4.3 mole per liter, respectively) which cause complete precipitation of globulin free serum albumin differ in their antiseptic action inasmuch as propyl alcohol in 4.3 molar concentra¬ tion kills bacteria much more rapidly than methyl and ethyl alcohol in 17.5 and 9.0 molar solutions, respectively. Neither was there a definite relation between the surface tension and the antiseptic action of these alcohols, as illustrated in table 20 which shows that the in¬ crease in surface tension is of an entirely different order than the in¬ crease of the molecular coefficient. Quite different from the changes of the surface tension of the alcohols themselves are the changes of the surface tension of their aqueous solutions with different concentra¬ tions. Kisch (1912) determined the surface tension of various con¬ centrations of a number of alcohols by means of the capillary manometer, as illustrated in figure 11. This figure shows that the surface tension of 0.5, this being one-half the surface tension of water/air, is obtained with 44 percent methyl alcohol, 28 percent ethyl alcohol, 9 percent propyl alcohol, 5 percent isobutyl and 1.5 percent isoamyl alcohol. He found that the minimal inhibiting con¬ centrations of methyl, ethyl, isobutyl, and isoamyl alcohol on the germination of yeast cells were 45, 28, 6, and 2 percent which caused a reduction of the surface tension of 0.4725 to 0.5058, 0.4823, 0.4339, and 0.4941, respectively from that of water/air. If the ratio of the concentrations of the alcohols, required to reduce the surface tension » 146 of water/air to 0.5 of the original value, is compared with tha ratio of the phenol coefficients established by Tilley and Schaffer (1926), a good agreement is found. As shown in table 20, methyl, ethyl, and propyl alcohol are miscible with water, whereas the higher homo- logues become increasingly less soluble. On the other hand, the precipitant action of the higher homologues on proteins increases, with the molecular weight, from methyl to butyl alcohol. Neither of these functions offers an adequate explanation for their antiseptic action. It appears, however, that as soon as the alcohol concentra¬ tion in the medium reaches a point sufficient to lower the surface tension to approximately 0.4 of that of water over air, it may readily penetrate into the cells (Christiansen, 1918). This may explain, to EFFECT OF ALCOHOLS ON THE SURFACE TENSION OF WATER Figure 11.—This figure illustrates the reduction of the surface tension of water ( = 1.00) by various concentrations of aliphatic alcohols. (Drawn from data of Kisch, 1912.) a large extent, the superiority of higher alcohols as antiseptics. The rate of penetration at the same surface tension is further increased by elevation of the temperature. After their penetration into the cell, the alcohols will precipitate the proteins. With the lower homo¬ logues this may be largely caused by dehydration because of their great solubility in water, and with the higher homologues other fac¬ tors may play a role. Of the studies on the effect of aliphatic alcohols on other simple organisms, those of Loeb (1912) with sea urchin eggs should be mentioned. He found that the permeability of the oval membrane of fundulus eggs is equally increased by 2 molar solutions of methyl alcohol, molar solutions of ethyl alcohol and 8 molar so¬ lutions of butyl alcohol, and that % molar concentrations of the latter correspond in their effectiveness to a y 16 molar solution of amyl al- 147 cohol. Comparison of these data with the concentration of the var¬ ious alcohols which cause a 50 percent reduction of the surface tension, as illustrated in figure 11, shows the close relationship between this and the effect on the permeability of cell membranes. Singer and Hoder (1929) studied the effect of different alcohols on spleen tissue cultures of guinea pigs with regard to inhibition of emigration of leucocytic and lymphocytic elements, inhibition of growth of fibroblasts, and the stimulant effect on growth and the intensity of growth, as illus¬ trated in table 22. It also shows that in this respect the toxicity of Table 22 .—Effect of aliphatic alcohols on tissue cultures (spleen of guinea pigs) [Singer and Hoder, 1929] Alcohol Concentrations, in percent, which cause Death Inhibition Stimulation Methyl ____ . . _ _ _ _ Percent >2 2 1 1 ' 0.1 1 1 Percent 1 1 0.1 .1 .1 to .01 .1 .1 Percent 0.1 .01 to .001 (?) • 01(?) (?) .01 .1 Ethyl , _ _ . _ _ _ _ _ _ Normal propyl. .. . .. _ _ - _ Isopropyl -. _. - - - . __ _. Normal butyl. _ . _ _ ___ _ _ _ __ Secondary butyl __ _ - _ _ _ - _ _ _ - . - Tertiary butyl- _ .. _ _ _ _ alcohols increases with the molecular weight, but the available data do not allow a more detailed analysis of these results. Similar re¬ sults were reported by Kirihara (1932) with fibroblast cultures. With regard to the fate in the metabolism of the various aliphatic alcohols, it appears that the primary alcohols are generally oxidized over the corresponding aldehydes to carboxylic acids, and, further, to carbon dioxide and water, depending upon the stability of the acid radicle towards oxidative processes. Thus, methyl alcohol is oxidized to formaldehyde and formic acid; ethyl alcohol to acetaldehyde and acetic acid, and, further, to carbon dioxide and water; and normal propyl alcohol to propionic acid, which, in turn, is oxidized to carbon dioxide and water. According to Weese (1928), normal butyl alco¬ hol is also completely oxidized in metabolism. The secondary alcohols, on the other hand, are oxidized to ketones. Thus, isopropyl alcohol is oxidized to acetone. According to Neu- bauer(1901), secondary alcohols are excreted also, partly in conjuga¬ tion with glucuronic acid. Tertiary alcohols are resistant to oxidation and they are excreted in conjugation with glucuronic acid (Neubauer, 1901; and Frankel, 1911). The pulmonary excretion varies with different alcohols. Accord¬ ing to Pohl (1908), after their intravenous administration to dogs, methyl, ethyl, and amyl alcohol are excreted only in small quantities through the lungs, whereas isopropyl alcohol and tertiary amyl alco- s 148 liol are excreted to a considerable extent. With regard to methyl, ethyl, and isopropyl alcohol, Cushny (1910) believed that their pul¬ monary excretion is comparable to their evaporation from aqueous solutions; that it depends not so much on their volatility, as de¬ termined by their boiling point, as on their miscibility with water; and that the pulmonary excretion decreases with their solubility in water. Aside from their different fate in the organism, the speed of oxidation and elimination of the different alcohols varies consid¬ erably and, therefore, also, the duration of their action which may be an important factor in their toxicity. With regard to the effect of aliphatic alcohols on the central nervous system , Richardson (1869) showed that the depressant effect of alco¬ hols on the central nervous system, body temperature, heart action, and respiration increases with the molecular weight, as indicated by a comparison of the effect of methyl, ethyl, propyl, butyl, and caprylic alcohol. Meyer (1899) and Overton (1901) showed, with a number of alcohols, that the increase of the narcotic action, as determined in tadpoles, increased with their partition coefficient oil/water, as will be discussed in a later section. Munch and Schwartze (1925) deter¬ mined, in rabbits, the minimal narcotic and the minimal lethal doses of a greater number of alcohols with oral administration, as illustrated in table 23. This table confirms Richardson’s law, in that the toxicity Table 23 .—Minimal narcotic and certain lethal doses of alcohols as determined by oral administration to rabbits [According to Munch and Schwartze, 1925] Alcohol Average cc/kg. Mole/kg. Ratio (ethyl alcohol=l) Minimal narcotic dose Certain lethal dose Minimal narcotic dose Certain lethal dose Minimal narcotic dose Certain lethal dose Methyl_ _ _ _ _ J. 7.5 18.0 0.1875 0.4500 0.5 0.48 Ethyl_ 5.5 12.5 .0945 .2150 1.0 1.00 Normal propyl _ _ 1. 75 3.5 .0236 .0472 4.0 4. 6 Isopropyl_ 2. 85 10.0 .0380 . 1333 2.5 1.6 Normal butyl_ ... 1.05 4.5 .0115 .0465 8.2 4.6 Isobutyl_ 1.75 3. 75 .0191 . 0410 4.9 5.2 Secondary butyl._ _ 1.25 6. 00 .0137 . 0655 6.9 3.3 Tertiary butyl_ 1.80 4.5 .0191 .0480 4.9 4.5 Isoamyl . _ _ 0. 875 4. 25 .0080 .0391 11.8 5.5 Secondary amyl _ . . * .50 3.5 .0046 .0322 20.5 6.7 Tertiaryfamyl _ _ _ .75 2.5 .0069 .0230 13.7 8.6 increases in the normal series with the molecular weight. It also shows that, with this form of administration, the iso compounds are less effective than the normal alcohols, the secondary and tertiary alcohols ranking in between. Lehman and Newman (1937b) de¬ termined the minimal anesthetic dose with intravenous injection in rabbits for methyl, ethyl, n-propyl, isobutyl and isoamyl alcohol as 10.5, 5.6, 1.71, 0.93 and 0.85 gm., respectively. The results of a simi¬ lar study by Lendle (1928), with intraperitoneal injection in rats, 149 is given in table 24 which shows that, whereas the toxicity and nar¬ cotic action of alcohols increases with the molecular weight, the Table 24 .—Minimal narcotic and minimal fatal doses of alcohols with intra- peritoneal injection in rats [Lendle, 1928] Alcohol Narcotic dose cc./kg. Lethal dose cc./kg. Margin of safety Median time of recovery from narcosis in minutes Ethyl _ _ ^ _ 4.5 1.5 .76 >.36 (0.45) .5 .65 .90 8.0 4.0 1.2 i. 6 (0. 75) 1.0 1.0 1.6 1.8 2.66 1.6 1.7 2.0 1.5 1.8 210 to 360. 90 to 200 (approximate). 54 to 106. 35 to 80. 40 to 51. 93 to 180. 