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19/7/1 0108198 N I OSH-0i_r 132689 Sputum Cytology After Inhalation of Heated Propylene Glycol. A ClinicalCorrelation Olsen, C. R., H. F. Froeb, and L. A. Palmer Journal af the American Medical Association, Vol. 178, No. 6, pages254-256, 15 references Novermber 11,1961 CODEN: JAMAAF' Inhalation of heated propylene--glycol (57556) (F'G) as a tool for sputumcytology was tested. Since some patients are unable to raise sputum, a clinical trial was run on the inhalation of heated F'G. There were three groups o•f patients: patients with suspected diagnosis of cancer, patients with a history of heavy smoking, and patients with undiagnosed pulmonary disease. Many s!tffered fr-om chronic bronchitis or emphysema. Seventy nine percent of the patients were from 40 to 69 years of age. Heated PG was inhaled for '-':'0 minutes. After inhalation, sputum was collected in alcohol and smears were prepared. Cell blacks were prepared with the remainder of the sample. Patient acceptance of the method was good and the warm vapor was soothing for many. Patients previously unable to raise sputum were ableto give adequate samples after inhalation of PG. In those who were able to raise sputum without F'G, their samples were improved in quality after inhalation of PG because of a decrease in nasopharyngeal secretions. Sputum cytology provided the first definite proof of pulmonary malignancy in eight patients. Identification of tumor type was not always possible. In some cancer patients, cell blocks showed malignant cells but smears did not. The authors conclude that inhalation of heated F'G is a useful tool for sputum cytology.

1 C 19/7/' t,1 060~26 Pd1QLH-0 C) 1:'98,2 Production of Rat Sarcoma Esy I n j ect i ons of Fropyl ene Gl ycol Solution of p-nuinone Umeda, Gann, hi. ' Vol. 48, No. 2, pages 139-144/p late, 13 r efer-ence s June 1957 The carcinogenic effects of 1,4•-benzoguinone (106514) (ON) and propylene-glycol (57556) PG) were examined in rats. Subcutaneous injections of ON dissolved in PG at the concentra tion of 1 gram deciliter (gdl) were given weekly to 15 Wistar- rats and 9 hybrid rats in 0.5 cubic centimeter (cc) amounts. Injections were delivered into the same site on the back of the rats. Concentrations of ON were reduced to ().2gdl after 53 days, and increased to Cr.4gd1 after 173 days. Of the 24 rats receiving ON, 17 survived the test period of 394 days, having received 32 injections for a total of 81 milligrams ON and 16.5cc PG. Fibrosarcomas developed in two rats. A tumor was palpated in one rat at •'94 days and the animal died at 423 days. A tumor was -found in a second animal at 417 days and the rat was sacr i f i ced i n a wea4::ened cond i t i on at 481 days. A macroscopic metastasis was found in the left axillary lymph node of the second rat. A cysticercus sarcoma of the liver was found in a third rat that died at 566 days. The two fibrosarcomas were found in subcutanQous tissue at the injection sites. In a second experiment, 18 rats received weekly injections of icc PG for 88 weeks. After 15 months, the amount of PG was reduced to 0.5cc. Eleven rats survived 300 days or more. One survived 614 days. No tumors were found at the site of injection in rats receiving PG. The local tissue at the PG injection sites showed hyaline fibrosis. One of the rats died at 403 days. At autopsy, and adenoma of the hypophysis was found. The author concludes that PG may facilitate the penetration of ON into the cells.

19/7/7 0091472 NIQSH-•00120102 Contact Allergy From Propylene Glycol Angelini, G., and C. L. Meneghini Contact Dermatitis, Vol. 7, REo. 4, page 197-198, 8 references 1981 CODEN: CODEDG Allergic reactions to propylene-glycol (57556) were studied in 400 subjects with eczematous contact dermatitis. A?0 per cent propylene-glycol solution was applied to the subjects by patch tests. Positive reactions to propylene-glycol were recorded in six individuals. Adverse reactions were confined to the face, hands, or forearms. The authors note that all six of the subjects with a positive response had a history of prolonged contact with propylene-glycol through pharmaceutical and cosmetic preparationc. 19/7/9 0082044 hlI OSH-0c i 1 1 090b Results of Feeding Propylene Glycol in the Diet to Dogs.for Two Years Weil, C. S., M. D. Woodside, H. F. Smyth, and C. F'. Carpenter Food and Cosmetics Toxicology, Vol. 9, No. 4, pages 479-490, 14 references 1971 CODEN: FCTXAV The effects of long term feeding of propylene-glycol (57556) were studi ed i n dogs. Eieagl e-dogs were f ed 2.0 or 5.0 grams per kilogram (g/kg) propylene-glycol for 2 years. Animals were weighed weekly, and hematological, urological, and histological analyses were performed. Mean body weights of propylene-glycol treated dogs were comparable to those of controls throughout the experiment. There were no significant differences between treatment and control groups in mortality, water con sumption, or diet utilization. At the 2g/kg propylene-glycol dose, there were no differences in hematological, histological, or urological parameters in the experimental animals. In the high dose group, the rate of erythrocytic hemolysis increased, but this effect was reversible and not permanently damaging to the spleen or bone marrow. In males fed 2g!!:g/day, there was a significant reduction compared to feeding of per day does in lipid formation rate in the liver controls. The authors conclude that propylene-glycol in amounts as high as not have adverse effects in dogs. long term 8 percent

19/7: 17 0034021 NIOSH-00042385 Comparat i ve Ef f ects of Propylene G1 ycol , Other Gl ycal s, and Alcohol on the Liver Directly Newman, H. W., W. Van Winkle, Jr.,N. K. F::ennedy, and M. C. Morton Journal of Pharmacology and Experimental Therapeutics, Vol. 68, No. 1, pages 194-200, 13 references January 1940 Comparative effects of propylene glycol, other glycols, and alcohol on cat livers were investigated in experimental studies. Propylene glycol decreased the oxygen consumption and carbon dioxide production of per-fused isolated cat liver, but increased glycogen of the liver and lactic acid content of the blood and decreased utilization of dextrose by the liver. Addition of insulin to the perfusion with propylene glycol caused further depression of oxygen consumption of the liver, prevented increase of blood lactic acid, and hastened utilization of glycol. Ethylene glycol, diethylene glycol, and dipropylene glycol were not utilized by perfused liver, but depressed oxygen consumption and increased lactic acid production, dipropylene glycol being least toxic in these respects. Ethyl alcohol was metabolized directly by perfused liver, but depressed its functional activity; blood lactic acid was increased and liver glycogen decreased. The direct action of propylene glycol on isolated liver stands apart from the actions of ethyl alcohol and other glycols; propylene glycol is the least injurious and objectionable of all these solvents. 19/7/18 00.33737 NIOSH-40042564 Comparative Effects of Propylene Glycol and Some Other Agents on Oxygen Consumption of the Organism Van Winkle, W., Jr., Journal of Laboratory and Clinical Medicine, Vol. 27, No. 6, pages 770-773, 2 references March 1942 The metabolic actions of propylene glycol, using oxygen consumption as the criterion, have been studied. Propylene glycol was found to depress the oxygen consumption of white rats, this depression not being due to a decrease in activity, since the depressions of pentobarbital and chloral in the. same rats did not significantly decrease the oxygen consumption. These results on whole animals are in agreement with previous results on isolated liver perfused with propylene glycol, which also showed a decrease in oxygen consumption. The doses of propylene glycol used were beyond those likely to be taken as solvent or vehicle in food or medicinal agents, but the depression of oxygen consumpti on could occur with very large or toxic doses. This result is essentially of scientific importance, because the use of propylene glycol has a wide margin of safety.