10 to 13 hours. Normal propyl_ Normal butyl_ _ _ Normal amyl _ Isoamyl_ _ _ Secondary amyl._ _ _ Tertiary amyl._ _ _ _ 1 Corrected value because normal amyl alcohol was given in dilute ethyl alcoholic solution. median time of recovery from the narcosis decreases. Comparison of the narcotic action of isoamyl alcohol, secondary amyl alcohol, and tertiary amyl alcohol with that of normal amyl alcohol shows that the narcotic, and, less markedly, the minimal fatal doses and the time required for the recovery from the narcosis increases with the branch¬ ing out of the side chains. As stated by Lendle (1928), the onset of death resulting from the administration of fatal doses of normal butyl and normal amyl alcohol occurs earlier than with the lower homo- logues. This observation and the much more rapid recovery from the narcosis mentioned seem to indicate: (1) that these alcohols dif¬ fuse more rapidly into and out of the tissue than the lower homo- logues; and (2) that, if the latter is correct, they must disappear more rapidly from the circulation, as indicated by the findings of Neymark (1938) and Berggren (1938) who found that the rate of oxidation of methyl, ethyl, propyl, and butyl alcohol increases with the molecular weight. Schneegans and von Mering (1892) had found, in rabbits, with administration of aqueous solutions of various alcohols by stom¬ ach tube, that the narcotic action of primary alcohols is less marked than that of the secondary and tertiary alcohols, and they had assumed that with tertiary alcohols the narcotic action depends upon the type of alkyl radicle linked to the tertiary carbon atom, in that the nar¬ cotic action, as determined by their procedure, was relatively poor when a methyl radicle was substituted, was better when this was replaced by an ethyl radicle, and increased with the number of ethyl radicles linked to the tertiary carbon atom. Similarly, Macht, Bryan, and Grumbein (1938), in a comparative study of the narcotic actions of (1) 2;2-dimethyl-propanol, (2i) 2,2-dimethyl-butanol, (3) 2-ethyl- 2-methyl-butanol, and (4) 2,2-diethyl-butanol, found the alcohol with the largest number of ethyl radicles most effective. It should, how¬ ever, be pointed out that this alcohol (4) had a much higher molecu¬ lar weight than the lowest member of this series (1). 150 As shown above, the findings of Schneegans and von Mering (1892) are not in accordance with those reported by other investi¬ gators. Kochmann (1923) thought that the limited solubility of alcohol in water resulted in a delayed absorption of normal amy] alcohol from the stomach, but Lendle (1928) pointed out thal Schneegans and von Mering (1892) did not determine the toxicitj by establishing the minimal fatal dose in cc. per kg. but by meas¬ uring the duration of the effects caused by the same doses, and that,, in this way, the rate of elimination may influence the duration of the effect. The same holds true for the extensive study of Hufferd (1932), as illustrated in table 25. He studied the narcotic action of alcohols in guinea pigs with administration by stomach tube, and used the following criteria: (1) sluggishness or drowsiness, (2) loss of control of hind legs, (3) loss of control of hind and fore legs, sufficient to make locomotion impossible, (4) narcosis from which the animal cannot be aroused by holding it by the hind legs and shaking it violently, and (5) narcosis, so that no reaction is produced by pinching the skin. Choosing criterion 3, as illustrated in table 25, for comparison of the narcotic action, it is evident that the effective¬ ness of normal alcohols increases, with their molecular weight, from methyl to normal amyl alcohol, and that, with the higher homo- Table 25 .—The narcotic action of alcohols with oral administration to guinea pigs [Hufferd, 1932] Alcohol Methyl (acetonefree). Methyl (synthetic)... Ethyl (100 percent). Ethyl (96 percent)_ Normal propyl_ Isopropyl_ Normal butyl_ Isobutyl_ Secondary butyl_ Tertiary butyl_ Normal amyl_ Isoamyl_ Secondary amyl_ Tertiary amyl_ Normal hexyl_ Secondary hexyl_ Tertiary hexyl_ Normal heptyl_ Secondary heptyl- Normal octyl_ Normal nonyl. Mole per 100 gm. body weight 0. 0005 to .0016 .0005 to .0014 Stage 1 0.099 .0070 .0045 .00205 .00249 .00082 . 00087 .00077 . 00096 . 00062 . 00060 . 00034 . 00037 . 00074 . 00085 Stage 2 0. 0136 .0129 .0071 .0052 . 00295 . 00302 . 00073 . 00099 . 00096 . 00126 . 00067 . 00060 . 00049 . 00046 Stage 3 0.0173 .0148 .0084 .0070 .00322 . 00393 . 00089 . 00108 . 00093 .00176 .00067 .00063 .00052 .00046 . 00039 .00025 .00046 Stage 4 0.0357 .0208 .0093 .0070 . 00322 . 00434 . 00102 . 00114 . 00114 .00182 . 00069 .00067 . 00045 .00051 .00076 . 00043 . 00028 . 00106 . 00040 Stage 5 0. 0133 .00075 . 0UU2o logues, the effect is too irregular to allow definite conclusions. Iso¬ propyl and isobutyl alcohol have more marked narcotic action than the normal alcohols, whereas the secondary butyl alcohol and the secondary amyl alcohol are more potent than the corresponding iso 151 alcohols, and the tertiary butyl alcohol and the tertiary amyl al¬ cohol are more toxic than the corresponding secondary alcohols. Genuit (1940) studied the antipyretic action of methyl, ethyl, propyl, and amyl alcohol in rabbits rendered hyperpyretic by the subcuta¬ neous injection of coli toxin and found that this increases with the molecular weight, but that the effect of amyl alcohol and-fusel oil was not as great as might have been expected. Weese (1928) studied, in mice, the narcotic action and toxicity of vapors of aliphatic alcohols, using as a criterion the period of exposure to a certain concentration which is required to produce deep narcosis (toleration of back position) or which is required to cause death after termination of the exposure, as illustrated in figures 12 and 13. NARCOTIC CONCENTRATION OF ALCOHOLS FOR MICE IN MOLE PER LITER Figure 12.—This figure illustrates the narcotic concentrations of vapors of aliphatic alcohols in mole per liter, as measured in mice by the period of time, in minutes, re¬ quired to produce narcosis (toleration of back position) with exposure to certain concentrations. The asterisks indicate the saturation point of the various alcohols at 20° C. The curve for secondary butyl alcohol is identical with that of the tertiary butyl alcohol. (Redrawn from Weese, 1928.) These curves start with the smallest amount of alcohol expressed in moles, the vapors of which, in 5 liters of air at 20° C., may cause nar¬ cosis (figure 12) or death (figure 13). Corresponding to the slower action of lower vapor tensions, the curves first decline steeply and then, in the region of the saturation point, they turn sharply and run nearly parallel to the abcissa, indicating the time required to produce the desired effect at vapor saturation at 20° C. As pointed out by Weese (1928), it will be noted that in many instances the calculated saturation point does not coincide with the bent of the curve, as in¬ dicated on figure 12 by stars. This may indicate that the vapor air mixture is not uniformly distributed within the exposure chamber (narcosis bottle) or it may be caused by differences in the temperature 152 in the immediate neighborhood of the animal and the rest of the narcosis bottle. The different position of the curves above the ab- FATAL CONCENTRATIONS OF ALIPHATIC ALCOHOLS FOR MICE IN MOLE PER LITER Figure 13.—This figure illustrates the fatal concentrations of aliphatic alcohols, in mole per liter, as measured by the shortest period of exposure required, with certain concentra¬ tions, to cause death after discontinuation of the exposure. (The curve of secondary butyl alcohol is identical with that of tertiary butyl alcohol.) (Redrawn from Weese, 1928.) cissa, i. e., with vapors resulting from equimolecular quantities of the alcohols, is the outcome of three factors: (1) the vapor tension, (2) the resorbability, and (3) the specific toxicity of the alcohols. Table 26 .—Vapor tension of alphatic alcohols [Weese, 1928] Alcohol Satura¬ tion pres¬ sure at 20° C.in mm. Hg. Minimal quantity of liquid caus¬ ing satura¬ tion pressure at 20° C. in cc. Alcohol Satura¬ tion pres¬ sure at 20° C. in mm. Hg. Minimal quantity of liquid caus¬ ing satura¬ tion pressure at 20° C. in cc. Methyl.... ... 96 1.1 Normal butyl. 5 0.13 Ethyl_ __ _ 44 .7 Isobutyl .. _ . . 8.6 .22 Normal propyl. *_ Isopropyl___ 15.2 19.2 .3 .4 Secondary butyl_ Tertiary butyl_ 16.6 40.6 .42 1.1 i Table 26 gives the vapor pressures oh the alcohols used in this study at 20° C. It shows that the vapor tension of normal alcohols decreases from methyl to butyl alcohol; that the vapor tension of the iso alcohols is greater than that of the normal compounds; and that the same holds true to a more marked degree for the secondary, and to an even greater degree for the tertiary alcohols. As shown in 153 figures 12 and 13, the narcotic and the toxic actions increase with the molecular weight in the range of unsaturated vapors, that is, as long as the vapor tension of equimolecular concentrations of the normal alcohols is uniform. The iso compounds are less effective than the normal alcohols but the secondary and tertiary butyl alcohols are more potent than the normal butyl alcohol. In the range of saturated vapors, however, an additional factor becomes manifest which influ¬ ences considerably the effectiveness of the different alcohols. With methyl, ethyl and propyl alcohol the narcotic and toxic action in¬ creases with the molecular weight in spite of a decreasing saturation pressure of the three isomers. Butyl alcohol differs from the three lower homologues. Although the specific toxicity of butyl and isobutyl alcohol is greater than that of methyl, ethyl and propyl alcohol, their vapor tension, which controls their availability to blood and nervous system, is so low that the narcotic effects are less than with propyl alcohol. With the secondary and tertiary butyl alcohols, on the other hand, the saturation pressure is so much higher that, in spite of their lower specific toxicity, their narcotic effect is greater. As shown in figure 13, their toxic action is lower, ranging between ethyl and propyl alcohol, because, as shown by Pohl (1908), both are eliminated through the lungs within 6 hours to the extent of 77 and 65 percent, respectively. This synopsis shows that the systemic delayed effects in many in¬ stances do not follow the same pattern as the findings with micro¬ organisms, tadpoles, and isolated organs, with which the toxicity of alcohols increases with the molecular weight, the iso compounds are less effective than the normal alcohols, and secondary and tertiary al¬ cohols are also less toxic. With regard to the effect of aliphatic alcohols on the peripheral nerves , Efron (1885) studied their effect on the nerve fiber with the nerve muscle preparation of the frog by using various aqueous solu¬ tions. He found that these cause, first, stimulation and, subsequently, depression of the nerve. With methyl alcohol the primary stimulation was less marked than with ethyl alcohol, and normal propyl alcohol caused only depression, whereas isopropyl alcohol caused a marked primary stimulation. He found the depressant action of isobutyl alcohol more marked than that of the tertiary isomer, and amyl alcohol more effective than any of the other alcohols tested. In the same way, Breyer (1903) determined the stimulant concentrations of various alcohols and determined the maximal concentrations producing this effect as follows: Methyl alcohol- 2 molar = 8.02 percent Ethyl alcohol- 2 molar = 11.28 percent Propyl alcohol-1/20 molar = 0.37 percent Butyl alcohol-1/20 molar = 0.46 percent Amyl alcohol-1/40 molar = 0.27 percent 555178—43-11 154 Bonnet and Lelu (1933), in studying the effect of alcohols on the nerve-muscle preparation of the frog, found that the depressant effect on the nerve fiber increases from methyl to butyl alcohol (see table 27), Table 27 .