19/7/20 i~0256=~ hIIOSH-i~i~~~•-:1921 Hematologic Effects following the Intravenous Injection of Propylene Glycol in the Rabbit Brittain, R. T., and P. F. D'Arcy To:; i col ogy and Appl i ed Pharmacol ogy, Vol. 4, No. 6, pages 738-744, 5 references Novermber 1962 Hematologic effects following intravenous injection of propylene glycol in rabbits were experimentally studied. The administration of concentrations of propylene glycol (4 ml/I::g) in saline (12.5, 25, and 50 percent) to rabbits had no effect on red blood cell count, packed cell volume, hemoglobin concentration, or total white blood cell count. There was, however, an increase in the number of circulating polymorphs and a decrease in the lymphocytes. Monocyte, eosinophile, and basophile counts were not affected. Blood clotting time markedly decreased and there was an accompanying increase in platelet count. The •fragility of the red blood cells was not altered. 19/7/21 0025332 NIOSH-00062579 Observations on the Chronic Toxicities of Propylene Glycol, Ethylene Glycol, Diethylene Glycol, Ethylene Glycol Mono-ethyl- ether, and Diethylene Glycol Mono-ethyl-ether Morris, H. J., A. A. Nelson, and H. 0. Calvery Journal of Pharmacology and Experimental Therapeutics, Vol. 74, pages 266-273, 21 references March 1942 The resul ts of chroni c to;, i c i ty studi es of propyl ene gl ycol , ethylene glycol, diethylene glycol, ethylene glycol monoethyl ether, and diethylene glycol monoethyl ether on experimental rats are presented. The results obtained by continuing the experiments for two years that would not have been noted if it had been discontinued at the end of one year were the occurrence of urinary calculi in each of the series of the animals receiving ethylene glycol and diethylene glycol. It is possible also that the microscopic lesions and testicular enlargement observed would not have been as distinctly different between the experimental and control animals if the experiment had been continued f or only one year. Fully two-thirds of the animals on ethylene glycol monoethyl ether showed marked testicular enlargement, edema, and tubular atrophy. This condition occurred less frequently in the group of diethylene glycol monoethyl ether and only occasionally in the other experimental groups and in the control groups. Chronic kidney damage was marked and renal concretions of calcium oxalate frequent only in the case of those animals receiving ethylene glycol. The group of animals receiving propylene glycol differed only very slightly from the controls.

19/7/22 t=>023982 P.! I OSH-000',Tc?27 Propylene Glycolc A Potentially Toxic Vehicle in Liquid Dosage Form Martin, G., and L. Finberg Journal of Pediatrics, Vol. 77, No. 5, pages 877-878, 8 references Novermber 1970 A case report is presented for a 15-month-old male patient exhibiting toxic symptomatology while receiving large doses of vitamin C suspended in propylene glycol, commonly employed in preparing oral and injectable medications such as barbiturates, antihistamines, and vitamins. The form of intoxication from the glycol is similar to the type resulting from an overdose of ethanol, with irregular apical heart rate and sinus arrhythmia being observed in the present case. The occurrence of symptoms in the patient suggests that propylene glycol may be toxic when unusual doses are administered, especially to children. f 19/7/2) 4 0022950 PdIOSH-00062841 Studies of Skin Reactions to Propylene Glycol Warshaw, T. G., and F. Herrmann Journal of Investigative Dermatology (Paper presented at 13th Annual Meeting of the Society for Investigative Dermatology, Inc., June 8, 1952), Vol. 19, pages 423-430, 20 references December 19 Clinical studies of skin reactions to propylene glycol have been reported in which undiluted propylene glycol produced positive patch test reactions in 138 (nearly 16 percent) of 866 subjects attending the clinic because of various allergic or possibly allergic dermatoses. Although it was not possible to decide whether the positive reactions were due to specific sensitizaiton, it appeared more likely that they were caused by pr i mar-y i r-r i t at 4on. I t i s suggested that ex cessi ve dehydrat i on of skin may be an important •factor predisposing to the reactions. In conformity with this assumption, the incidence of inflammatory responses was at its minimum during the hot and humid season, and high during periods of low environmental temperature and humidity, when there is normally a greater tendency to dehydration of the skin's surface tissues. Similarly, a distinct reduction in the intensity of the patch test response was observed in 2 of 3 subjects tested after stimulation of sweating by exposure to heat. (Discussions with Dr. Warshaw's replies appear following the article.)