—Effect of alcohols on the nerve-muscle preparation [Bonnet and Lelu, 1933] Alcohol Con¬ centra¬ tion in mole per liter Time of onset of 1 paralysis (in minutes) Alcohol Con¬ centra¬ tion in mole per liter Time of onset of paralysis (in minutes) Of muscle Of nerve Of muscle Of nerve Methyl__- Ethyl_ Normal propyl__ 0.0248 .0171 .0134 88 90 90 103 100 90 Isopropyl.__... Normal butyl_ Isobutyl.- _ _ 0. 0131 .0109 .0108 (9 10 10 0) 30 10 1 No effect after 130 minutes. isopropyl being less toxic than normal propyl alcohol but isobutyl alcohol being slightly more effective than the normal compound be¬ cause, as they assumed, the former is a secondary and the latter a pri¬ mary alcohol. Since it has been shown above that changes of the per¬ meability of cell membrane are closely paralleled by the effect of alco¬ hols on the reduction of the surface tension, it appears quite possible that similar changes regulate the effect of alcohols on nerve structures, but the available data are not sufficient to establish this possibility. Raether (1905) studied the effect of alcohols on various nerve struc¬ tures, as summarized in table 28, which shows that the effect on the Tablei 28 .—The effect of aliphatic alcohols on various nerve structures [Raether, 1905] Alcohol Paralysis of the sciatic nerve of the frog Irritation of the cornea of the frog Irritation of the skin of the frog Irritation of the human tongue Concen¬ tration Concen¬ tration Concen¬ tration Concen¬ tration Concen¬ tration Concen¬ tration Concen¬ tration Concen¬ tration Percent mole lliter Percent mole lliter Percent mole/liter Percent molelliter Methyl_ 24.00 7.5 12.0 3.8 40.1 12.5 12.0 3.8 Ethyl_ 11.24 2.44 5.6 1.22 28.1 8.0 5.6 1.22 Propyl_ .. 2.5 0. 42 0.8 0.13 14.98 2.5 0.75 0.125 Butyl_ 1.5 .2 .33 .044 4.6 0.62 .38 .05 Amyl_ _ 0. 54 .06 .14 .016 2.16 .25 .14 .016 1 different functions studied increases with the molecular weight of the alcohols. A similar study with regard to the effect of alcohols on the perception of taste was published by ITallenberg (1914), as illus¬ trated in table 29. Macht and Davis (1933) studied the depressant effect of aliphatic alcohols on the sensory nerve endings in the rabbit’s cornea and the skin of the frog. They found that neither propyl, butyl, primary, secondary or tertiary amyl alcohol, nor the higher al¬ cohols with from 13 to 18 carbons had local anesthetic properties, but 155 Table 29 .—Effect of alcohols on the perception of taste [Tlallenberg, 1914] Minimal effective concentrations r Alcohol Nauseous taste Bitter taste Burning taste Volume Molar Volume Molar Volume Molar percent solution percent solution percent solution Methyl ... .......... 0.1 0.025 6.5 1.62 11.5 2.87 Ethyl_ .009 .0016 2.6 0.45 5.0 0.86 Propyl .003 .0004 1.2 . 16 Butyl .0004 .00004 0.6 .07 that heptyl and nonyl alcohol had some and octyl alcohol had distinct local anesthetic properties. The physico-chemical data on these higher alcohols reported in the literature are too incomplete to allow an attempt to offer an explanation for these findings. With regard to the effect of aliphatic alcohols on the circulatory ap¬ paratus , Ringer and Sainsbury (1883) found, in the isolated frog heart, that the same degree of depression is produced by 12.1 cc. methyl alcohol, 6.73 cc. ethyl alcohol, 3.5 cc. propyl alcohol, 1 cc. butyl alcohol and 0.4 ec. amyl alcohol, and Dold (1906) found a very similar rela¬ tion, the respective toxicities being: methyl alcohol, 1; ethyl alcohol, 1.75; propyl alcohol, 2; butyl alcohol, 6; and amyl alcohol, 35. Similar studies reported by Fiihner (1921), Pickford (1927) and Clark (1930) are summarized in table 30. These studies show that Table 30 .—Depressant effect of aliphatic alcohols on the isolated frog heart Alcohol Depressant concentration in mole per liter Effect on surface tension Solubility in water mole/liter Fiihner (1921) 1 Fiihner (1921) 2 Pickford (1927) 3 Clark (1930) Number of drops water=39 Molecular concentra¬ tion reducing surface ten¬ sion of water to 63 dynes/ cc. Clark (1930) Methyl. ... . . _ 3. 740 0.9 1.6 5oy 2 1.5 Miscible Ethyl _ _ 1. 206 .35 .65 51M .5 Miscible Normal propyl- _ . . _ . 369 . 17 51 y 2 . 14 Misp.ihlp Normal butyl_ . 109 .03 .05 si y 2 .043 0.919 Normal amyl__ _ .02 .018 Normal heptyl _ _ .003 .0007 51K 0024 .008 Normal octyl __ .0003 .0002 . 0006 Normal decyl _ . 00003 . 000094 Normal dodecyl- _ . . 000006 Normal tetradecyl _ .0001 Isopropyl.. - _ - .655 54 Miscible Isobutyl. . _ . . 135 53 y 2 1 351 Isoamyl ... . . ... .039 52V6 . 230 Teritary butyl... . _ .. .637 62% Miseible Tertiary amyl_ . 184 57H 1.420 1 Concentrations causing cardiac arrest. 2 Concentrations causing 50 percent reduction of heart beat. 3 Concentrations causing reduction of response of frog’s ventricle to H normal 156 the depressant action on the heart of aliphatic alcohols increases with their molecular weight up to dodecyl alcohol; that the iso com¬ pounds are less effective than the formal alcohols; and that the tertiary alcohols are less effective than the former. Similar results were reported by Wolff (1922) who stated that with methyl alcohol the isolated frog heart developed diastolic tendencies in contrast to systolic tendencies observed with the higher homologues. He noted, with ethyl and isopropyl alcohol, some indication of a stimulant action. Similary, Takahashi (1933) noted, with low concentrations of methyl, ethyl, n-propyl, n-butyl, n-amyl, n-hexyl, and n-octyl alcohol, mostly depression of the ventricular action and only a questionable stimula¬ tion of the auricle. He believed that intermediate and high doses cause damage of the myogenic and neurogenic apparatus, charac¬ terized by a decrease of the amplitude of the contraction, bradycardia, extrasystoles, and slowing of the auricular ventricular conduction of stimuli, and, finally, cardiac arrest. As indicated in table 30 and as found by Clark (1930) there is a close parallelism between the effect of the lower alcohols on the heart, their faculty to lower the surface tension of water, and the fact that both increase with the molecular weight. As pointed out by Clark (1930), this uniform increase is the more remarkable because the lower alcohols form true solutions whereas those higher than butyl alcohol form colloidal suspensions. He assumed that the depressant effect of alcohols depends on a surface action which occurs rapidly and that the drug also enters the cells but that, thereafter, it ceases to produce pharmacological effects. Continued exposure of the cell to the same concentration of alcohol will, therefore, increase its concentration within the cell without in¬ creasing the pharmacological action. Since recovery by lavage re¬ moves only the alcohol adsorbed to the surface of the cell, which is replaced by alcohol coming from the interior of the cell, recovery takes more time after continued exposure than after short exposure to the same concentration. Table 31 gives the amounts of alcohol Table 31 .—The concentration of alcohols calculated to occur within the cells of the cardiac muscle [Clark, 1930] Alcohol Millimolar concentra¬ tion ap¬ plied to the outside Millimolar concentra¬ tion calcu¬ lated to oc¬ cur in the cells Ratio be¬ tween the concentra¬ tions inside and outside of the cells Alcohol Millimolar concentra¬ tion ap¬ plied to the outside Millimolar concentra¬ tion calcu¬ lated to oc¬ cur in the cells Ratio be¬ tween the concentra¬ tions inside and outisde of the cells Methyl_ 1600 2000 1.3 Octyl . .22 6.0 27 0 ButyL_ 52 68 1.3 Decyl..- . .03 1. 5 50.0 Amvl_ 20 50 2.5 DodecyL .1. .006 1.0 1700 Heptyl_ 0.7 2.5 3.0 taken up by the cells of the frog’s ventricle when sufficiently strong concentrations are applied to reduce the response to one-half its normal 157 value. It shows that in the case of the less potent alcohols (methyl to amyl alcohol) the amount of alcohol present in the cells when the depression is of equal intensity varies from 2,000 to 50 millimolar concentrations, whereas with the more potent alcohols (heptyl to dodecyl alcohol) the concentration calculated to occur within the cell when an equal degree of depression is produced varies only from G to 1.0 millimolar. This observation appears to support the hypo- EFFECT OF ALCOHOLS ON THE TORTOISE HEART Figure 14.—This figure illustrates the effect of aliphatic alcohols on the tortoise heart. Methyl alcohol- Ethyl alcohol- Isopropyl alcohol- Normal propyl alcohol Tertiary butyl alcohol- - I Tertiary amyl alcohol- VI _ II Isobutyl alcohol_ VII _ III Normal butyl alcohol_ VIII - IV Isoamyl alcohol_ IX _ V (Redrawn from Vernon, 1911.) thesis that the depressant action of these alcohols depends largely on the amount adsorbed on the surface of the cell. With the higher alcohols the quantity fixed in this way is of the order necessary to cover the cell surfaces with a monomolecular film, which supports Warburg’s hypothesis that narcotics form a monomolecular layer over the cell surfaces. Similar studies with regard to the effect of alcohols on the turtle heart were reported by di Cristina and Penti- malli (1910) who found that the effects of ethyl, butyl, and amyl alcohol increase with their molecular weight and that they reduce the dynamic force of the heart muscle and interfere with the intrinsic regulatory mechanism. Yernon (1911) compared the toxic action of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, 158 tertiary butyl, isoamyl, and tertiary amyl alcohol on the tortoise heart. As illustrated in figure 14, the toxicity of these alcohols in¬ creases with the molecular weight, the iso compounds being less toxic than the normal alcohols, the secondary alcohols less effective than the iso alcohols, and the tertiary alcohols less potent than the secondary alcohols. The parallelism between these findings and the hemolytic effect of these alcohols confirms the supposition presented above that in the isolated heart of cold-blooded animals the toxic action of alcohols is closely affiliated with a surface tension phe¬ nomenon. Spealman (1940) believed that only those substances which are osmotically active cause slowing of the heart beat. With regard to the effect of aliphatic alcohols on the mammalian heart , Hemmeter (1889a, b) studied this in the heart-lung preparation of dogs, using the reduction of the output within a period of 30 seconds as criterion and perfusion this with 0.2 percent solutions in blood. He found that with perfusion of methyl alcohol the output was reduced by 19.46 cc.; with ethyl alcohol, by 17.45 cc.; with propyl alcohol, by 79.705 cc.; with butyl alcohol, by 161.121 cc.; and with amyl alcohol, by 322.32 cc. It will be noted that in the mammalian heart also the depressant action of the alcohols increases with the molecular weight but that methyl alcohol is apparently more potent than ethyl alcohol. This discrepancy, with similar observations made in the frog heart, is presumably due to the fact that the greater toxicity of methyl alcohol is caused by its metabolites—formaldehyde and formic acid—which may be formed under these conditions, and which, as was shown, are more toxic than methyl alcohol itself. Kuno (1913) determined the concentrations of various aliphatic alcohols which were just sufficient to depress the function of the mammalian heart and those which were sufficient to cause cardiac arrest within a few seconds, as illustrated in table 32, which confirms the findings of Hemmeter (1889a, b). Table 32 .—The effect of aliphatic alcohols on the mammalian heart [Kuno, 1913] Alcohol Minimal effective concentration in mole/liter Minimal paralyzant concentra¬ tion in mole/liter Alcohol Minimal effective concentration in mole/liter Minimal paralyzant concentra¬ tion in mole/liter Methyl_ 0. 025 to 0. 2 0 5 Normal butyl.. __ . 0025 to . 002 0. 60 Ethyl'._ . 17 .5 Amyl.. . . _ . 0Q066 to . 0005 .066 Normal propyl_ .005 .1 Genuit (1940) studied the effect of aliphatic alcohols on the blood vessels by determining, in the perfused rabbit’s ear, the dose of alcohol required to antagonize the vasoconstrictor effect of a standard dose of 159 epinephrine. He found that the following molar concentrations pro¬ duce this effect: • Methyl alcohol_2.19 to 2.8 (7 to 9 percent). Ethyl alcohol___ 0.436 to 0.65 (2 to 3 percent). Normal propyl alcohol_0.33 to 0.5 (2 to 3 percent). Normal amyl alcohol_:_0.0017 to 0.0023 ( 0.15 to 0.3 percent). Fusel oil_0.2 to 0.3 percent. It appears, therefore, that the vasodilator effect of alcohols increases from the methyl to the amyl compound. A similar relation was ob¬ served with regard to the depressant effect of these alcohols on the body temperature. With regard to the effect of aliphatic alcohols on the blood , Yande- velde (1903 and 1905), Fuhner and Neubauer (1907), and Fuhner (1923) .studied their hemolytic action on red blood cells. As pointed out by Fuhner (1923) the hemolytic action varies to a certain extent with the treatment of the blood cells—whether and how long they have been washed, centrifuged, or kept before use; the temperature at which the experiments were performed; and other factors—so that experi¬ ments carried out at different times with different blood samples do not give identical results. This may explain minor discrepancies in the data found by these investigators as illustrated in table 33 which gives Table 33 .—The hemolytic action of aliphatic alcohols on red blood cells Hemolytic concentration Molecular concentration reducing sur¬ face tension of water to 63 dynes/cc. 8 Alcohol Volume percent 1 Mole/liter 2 Volume percent 3 Mole/liter 4 Solubility in water mole/liter 8 Methyl . _ _ _ _ 36.0 7.34 ** 26.00 6.5 Miscible 1.5 Ethyl . . . 24.7 3.24 < B 17.00 2. 92(2.3) .93(3.14) . 32(2. 9). Miscible .5(3.0) .14(3. 6) .043(3. 2) .018(2. 4) .0024(7. 5) .0006(3. 0) Normal propyl._ 11.0 1.08 7. 00 Miscible Normal butyl.._ . .318 3. 00 0.92 Amyl _ __ 12. 52 .091(3. 4) .012(7. 6) .004(3. 0) Heptyl _ _ . 84 .008 Octyl . . ._ l 89 Isopropyl _ ... . _. 16.0 12.00 1.56 Miscible Isobutyl _ 2 28. 79 4. 25 .46 1.35 Isoamyl __ . . ... .. 1.50 . 14 .31 Tertiary amyl_ _ _ 5.2 .48 1.42 1 Vandevelde, 1903. 2 Fuhner and Neubauer, 1907. 3 Fuhner, 1923. 4 Fuhner, 1923. 5 Fuhner, 1923. 8 Clark, 1930. 1 Vandevelde, 1905. a summary of their results. As will be seen from this table, the hemo¬ lytic action increases with the molecular weight from methyl to octyl alcohol, the iso compounds are less effective than the normal alcohols, and the tertiary alcohols are less effective than the iso alcohols. Fuh¬ ner (1923) pointed out that with the higher members of this series (normal and isobutyl alcohol, iso and tertiary amyl alcohol) there is 160 a certain relation between their hemolytic action and their solubility in water, in that the ratio of their solubility in water, in mole per liter, over their hemolytic concentration, expressed in the same way, is approximately constant, being 2.9. But such a relation cannot be established for the lower homologues (methyl, ethyl, and propyl alco¬ hol) which are miscible in water. The last column in table 33 gives the molar concentrations necessary to reduce the surface tension of water to 63 dynes per cc., as determined by Clark (1930) for the normal alcohols. Comparison of the increase of the hemolytic action, as pro¬ duced by adjoining homologues, and their effect on the surface tension of water (both figures being given in parentheses) shows that there is a very close relation between the two functions. This appears also to be the intrinsic phenomenon in the depressant effect of aliphatic alco¬ hols on the leucocytic movements which, as shown by Baglioni (1927), increases, with the molecular weight, from methyl over ethyl to propyl alcohol. The effect of aliphatic alcohols on the striated muscle was studied by Blumenthal (1896) and Kemp (1908) both of whom found that the depressant effect on the muscular contractibility increases with • the molecular weight. According to the latter, the iso, secondary, and tertiary butyl alcohols are decreasingly less effective than the normal butyl alcohol. Schwenker (1914) showed that, in addition to this depressant effect on the excitability of the muscle, the aliphatic alco¬ hols cause a contracture of the muscle, and that their effectiveness in this respect increases rapidly with their effect on the surface activity. The contracture may continue after the excitability of the muscle has been completely abolished, therefore it must be caused by a different mechanism. Laporta (1929) found, by perfusing the gastrocnemius of the frog in vivo with solutions of aliphatic alcohols in Ringer’s solution, that the time between the beginning of the exposure and the contraction decreased with increasing concentrations of the alcohols. With the use of equimolecular concentrations he found that a similar decrease occurred with the increasing molecular weight of the alco¬ hols. He noted, however, that the form and the general behavior of the contracture varied with different alcohols, in that with all concentrations of methyl alcohol used the main contraction was inter¬ spersed with rapid, almost rhythmical, jerks which were less distinct with ethyl and propyl alcohol and absent with isoamyl alcohol. With lower concentrations the contracture is reversible, whereas with higher concentrations it is permanent. With regard to the effect of aliphatic alcohols on structures with smooth muscles , Kuno (1914) found that this increases, with the mole¬ cular weight, «from methyl to amyl alcohol. Several studies deal with the effect of aliphatic alcohols on the oxy¬ gen metabolism . of cells . Warburg (1910 and 1921) studied the effect 161 of several alcohols on the respiration of nuceleatecl red blood cells by determining the concentration causing 50 percent inhibition of the respiration. As illustrated in table 34, the depressant effect in- Table 34 —Effect of alcohols orilthe oxygen\metabolismlpf cells [Warburg, 1910jand]il921] P Alcohol Concentration causing 50 per- Surface tension aW-aL Solubility in oil over that in water (according to Overton, 1901, and Meyer and Gottlieb-Billroth, 1920) cent inhibition of respiration in mole/liter o .s w o pi 05 O 00 00 00 ^ 10 t—I 05 04 rH 00 O 00 O CO 10 .05 04 h 04 r- CO 04 04 CO » o O CO 10 CO 04 05 & 3 s (-4 o fa w o c* H o o W a 0 H 0 n W O 0 « W W Q 0 w w 0 1 w 0 H H 0 0 1 0 W 0 m W L pq w 0 0 0 O w w i do o wW L g§M ^g^w W 1 I o o «o I fig L?w 9§w Lo ifiSgfi t'fggs W « oH 0W0 |0 £9 1 o o«w L 090 w go a o Wo W © a © £ T3 a © ft O O « t>» r —1 bu © a 0) >» 33 o © >> '3) © a © >>^-C ft« O - ft ft CO X} a © 0 . o l-H ft 'O a © 3 33 O © ’3) ® a © p—« >» 72 . ft ft o o“8 ’he be © © 3 S 3 ® © ® *>ftq 3 ft 0 r ^_ — J* ® •2.&-C fifiB o o >> r~* bJD © 3 © 33 -u © 03 © o 8 o 2 p>.