19/7/25 ^2554 hdIQSH-<_~i~t)u14 ~ The General F'ropert i es, Act i ons, and To>, i c i ty of Rropyl ene Glycol Seidenfeld, M. A., and P. J. Hanzl i Et Journal of Pharmacology and Experimental Therapeutics, Vol. 44, pages 109-121, 6 references 1932 The general properties, irritant and toxic actions of propylene glycol are discussed and compared with ethylene glycol from the standpoint of its usefulness, and its substitution for ethylene glycol, as a vehicle and solvent -For pharmaceutical prepar-ations in medicine. In experimental and clinical studies, propylene glycol caused a moderate, though fleeting, local irritation of mucosae, and in the muscles and subcutaneous tissues of rats, rabbits and men, the irritation more marked than that of ethylene glycol and glycerol. This action is due to hyper- tonicity. In rats and rabbits, the symptoms of toxicity were characterized by general motor depression, increased respiratory rate, followed by tremors, coma and death after the largest doses. The continued drinking of 1, 2, 5, and 10 percent solutions in water of propylene glycol by rats during about one-eighth of the normal span of life caused no demonstrable effects on growth and body weight. Practically no pathological changes in the viscera examined were demonstrated. As a solvent and vehicle, propylene glycol offers generally all the advantages of ethylene glycol, and at the same time, it is much less toxic and causes no demonstrable cumulative effects, at least in animals. It remains to be demonstrated an a much larger scale if the apparently somewhat greater local irritation of the propylene glycol might outweigh the apparent advantages of low systemic toxicity in its general use as a vehicle and solvent in medicine and pharmacy. I

19/7i";=7 i_rt_a? 1?5- Pd I OcH-s )i ~i ~h 1415 Tests for the Chronic Toxicity of Propylene Glycol and Triethylene Glycol on Monkeys and Rats by Vapor Inhalation and Oral Administr ation Robertson, O. H., C. G. Loosl i, T. T. Puck, H. Wise, H. M. Lemon, and W. Lester, Jr. Journal of Pharmacology and Experimental Therapeutics, Vol. 91, pages 52-76, 27 references September 1947 With a view to determining the safety of employing the vapors of propylene glycol and triethylene glycol in atmos- pheres inhabited by human beings, experimental monkeys and rats were exposed continuously to high concentrations of these vapors for periods of 12 to 18 months. Equal numbers of control animals were maintained under physically similar conditions. Long term tests of the effects on ingesting triethylene glycol were also carried out. The doses administered represented 50 to 700 times the amount of glycol the animal could absorb by breathing air saturated with the glycol. Com- parative observations on the growth rates, blood counts, urine examinations, kidney function tests, fertility and general conditions of the test and control groups, exhibited no essential differences between them with the exception that the rats in the glycol atmospheres exhibited consistently higher weight gains. Some drying of the s~::in of the monkeys' faces occiirred after several months continuous exposure to a heavy fog of triethylene glycol. However, when the vapor concentration was maintained just below saturation by means of the glycostat this effect did not occur. Examination at autopsy likewise failed to reveal any differences between the animals kept in g.lycolized air and those living in the ordinary room atmosphere. Extensive histological study of the lungs was made to ascertain whether the glycol had produced any generalized or local irritation. None was found. The kidneys, liver, spleen and bone rnarrow also were normal. The results of these experiments in conjunction with the absence of any observed ill effects in patients exposed to both triethylene glycol and propylene glycol vapors for months at a time, provide assurance that air containing these vapors in amounts up to the saturation point is completely harmless.