>* "3 wi © M O © 25 o> © r-H © w +* c3 05 05 a> cu ^pa o o w w co T3 H O <0 o co ^ §§ o ^ 33 © o 05 •» . 1 —« >> ^5 05 ^ co hh cOpW > 2’032^’3 '33 t-i 18 133 2 3 a 9P- . w o o o ■ -1—■ -t —• ■ • O o 3 © O ft © ©ft i<0Q02i< tuo 3 § t>ft o o X) T -'3 ■‘H ■*-> 3 ±< >H 3 bflbfi ©ftft © 0 (Z( 3 rT rf 3 'O T 3 ©tsti ©St-. >>>>>>00 © J?-*- 3 v 0 © H H © O O ft CGCGft-<-< Table 42 .—Comparison of the toxicity of certain monovalent and bivalent alcohols with regard to their chemical constitution Name Formula Boiling point °C. Solubility in Fatal dose orally cc./kg. Water Alcohol Ether Ethyl alcohol_ CH 3 CH 2 OH 78.4 12.5 (rabbit). Ethylene glycol—_ HOCH 2 CH 2 OH 197.4 /v/ r 1:100 7.7 (rat). Propyl alcohol_ CH 3 CH 2 CH 2 OH 97.8 3. 5 (rabbit). Propandiol-1,3_ HOCH 2 —CH 2 —CH 2 OH 214 /%/ 8:100 16 (rat ). 1 CHs | 82.5 /v/ Isopropyl alcohol_ - CHs—CHOH 10.0 (rabbit). CHs 1 188 to 189 rs/ rv 8:100 Propandiol-1,2. .. HOCH 2 —CH—OH 25.3 (rat). CH 3 | 99.5 12.5 /N/ Secondary butyl alcohol. CH 3 —CH 2 —CH 2 OH 6.00 (rabbit). i CHs 1 185 to 195 /V/ ( 2 ) Butandiol-1,3.. HOCH 2 —CH 2 —CHOH 18.2 (rat). 1 Quoted from van Winkle (1941a). 2 Slightly soluble. Note.— Toxicity data for rabbits are quoted from Munch and Schwartze (1925); data for rats are quoted from Smyth, Seaton, and Fischer (1941). administration are available for rats. Comparison of the acute tox¬ icity of the monovalent alcohols and the corresponding glycols, with the exception of ethyl alcohol and ethylene glycol, shows that the monovalent alcohols are generally more toxic than the corresponding glycols and that this is evidently, at least in part, paralleled by their solubility in ether and presumably also in oils and fats. The excep¬ tional position of ethyl alcohol and ethylene glycol may possibly be explained by the different rates of absorption, the former being ab¬ sorbed more readily than the latter. With regard to the chronic tox¬ icity of these compounds, ethylene glycol appears to be definitely more toxic than ethyl alcohol, presumably because it is oxidized to oxalic acid which forms insoluble calcium salts, whereas the monovalent alcohol is completely oxidized in the organism. C. TRIVALENT ALCOHOLS Glycerol The main representative of trihydric alcohols is glycerol or glyc¬ erin. Chemical characteristics. —Glycerol, HO CH 2 CH OH CH 2 OH, has the molecular weight 92.09. It is a colorless liquid with a sweetish taste. 20 ° It has the specific gravity 1.260 at C. Its melting point is 17.9° C. but it solidifies at a much lower temperature, and it boils at 290° C. It is miscible with water and alcohol but is insoluble in ether, fats, and oils. Glycerol is very hygroscopic and can be volatilized with steam. Identification. —1. Interaction with hydroiodic acid yields allyl io¬ dide (C3H5I) which boils at 101° to 102° C., and, further, isopropyl iodide (C 3 H 7 I) which boils at 59.5° C. (Rosenthaler, 1923). 2. When shaken with six times its volume of benzoyl chloride and an excess of sodium hydroxide it forms tribenzoyl glycerol which represents long needles melting at 76° C. (Rosenthaler, 1923). 3. Short heating with 5.1 parts of a-naphthylisocyanate and recrys¬ tallization from pyridine yields glycerol-a-naphthyl urethane, (C 10 H 7 NOCO) 3 OC 3 H 5 , which represents needles melting at 279° to 280° C. (Rosenthaler, 1923). 4. It may be identified by dehydration or oxidation to acroleine, or by oxidation to dioxyacetone by heating it with bromine water. The latter method gives the same reactions mentioned for the oxidation product of ethylene glycol (Rosenthaler, 1923). Uses. —Glycerol is used extensively as a vehicle in the pharmaceu¬ tical and cosmetic industries, as lubricant for specific purposes, as plasticizer, and as starting material in the manufacture of nitroglyc- erol and nitroglycerol explosives. Determination. —According to Fleury and Fatome (1935), glycerol may be determined by oxidation with an excess of standardized per¬ iodic acid and titrimetrical determination of the remaining periodic acid. In case sugars are present, these first have to be removed by precipitation with barium hydroxide and alcohol and filtration; the excess barium is precipitated with sulfuric acid or carbon dioxide and the alcohol by careful evaporation. Nicloux (1903b, d) worked out a method for the determination of glycerol in blood which can also be applied to urine. The proteins are precipitated by boiling with 1 percent acetic acid, filtered, and ( 191 ) 192 from the filtrate glycerol is removed by vacuum distillation with steam. After the distillate is concentrated by careful evaporation, glycerol is determined by oxidation with chromic acid. If a con¬ centration of 1.9 percent potassium bichromate is used for this pur¬ pose, the number of cubic centimeters used for the oxidation corre¬ sponds approximately to those of glycerol present. Antiseptic properties .—Glycerol has moderate antiseptic properties. According to Winslow and Holland (1919), a concentration of 9 per¬ cent has no appreciable effect on the vitality of B. coli , but concentra¬ tions of 28 to 100 percent are increasingly effective. Absorption , fate , and excretion .—As demonstrated by animal ex¬ periments with mice and rabbits, glycerol evidently is not absorbed through the intact skin in sufficient quantities to cause toxic effects (Sander, 1933 and Deichmann, 1941). According to Johnson, Carl¬ son, and Johnson (1933), it is not absorbed readily from the stomach, but 50 percent of the glycerol introduced into the intestine of anes¬ thetized dogs was absorbed during the first 2 to 3 hours. Similarly, Hober and Hober (1937) found that 73 percent is absorbed from iso¬ lated loops of rat’s intestine. As indicated by the reports of Mueller (1894) and Pfannenstiel (1894), sufficient quantities of glycerol may be absorbed from the pregnant uterus to. cause severe toxic effects. There is no information available as to what extent glycerol may be absorbed through the lungs, but, in view of its high boiling point (290° C.), this possibility appears to be quite remote. With regard to the fa\te of glycerol in the metabolism , Berthelot (1857) suggested that certain tissues may metabolize glycerol to glu¬ cose. Cremer (1902) and Luthje (1904) (both quoted from Voegt- lin, Thompson, and Dunn, 1925) found that the feeding of glycerol to rabbits increases the blood sugar level. Hockendorf (1909-10) noted that, in phlorhizinized dogs, glycerol increases the sugar excretion, in¬ dicating that it may be metabolized into sugar; and Chambers and Deuel (1925), reported that in such animals 55.9 to 98.4 percent of the glycerol given could be accounted for in the urine as extraglucose. Similarly, Ferber and Rabinowitsch (1929) found that, in diabetic patients, the administration of glycerol caused, in 67.5 percent of the cases, an increase of 20 mg. or more in the blood sugar level. Voegtlin, Thompson, and Dunn (1925) showed, in rabbits, that the oral and intraperitoneal administration of glycerol (4 gm. orally) causes a pro¬ gressive rise of the blood sugar, the maximum of 100 percent being reached in 1 hour, followed by a rapid decline, indicating that glycerol may be converted into sugar. Johnson, Carlson, and Johnson (1933) found, in feeding experiments with rats, indications that, within limits, glycerol may replace carbohydrates in the diet. Whereas Noble and MacLeod (1923) claimed that, in rabbits, insulin convulsions were not relieved by the subcutaneous injection of glycerol although 193 there was a very moderate increase of the blood sugar level (from 0.054 to 0.064 percent) shortly after the injection. Voegtlin, Dunn, and Thompson (1925) found that the administration of adequate doses of glycerol may relieve the symptoms of hypoglycemia in rats treated with minimal fatal doses of insulin. It appears, therefore, that glycerol may be partly converted into glucose in the organism. Luchsinger (1874) demonstrated that the administration of glycerol increases the glycogen content of liver and muscle which he interpreted as assimilation of glycerol to glycogen. Catron and Lewis (1929) showed that the feeding of 2 cc. of 50 percent glycerol to starved rats increased the glycogen content of the liver in the course of 1 to 6 hours, progressively, to an average of 142.55 mg. per 100 gm. body weight (3.24 percent) as compared with 0.09 percent in the controls. Similar results with rabbits and rats were reported by Lederer (1936) who also showed that in vitro liver tissue may form glycogen from glycerol. He found that in a dog the intravenous injection of 1 gm. of glycerol per kg. caused an increase of the glycogen content of the liver and a rise of the blood sugar level. He noted that four-fifths of the glycerol injected disappeared from the blood after 5 minutes and the rest disappeared within 90 minutes. Nicloux (1903a, b, c, d, e) studied the rate of disappearance of glycerol from blood follow¬ ing its intravenous injection in rabbits and dogs, as illustrated in table 43, which shows that the glycerol level is reduced very rapidly at first, then gradually, until after 3 y 2 hours, glycerol has disappeared almost entirely from the circulating blood. According to the same author (1903c) the “normal” glycerol level in the blood of dogs is, on an average, 0.0033 gm. per 100 cc. with 0.0019 and 0.0049 gm. per 100 cc. as extremes; and this is said to be essentially the same whether the animals are starved or fed a diet rich in fat. Trabucchi (1932) claimed that the rate of disappearance of glycerol from the blood is increased after the administration of insulin. With regard to the excretion of glycerol , the results of different in¬ vestigators do not agree, and this may be attributed, in part, to the analytical methods used for its determination. Ustimovitsch (1876) noted in the urine of dogs, after oral administration of glycerol, a re¬ ducing substance other than sugar, and he assumed that this was a metabolite of glycerol. Plosz (1877) claimed that he had isolated glycerol aldehyde under similar conditions but the validity of this statement appears to be questionable. Miura (1911) was unable to detect glycerol in the urine of dogs and rabbits after oral and sub¬ cutaneous administration, nor did he find evidence that it is excreted in conjugation with glucuronic acid. Catillon (1877) was able to re¬ cover from human urine 3 to 3.5 gm. after the ingestion of 30 gm. of glycerol, and he pointed out that with very large doses the excretion is - not proportionate to the dose but relatively smaller. Leo (1902) / 194 showed that the excretion of glycerol with the urine depends, in part, upon the dose administered, in that he found no glycerol in human urine after the administration of 8.93 gm., only traces after 20.08 gm. and quantities (0.5 to 1.0 gm.) after the ingestion of 26.76 gm. Simi¬ larly, Munk (1879) found only traces of glycerol in the urine of dogs after the oral administration of 25 to 30 gm. of glycerol, and Lederer (1936) detected only small amounts in the urine of man and rabbits. Tschirwinsky (1879), on the other hand, recovered from 38 to 60 per¬ cent of the glycerol administered from the urine of dogs which had been fed doses up to 200 gm. mixed with the food; and according to Arnscliink (1886) 25 percent is excreted by dogs after oral adminis¬ tration. Nicloux (1903b, c) found that, following the intravenous injection of 2 cc. per kg. in 20 percent solution into a 14 kg. dog, 0.112 gm. was excreted after the first 15 minutes, 3.067 gm. during the next 75 minutes, 1.409 gm. during the subsequent 67 minutes, and 0.158 during the last 3 hours of the experiment. It appears, therefore, that the concentration of glycerol in urine depends to a large extent upon the time of its collection after the administration, and this may offer an explanation for the contradictory findings reported by different students of the subject. In the experience of Mcloux (1903b, c) 17 percent of 28 gm. of glycerol given intravenously was recovered from the urine after 5 hours and 37 minutes, and in another experiment 27.7 percent of 19.5 gm. was recovered after 7 hours and 45 minutes; and Schubel (1935-36) was able to recover a total of 40 to 50 percent of the amount of glycerol given intravenously to cats. The effect of glycerol on various 'physiological functions .—With re¬ gard to the effect of glycerol on the nervous system , Macht and Ting (1922) found that glycerol has only moderate narcotic properties, in that doses of 160 mg. per 100 gm. body weight produce the same degree of depression in rats in a maze as is produced by 80 mg. per 100 gm. of ethyl alcohol and by 120 mg. per 100 gm. of ethylene glycol. This was confirmed by Latven and Molitor (1939) who determined the minimal hypnotic dose in mice as 10 cc. per kg. with oral, 8 cc. per kg. with . subcutaneous, and 3 cc. per kg. with intravenous administration, the corresponding figures for ethyl alcohol being 3 cc., 2 cc. and 0.8 cc. per kg. body weight. Schubel (1936) noted, in frogs, that the depression is preceded by excitation, and he saw, in mice, after fatal doses, dysp¬ nea, circus movements and convulsions which could be elicited by audi¬ tory stimuli similar to those observed in strychnine poisoning; and Deichmann (1941) noted inactivity and tremors after oral admin¬ istration to rabbits. Langendorff (1891), who had noted tetanic and clonic convulsions also, believed these to be partly of central, partly of peripheral neural, and partly of muscular origin. Langendorff (1891) believed that glycerol caused irritation of the peripheral nerves by its dehydrating action, and Santesson (1903) Table 43.—Rate of disappearance of glycerol from blood of rabbits and dogs [Nicloux, 1903e] 195 d o -u © © m 3 o a © > c3 bfl | * O -3 o 3 a •H 3 o © o '5b a o a < _ „ .’O ut g o o " Q< r* “ 9 £ 8 - Om h o © o 'S § > £•§ Lj O ©£ s ■4J 93 © O ft • 'd u. g O o © Q< O O O . _ rd oS) H o 03 # O > ft «rH r, q) +-> |«8 ■3 .g 9^ o o © Q* o o O . ;?a§e O o '3 § toB ©e 9 c 3 .; © .a oS .9 i-i 2 o o © a< © o SgS 3 o o C3 £ © ©£ ■a 3 o t! • 'a © a< © o BaS 2 O §>’ - 'o 'S § >£•£ ®eg os.: .a O £ .T) © Q< © O o i i^a'S- 0 O w)" 1 o a? a to Q s: «t3 03.® ©; 51 a? a to O > L, O-P © £ « a *•?? ►H .9 TtH o o d a s 00 o o CO 03 -4-3 d .a a o r—I CM CO o a o CM CO © -4-9 d .a a o o> oo *0 *0 AO t-H rH i—l t-H o CO CO CO CO © © © © - 4 -> - 4 -^ - 4-3 - 4-3 d d d d .a .a .a .9 asaa o o o o CO ^ CO CO t> co r- CM CO CO CO © CO CO © © 3 -4-9 gdd •pdd 5aa Nf^ r-^- UO »0 Tt- CO CO CO CO O © T3 T3 ■a a a a 200d a © ©-g ■s © © a a ot tn m O O CM CO CO rH CO © 8 , m .q^hN rC/rCl beta 03 e8 O O 1196 showed, in frogs, that glycerol lowers the threshold of the peripheral nerves to electric stimuli. Several investigators (Catillon, 1877; Plosz, 1877; and Arnschink, 1886) noted an increase of the body temperature after administration of large doses of glycerol, and similar observations were made by Mueller (1894) and Pfannenstiel (1894) following the intrauterine injection of glycerol. Johnson, Carlson, and Johnson (1933) noted no increase of the body temperature following the administration of smaller doses, and there is no definite explanation of the observations of the earlier authors. Glycerol causes definite irritation of mucous membranes when in direct contact, presumably on account of its dehydrating action. Ac¬ cording to Braun and Cartland (1936) the subcutaneous injection causes severe but transient irritation, and in the experience of Latven and Molitor (1939) the intradermal injection is distinctly irritant and application to the rabbit’s eye causes edema and hyperemia. As pointed out by Flinn (1935), the combustion products of glycerol cause distinct irritation of the throat when used as hygroscopic agent in tobacco. With regard to the effect of glycerol on the circulation , Schubel (1936) found that the energy of the isolated frog’s heart is moderately reduced by concentrations of 1:1,000 of glycerol in Kinger’s solution, that concentrations of 1: 50 cause a moderate decrease of systole and diastole, and that concentrations of 1: 8 cause reversible cardiac arrest. In the experience of Spealman (1940) 1/10 molar solutions (9:1,000) do not affect the heart rate, and twice this concentration causes no change in the weight of the frog’s ventricle, as observed with some of the monovalent alcohols. As found by Schubel (1936), concentrations of 1:1,000 to 1:10 do not affect the diameter of the blood vessels of the perfused frog, but according to Maignon and Grandclaude (1930) repeated intravenous injection at the same site may lead to obliteration of the veins. With regard to the effect of glycerol on the blood pressure , Amidon (1881) noted that the intravenous injection of 0.5 to 1.0 cc. per kg. of glycerol causes a fall of the blood pressure accompanied by a dim¬ inution of the force of the heart beat, increased frequency of the heart rate, and irregularities of the heart action. These effects are not altered by decerebration, dissection of the vagi and atropinization, and, therefore, must be due to some peripheral mechanism. Simi¬ larly, Schubel (1936) noted that, in cats, following the intravenous injection of 0.5 to 1.0 cc. per kg., the blood pressure first was reduced and then rose again, sometimes above the original level. He be¬ lieved that the primary fall was caused by a temporary impairment of the heart action and the secondary rise by a hydremic plethora. However, such changes should not be expected after the oral admin- 197 istration of moderate doses, as indicated by the negative findings of Johnson, Carlson and Johnson (1933). With regard to the effect of glycerol on the blood , numerous studies deal with its hemolytic action. Simon (1915) showed that in vitro concentrations of 15 to 55 percent cause hemolysis of red blood cells. However, in the opinion of Schubel (1936) this effect is not as marked as is usually assumed. He saw no hemolysis with concentrations up to 40 percent in normal saline, and 50 percent in normal saline caused hemolysis after 16 to 24 hours whereas the same concentration in water caused hemolysis within 1 y 2 hours. He found aqueous solution of 2.55 percent glycerol isotonic with 0.9 percent solutions of sodium chloride, therefore the hemolytic action of glycerol must be due to other than osmotic properties. Parpart and Shull (1935) studied the penetration of glycerol into red blood cells, and Jacobs, Glassman, and Parpart (1935) pointed out that the glycerol hemolysis is greatly affected by small amounts of copper salts and by changes of the pH, both factors affecting considerably the permeability of the cells. The effect of glycerol on leucocytes is much less marked than that of ethyl alcohol. Baglioni (1927) found that concentrations of 0.25 percent and 0.50 percent have no effect on the motility and survival of leu¬ cocytes, only 2 percent showing a distinctly injurious effect. Simon (1920) claimed that, in rabbits, the intravenous injection of 4.5 gm. per kg. caused stimulation of the leucopoietic apparatus, as indicated by the increase in the number of erythrocytes and white blood cells. However, it appears to be questionable whether or not this cellular increase is due to an actual stimulation of the blood- forming organs, and it is more likely that this is the result of the increased viscosity of the blood on account of dehydration, as assumed by Schubel (1936), especially since Piras (1925) found no indications of hyperactivity of the bone marrow of such animals. That such changes are not the result of a permanent damage of the blood-form¬ ing organs is also indicated by the findings of Tompkins (1929) who noted, following the intraperitoneal injection of 5 cc. of 10 to 25 percent solutions of glycerol, leucocytosis which increased with the dose, increase of the number of polynuclear neutrophiles, and usually a slight increase of the monocytes. During the first 12 hours after the injection there was, at times, a moderate lymphopenia, but usually the number of lymphocytes remained within normal limits or in¬ creased with that of the leucocytes, and within 