19/7/'28 0021313. IVIOSH-00060780 To;: i ci ty of Fropyl ene 61 ycol Weatherby, J. H., and H. B. Haag Journal of the American Pharmaceutical Association, Vol. 27, pages 466-471, 8 references June 19_8 This experimental study examined the toxicity of propylene glycol. In rats the acute Average Fatal Dose of propylene glycol was f ound to be 33.5 gm per kg oral l y, 2-12. 5 gm subcutaneousl y, 14 gm intramuscularly and 6.8 gm intravenously. These figures are in agreement with those reported by other authors, with the exception of the intravenous fatal dose, which issomewhat less than half that reported by other authors. In rabbits the acute Average Fatal Dose on intravenous administration was found to be 6.5 gm per kg. The chronic toxicity of propylene glycol was st!tdied by the administration of the material to growing rats by way of their drinking water. Concentrations of ?"l% or less caused no appreciable change in rate of growth. A concen- tration of 1c_i% caused a temporary slowing 'in rate of growth which lasted for about ten days. Rate of growth after this initial slowing became essentially normal. No significant changes were found on microscopic examination of organs of these animals sacrificed at the end of the experimental period of 100 days. Hematuria was observed following the intravenous administration of sublethal doses of propylene glycol to rats. Hemolysis was produced in vitro by both diethylene glycol and propylene glycol in concentrations greater than 0.14 molar. This in vitro action seems to be due to the dilution of isosmotic sodium chloride solution with the osmotically inactive glycol solution, rather than to a specific hemolytic action of these glycols in the dilutions used. 19/7/29 0021162 N I OSH-0cJ0f,1 388 Chronic Toxicities of Propylene Glycol, Ethylene Glycol, Diethylene Glycol, Ethylene Glycol Monoethyl Ether and Diethylene Glycol Monoethyl Ether Morris, H. J., A. A. Nelson, and H. O. Calvery Journal of Industrial Hygiene and Toxicology, Vol. 24, No. 8, page 158, 1 reference October 1942 Chronic ta>;icities of propylene glycol, ethylene glycol, diethylene glycol, ethylene glycol monoethyl ether, and diethylene glycol monoethyl ether have been experimentally determined in rats. Rats were given the compounds (1-' percent in their diets) for two years. Propylene glycol did no apparent harm. Ethylene glycol and diethylene glycol produced numerous k:idney stones which consisted principally of calcium oxalate. About two-thirds of the rats receiving ethylene glycol monoethyl ether showed marked testicular enlargement, edema, and tubular atrophy. This condition occurred less frequently in the group, given diethylene glycol monoethyl ether, and only occasionally in the other experimental groups. (Only an abstract excerpted from Chemical Abstracts is presented in the Journal of Industrial Hygiene and Toxicology; the original article appeared in the Journal of Pharmacology, Vol. 74, 1942.) 88698252

1917i=:c_> 0020959 N I OSI-t-0i ro60790 Toxicity, Fats and Excretion of Propylene Glycol and Some Other Glycols Hanzlik, F'. J., H. W. Newman, W. Van Winkle, Jr., A. J. Lehman, and N. f::. Kennedy Journal of Pharmacology and Experimental Therapeutics, Vol. 67, pages 101-113, 6 references September 1939 Experimental studies were made on animals to determine the toxicity, fate, and excretion of propylene glycol as well as to determine the toxicity of other glycols. Very large doses of propylene glycol and dipropylene glycol act as central nervous depressants; these glycols are devoid of demon- strable toxicity when administered in smaller, though still large, doses for prolonged periods. While large single doses of ethylene glycol and diethylene glycol lack the central depressant action, repeated moderate doses of these glycols cause mar k:ed degenerat i on of the l i ver and k: i dneys wi th a fatal outcome. Accordingly, only the propylene glycol is suitable, at present, for internal or systemic use with food and medicinal products, without demonstraable hazards to health. The dipropylene glycol merits further investigation.