48 hours after the injection the blood picture had returned to normal. After the re¬ peated administration of 12 doses of 2 to 6 cc. per kg. over a period of 7 weeks, to rabbits, Deichmann (1941) noted a diminution of the red blood cells from 6 to 4 millions, reduction of the hemoglobin, and variations in the number of leucocytes; it should be pointed out that these animals were suffering from hemoglobinuria. Similar changes 198 were observed after intracardiac injections, whereas the intraperi- toneal injection was followed by a temporary leucocytosis. It should be pointed out that after oral administration of glycerol neither blood changes nor hemoglobinuria was observed, and this appears to in¬ dicate that the blood changes observed by various investigators were due partly to destruction of the blood cells, partly to local irritation of the tissues at the site of the injection, and partly to thickening of the blood. Much attention has been paid to the effect of glycerol on the muscu¬ lature. Husemann and Unmethun (1866) (quoted from Santesson, 1903) noted that the injection of glycerol causes, in frogs, spastic and convulsive symptoms which they attributed to the dehydrating effect of this chemical. Amidon (1881) noted that the subcutaneous in¬ jection of glycerol into frogs caused, after a primary irritation, clumsi¬ ness of the movements due to stiffness of the musculature, followed by fibrillary twitchings of the voluntary muscles and tetanic con¬ vulsions elicited by moderate pressure on the muscle; and that, later on, even moderate stimulation of this type may elicit general tetanic convulsions. In contrast to such stimulation, sensory stimuli caused only attempts at ordinary reflex action. He showed, in addition, that neither decapitation, pithing of the spinal cord and dissection of the peripheral nerves, nor curarization prevents the convulsion—which was confirmed by Schlibel (1935-36)—but that exclusion of the blood supply by ligation of the vessels would suppress the convulsions in the ligated limb. He concluded that this effect of glycerol is located in the muscle tissue proper. Langendorff (1891) made similar observa¬ tions but claimed that decerebration attenuated and curare prevented these convulsions which, in his opinion, were partly of central origin, caused by dehydration of the central nervous system. He assumed that the muscular tetanus was the result of “endogeneous” electric currents produced by pressure on the muscle. Santesson (1903) pointed out that the subcutaneous injection of glycerol into frogs caused the animals to make flash-like extensor movements, but, after this, permitted only slow adduction of the limbs. In isolated nerve- muscle preparations of such animals, single electric stimuli of the nerve caused abnormally high and long-lasting contraction of the muscle (tetanus) and the plateau of the contracture curve showed, after some time, a sudden decrease which later flattened out gradually, this effect being attenuated rather than abolished by curarization. He concluded that this hyperexcitability was due to an increased excit¬ ability of the nerve endings. He also pointed out that at the height of the tetanic contraction the muscle was refractory to electric stimu- - lation and the glycerol contracture represented a real tetanus, whereas with veratrine, which causes a similar picture, the curve is only a single twitch contracture; and he believed, like Langendorff (1891), 190 that on account of the increased hyperexcitability, the muscle is stimu¬ lated continuously by its own action currents. Yerzar and Peter (1925) believed that the prolonged contracture of the glycerolized muscle is due to an increased permeability of the cell membrane; and Dux and Low (1921) showed that glycerol causes a high degree of dehydration of the muscle which may reduce its weight to one-fifth of its normal value, and that such muscles show a rapid increase and subsequent decrease of their swelling curve, the former being due to the avidity of the tissue for water and to the accumulation of lactic acid. With regard to the effect of glycerol on smooth muscle structures, Pelzer (1891) (quoted from Mueller, 1894) showed that, in situ, the injection of glycerol stimulated the contraction of the uterus. Reach (1926) found that the local application of glycerol to the upper section of the duodenum caused relaxation of the sphincter muscles of the ductus choledochus. This may favorably affect the discharge of bile, the formation of which, however, is not favorably affected by glyc¬ erol, as was demonstrated by Winogradow (1927). Pal and Prasad (1935) showed that 0.4, 0.6, 0.8 and 1.0 percent solutions of glycerol in Ringer’s solution cause a temporary increase of the height of the contractions of the isolated rabbit’s intestine, the tone showing a pri¬ mary fall and subsequent improvement, and that contractions of the large intestine were increased proportionately to the concentration of the solution. Schiibel (1936) found that concentrations of 1:1,000 in¬ crease the peristaltic activity of the isolated ureter, concentrations of 1:100 increase the tone and the number of contractions, and concen¬ trations of 1:20 cause rapid depression of all movements. In his experience, concentrations of 1:1,000 to 1:150 reduce the tone of the isolated uterus and the intestine, and such solutions may antagonize the spasmodic effect^ of barium chloride (1:200) but not that of physostygmine. With regard to the effect of glycerol on the kidney function, this is characterized by a diuretic action and by hemoglobinuria. Usti- movitsch (1876) found that in dogs the intravenous injection and the oral administration of glycerol had a definite diuretic effect. Lewin (1879) made the same observation and attributed it to the hygroscopic properties of glycerol. Cugusi (1922) pointed out that the effect of glycerol on the kidney function varies with the dose, in that he found, in rabbits, that the intravenous injection of small and moderate doses stimulates the renal activity whereas large doses inhibit the renal function. According to Schiibel (1935-36) the same dose of glycerol, given intravenously, increases the urinary output to 10 times its normal amount, whereas with oral administration it is in¬ creased only by 3 to 5 times. He believed that the diuretic action is responsible for the increased viscosity of the blood of such animals. In the experience of Johnson, Carlson and Johnson (1933) the oral administration of glycerol always is followed by diuresis, whereas with intravenous injection, causing a fall of the blood pressure, the urinary secretion is reduced. In man, 3 doses of 30 cc. each, taken daily with orange juice after each meal, had no diuretic action. Rosenfelcl (1924) pointed out that the repeated daily oral adminis¬ tration of glycerol increased considerably the excretion of uric acid in man, and Grabfield and Swanson (1942) believed that uricosuric action of glycerol is due to a specific effect on the protein metabolism, whereas the diuretic action is presumably a function of its hyper- tonicity. Many experimenters have reported hemoglobinuria following the administration of glycerol. Amidon (1881), Filehne (1889), Miura (1911), Simon (1920), Deichmann (1941) and others noted it after the subcutaneous administration of glycerol; others, like Amidon (1881), Ustimovitsch (1876) and Deichmann (1941), saw it after intravenous injection, but it seems that hemoglobinuria has not been observed after the oral administration of glycerol. Afanassiew (1883) believed that the hemoglobinuria is not the result of injury to the kidneys but that it is due to the removal of hemoglobin from the blood cells because he noted in such cases of hemoglobinuria shadow cells in the blood and hemoglobin in the serum, so that it appears that the glycerol hemoglobinuria is of the same type as paroxysmal hemo¬ globinuria in man. As shown by Pfeiffer and Amove (1937), pre¬ medication with ascorbic acid afforded protection against glycerol hemoglobinuria. With regard to the effect of glycerol on the metabolism , Catillon (1877) claimed that glycerol decreased the protein metabolism as in¬ dicated by a reduction of the urea level in the blood and the urea excretion with the urine. However, Munk (1879) and Lewin (1879) found no evidence to show that it decreases the protein metabolism and that it has no food value in this respect. Tschirwinsky (1879) pointed out that findings indicating an increase of the protein metab¬ olism possibly may be overshadowed by a decrease of the urea ex¬ cretion, caused by its dehydrating and diuretic action. As pointed out above, Grabfield and Swanson (1942) believed that glycerol some¬ how affects the pur in metabolism, as judged by its uricosuric action and the increased excretion of allantoin in dogs. It has been pointed out above that glycerol may be substituted, within limits, for carbohydrates; and this also was shown by Johnson, Carlson and Johnson (1933). With regard to the effect of glycerol on the fat metabolism, very little information is available. Catillon (1877) believed that glycerol decreases the fat metabolism, and Arnschink (1886) thought that glycerol may save an equivalent caloric amount of fat. 201 Data regarding the effect of glycerol on the oxygen metabolism are contradictory. Leo (1902) refers to Scheretjewski (1869) as having observed an increase of the respiratory metabolism after the adminis¬ tration of glycerol. Similarly, Catillon (1877) found that, following administration of glyercol to dogs, the percent of carbon dioxide in the exhaled air increased from 4.3 to 6.0 and 7.0 percent after doses of 3 to 4 and 6 to 8 gm. per kg., respectively. Chambers and Deuel (1925) found, after feeding glycerol to phlorhizinized dogs, a de¬ crease of the respiratory quotient from 0.703 to 0.678; and Johnson, Carlson and Johnson (1933) noted no consistent effect in man after 3 daily doses of 30 cc. each. Table 44 .—Fatal doses of glycerol for different species of animals by various routes of administration ORAL ADMINISTRATION Species Dose cc./kg. Author Mouse_ 25 (M. F. D. 50)_ Latven and Molitor (1939). Smyth, Jr., Seaton and Fischer (1941). Do. Deichmann (1941). Rat_ _ 21.8 (M. F. D. 50)_ Guinea pig...__ Rabbit___ 6.1 (M. F. D. 50)1_ 21 to 23 (M. F. D. 60).. SUBCUTANEOUS ADMINISTRATION Mouse. .... 0.05____. Schiibel (1936). Do_.__ 10___ Latven and Molitor (1939). Do .. ca 10 _ Leake and Corbitt (1917). Rat___ 12.5_ Braun and Cartland (1936). Do__-. 15 to 16...__ Deichmann (1941). Dog ... - 8 to 10.... Plosz (1877).' Do... 6.4 to 8_ Dujardin-Beaumetz and Audigfi (1876). Horse.. 1__ Plosz (1877) J INTRAMUSCULAR ADMINISTRATION Rat.___ _ 6.0___ Braun and Cartland (1936). INTRAPERITONEAL ADMINISTRATION Rat.... 5 to 6_ Deichmann (1941). INTRAVENOUS ADMINISTRATION Mouse.... 6.0_ Latven and Molitor (1939). With regard to the toxicity of glyercol for animals , table 44 gives the minimal fatal doses for different species by various routes of ad¬ ministration as determined by various authors. The picture of acute poisoning, as described by various investigators quoted in this table, is essentially the same. Following the administration of toxic doses' of glycerol, rabbits first show an increase of the respiration; the pulse rate is first increased, later weakened and irregular; the animals first develop weakness of the musculature and, later, tremors, twitchings, convulsions, diuresis, and diarrhea; and they die of respiratory fail- 555178—43-14 202 ure and cardiac arrest. Mice first show gnawing movements of the jaws; they become dyspneic, discharge soft stools, develop trismus, show circus movements, and develop spasticity and strychnine-like convulsions; and with fatal doses death may occur after some time has elapsed. Dogs may show, in addition, vomiting and diarrhea, and colic has been reported in horses. Johnson, Carlson and Johnson (1938) saw no evidence of any toxic effects in rats from the continued feeding over a period of 40 weeks of a diet in which 41 percent of the starch had been replaced by glycerol. With complete replacement of starch by glycerol they noted a distinct impairment of growth which, however, evidently was caused not by a toxic action of glycerol but by an inadequate intake of food, as proved by the fact that the addition of 50 percent of glycerol to the complete diet not only did not impair the growth but even promoted it on account of the additional calories furnished. Similarly, Hoick (1937) saw no unfavorable effects on the growth of young rats fed a diet containing 20 percent of glycerol. Cases of glycerol poisoning in humans are exceptional. Robert (1906) reported on one fatal and one nonfatal poisoning in children after the ingestion of large doses of glycerol. Jaroschi (1889) re¬ ported on one patient who, after the repeated oral and rectal admin¬ istration of glycerol over a period of 2 weeks, suffered from debility, vomiting, diarrhea, and muscular cramps which disappeared promptly after discontinuation of glycerol. In view of the irritant action of glycerol on mucous membranes, and because of its dehydrating action, it appears quite possible that the above symptoms may result from such abuse, but in this specific instance it appears possible that the glycerol in question was contaminated with appreciable amounts of arsenic trioxide. Three other cases of glycerol poisoning were re¬ ported by Mueller (1894) and Pfannenstiel (1894). In these in¬ stances, 100 gm. of glycerol had been injected into the pregnant uterus in order to stimulate uterine contractions. One patient suffered, after 10 minutes, from vomiting and diarrhea and had, re¬ peatedly, paroxysmal attacks of a fever which was of a different type from that produced by infection. The second patient became cyanotic, the pulse was slowed, and there was a short but definite rise of the temperature. All three patients suffered from more or less severe hemoglobinuria. There are no reports on industrial poisonings from the handling of glycerol, and the possibility of toxic effects from its industrial use appears to be remote. With regard to 'pathological changes in glycerol poisoning , very little information is available. Plosz (1877) saw, after oral admin¬ istration of single large doses, hyperemia and inflammation of the mucous membranes of the gastro-intestinal tract, hyperemia and cloudy 203 swelling of the kidneys, hyperemia of the liver, and hyperemia and edema of the lungs. Piras (1925) noted, after repeated daily sub¬ cutaneous administrations of 0.5, 1.0, and 2.0 cc. per kg. for 45 days, hyperemia, hemorrhages and, with the largest dose, fatty degenera¬ tion of the liver; hemorrhages and cloudy swelling of the kidneys, and, with the largest dose, destruction of the tubular epithelium; and hyperemia, inflammatory reactions and small hemorrhages of the intestinal mucosa, even with small doses. The spleen was affected less and the lungs showed only moderate hyperemia. Other organs, in¬ cluding adrenals and bone marrow, were essentially normal. Similar but more marked changes were reported by Simon (1915) after the administration of single fatal doses of glycerol. Maignon and Grand- claude (1930) studied the local effects of repeated intravenous in¬ jection of glycerol on the vascular walls. They found that in 7 out of 14 experiments the first injection caused no changes of the vascular walls; in 4, the walls were somewhat thickened; and in 3 instances they were markedly sclerotic, with complete, or nearly complete, obliteration of the lumen. These changes became more marked after the second injection. Microscopically, the layers of the vascular walls became separated by sclerotic areas and infiltrated with leucocytes, the endothelium became indistinct and finally fused with a mass in the lumen, thus obstructing completely the lumen of the vessel, this clot finally becoming completely organized. Comparison of the narcotic actions of glycerol and propylene glycol shows that they are of the same order but that they are considerably inferior to that of the monohydric alcohol, propanol. This is paral¬ leled by the reduced solubility of propylene glycol and glycerol in fats and oils which, as pointed out before, is one of the factors controlling the narcotic action of alcohols. On the other hand, glycerol more nearly approaches the polyvalent alcohols and sugars, in that, within certain limits, it may be utilized by the organism and give rise to the formation of glycogen. D. THE POLYVALENT ALCOHOLS WITH MORE THAN THREE CARBONS The polyvalent alcohols with more than three alcoholic groups are of such low toxicity that they are of no toxicological importance. The tetravalent alcohol, erythritol or butantetrol, HOCH 2 (CHOH) 2 ch 2 oh, is said to cause diuresis in rats in doses of 18 gm. per kg. when given orally as 50 percent aqueous solution. It is excreted unchanged with the urine to the extent of 20 to 40 percent, and it does not signi¬ ficantly increase the respiratory quotient of rats nor favor the depo¬ sition of glycogen in the liver (Beck, Carr, and Krantz, 1938). Ac¬ cording to Hober and Hober (1937), it is absorbed from the intestine of the rat to the extent of 41.4 percent, whereas the corresponding fig¬ ure for glycerol is 73 percent. The pentavalent alcohol, adonitol , HOCH 2 (CHOH) 3 CH 2 OH, evi¬ dently has not been studied pharmacologically. According to Hober and Hober (1937) its absorption from the gastrointestinal tract is slower than that of erythrol. The hexavalent alcohol, hexanhexol, exists in the form of several isomeres— mannitol , dulcitol and sorbitol —of the general formula HOCH 2 (CHOH) 4 CH 2 OH. None of these has a distinct toxic action. Ellis, Carr, Wiegand and Krantz (1943) found that sorbitol com¬ prising 5 percent of the food intake did not affect deleteriously the rate of growth, liver glycogen storing capacity, or important metabolic viscera of white rats through three generations. Smith, Finkelstein and Smith (1940) noted no toxic manifestations in man after the in¬ travenous injection of 80 gm. sorbitol or mannitol or 50 gm. of dulcitol over a period of 2 hours. Jaffe (1883) believed that mannitol is not oxidized readily in the organism of dogs. Carr, Musser, Schmidt, and Krantz (1933) found that mannitol increases the storage of gly¬ cogen in the liver of rats after oral administration, and Carr and Krantz (1938) reported that it may cause moderate hyperglycemia in rabbits. Ellis and Krantz (1941) and Ellis and Carr (1941) found that it increases the glycogen deposit in the liver of monkeys in con¬ trast to sorbitol, with which such effect is absent. Dulcitol, on the other hand, increases, to a moderate extent, the glycogen storage in the liver of monkeys but does not increase the respiratory coefficient of rats. Spealman (1940) showed that Vio molar solutions of mannitol slow the beat of the isolated heart and twice this concentration de¬ creases the ventricular weight, presumably by dehydration. As shown by Hober and Hober (1937), the rate of absorption of ( 204 ) 205 polyhydric alcohols from the intestinal tract decreases with the in¬ crease of their molecular weight. None of them appear to have a specific toxicologic action and some of them may be converted to glycogen in the organism. Any effect on the functions of the organ¬ ism presumably are affiliated closely with their osmotic action. Smith, Finkelstein, and Smith (1940) found that after intravenous injection in man only 32 percent of 9 gm. sorbitol and 87 percent of 4 gm. dulcitol were excreted with the urine within 10 hours, indi¬ cating that the former is more readily metabolized. Grabfield and Swanson (1942) showed that the intravenous injection of 15 cc. of a 50 percent solution of sorbitol caused, in dogs, considerable diuresis and increase of the excretion of uric acid during the first hour to the extent of 3 times the original amount. Since mannitol and dulcitol do not share this uricosuric action, it appears that the optical configuration plays a role in this respect. 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