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    PROPAN-1-OL (n-PROPANOL)

    Explanation

         This extraction solvent was evaluated for acceptable daily intake
    for man by the Joint FAO/WHO Expert Committee on Food Additives in
    1980 (see Annex, Ref. 54). No toxicological monograph was issued.

         Since the previous evaluation, data have become available and are
    summarized and discussed in the following monograph.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

    Metabolism

         Orally administered n-propanyl alcohol is rapidly absorbed. In
    a study in rats, the rate of metabolism was 510 (8.5 mmol) kg/h with
    complete elimination from the blood, five hours post-dosing (Beauge et
    al., 1979). Metabolites identified include 1-propanaldehyde,
    1-propionic acid, as well as acetaldehyde and acetic acid (Rietbrock &
    Abshagen, 1971; Saito, 1975). Alcohol dehydrogenase (Auty & Branch,
    1976) and possibly catalase (Vatsis & Schulman, 1975) are involved in
    this metabolic process.

    Effects on enzymes and other biochemical parameters

         Varying biochemical effects of n-propyl alcohol have been
    investigated including swelling of mitochondria (Thore &
    Baltscheffsky, 1965), stimulation of erythrocyte peroxidation
    (Giannitsis, 1977), and disruption of their membranes (Slobozhanina et
    al., 1975), decreases in polypeptide chain elongation (Igarashi et
    al., 1975), increases in adenylate cyclase activity (Stock & Schmidt,
    1978), depletion of cerebral calcium levels (Ross, 1976), decreases in
    myocardial potassium levels (Golovinskaya, 1976), and degradation of
    myelin sheaths (Rumsby & Finean, 1966). n-propyl alcohol has been
    found to increase triglyceride levels in the liver of rats (Gaillard &
    Derache, 1966; Beauge et al., 1974, 1979). Alteration of the cell
    cycle and decreases in fibroblast proliferation have been reported at
    subtoxic concentrations (Blanquet & Collyn-d'Hooghe, 1979).
    Cytotoxicity to cultured neuroblastoma cells and various water
    organisms has also been described (Koerker et al., 1976; Canton &
    Adema, 1978).

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

         n-propyl alcohol was found to be inactive when tested at high
    concentrations in the Ames assay in Salmonella typhimurium strain
    TA-100 (Stolzenberg & Hine, 1979). In another Ames assay this alcohol
    was negative for mutagenic activity in strains TA-1535, TA-1537,
    TA-1538, TA-98 and D4 with or without the rat liver activation system
    (Litton Bionetics, 1978a). It did not increase mutations at the TK
    locus in L5178Y mouse lymphoma cells with or without activation at
    doses up to 12.5 Ál/ml (Litton Bionetics, 1978b). It was found to
    inactivate E. coli CA 274 in a concentration-dependent manner and to
    increase the reverse mutation rate (Hilscher et al., 1969).

    Acute toxicity
                                                                 

                              LD50
    Animal     Route        (g/kg bw)            Reference
                                                                 

    Mouse      Oral       4.5 g/kg         Weese, 1928

    Rat        Oral       5.4 g/kg         McNerney et al., 1962

               Oral       6.65 ml/kg       Golovinskaya, 1976

               Oral       1.9 g/kg         Smyth et al., 1954

               i.p.       MLD 4.0 ml/kg    Lendle, 1928

    Rabbit     Dermal     6.7 g/kg         McNerney et al., 1962

               Dermal     5.0 ml/kg        Smyth et al., 1954

               Oral       MLD 3.5 ml/kg    Munch & Schwartze, 1925

               i.v.       MLD 4.0 ml/kg    Lehman & Newman, 1937

    Cat        i.v.       MLD 1.6 ml/kg    Macht, 1920
                                                                 

         The signs of n-propyl alcohol intoxication in animals exposed
    to sufficient concentrations of the vapour include: irritation of the
    mucous membranes, ataxia, lethargy, prostration, narcosis, and death
    (Treon, 1963). Rats exposed to a minimum of 20 000 ppm (2%) of
    n-propyl alcohol in air for one hour survived the exposure and a 14-
    day observation period. Weight gain was reduced, however, no gross
    lesions were observed upon necroscopy (McNerney et al., 1962).

    Short-term studies

    Rat

         Groups of four-month old male Wistar rats were given a 1 M
    solution of n-propyl alcohol in water as their sole drinking fluid
    for four months. Lower weight gain to caloric intake ratio was
    observed in the dosed versus water control animals. The animals were
    killed and their livers examined histologically. No inflammation,
    cirrhosis, or other effects were noted (Teshke et al., 1974). In a
    similar study, albino rats were given 1 or 2 M solutions of n-propyl
    alcohol as their drinking water for several months. At necroscopy no
    liver effects were observed but in some animals Mallory's alcoholic
    hyaline bodies were seen (Hillbom et al., 1974).

    Long-term studies

    Rat

         Groups of Wistar rats were given n-propyl alcohol s.c.
    (0.06 ml/kg) and p.o. (0.3 ml/kg) twice per week from 10 weeks of age
    until death. Liver carcinomas and sarcomas, spleen sarcomas,
    proventricular carcinomas, and myeloid leukaemias were observed.
    Control rats were only subject to proventricular papillomas and
    mammary fibroadenomas. Malignant tumours were produced in 5/18 rats
    treated p.o. and in 15/31 rats treated by the s.c. route (Gibel et
    al., 1974, 1975). However, because of the limited data available for
    this study, it does not provide a basis for evaluating the
    carcinogenic potential of n-propanol.

    OBSERVATIONS IN MAN

         One fatal case of poisoning by ingestion of 400 to 500 ml of
    n-propyl alcohol has been reported and was reviewed by Browning
    (1965). No industrial instances of poisoning or epidemiological
    studies could be identified in the literature. The current TLV is
    200 ppm (0.02%) (Amer. Conf. Gov. Ind. Hyd,, 1980).

    Comments

         n-propyl alcohol is rapidly absorbed and metabolized.
    Metabolites identified include 1-propanaldehyde, 1-propionic acid, as
    well as acetaldehyde and acetic acid. In a short-term study, propyl
    alcohol in the water of rats caused no liver damage. Life-time
    administration of n-propanol to the Wistar rat by oral or
    subcutaneous routes was stated to result in a marked increase in the
    incidence of malignant tumours. However, because of the very limited
    data available for this study, it does not provide a basis for
    evaluating the carcinogenic potential of n-propanol. n-propyl
    alcohol has been shown to be inactive in Ames assay with and without
    activation, and in the mouse lymphoma cell system.

    EVALUATION

    No ADI allocated.

    FURTHER WORK OR INFORMATION

         Life-time feeding studies in two rodent species at appropriate
    dose levels.

    REFERENCES

    American Conference of Governmental Industrial Hygienists (1980) TLVs
         Threshold Limit Values for Chemical Substances and Physical
         Agents in the Workroom Environment with Intended Changes for
         1980, PO Box 1937, Cincinnati, OH 45201, ACGIH, 1980

    Auty, R. M. & Branch, R. A. (1976) The Elementation of Ethyl, n
         Propyl, n-Butyl and Iso-amyl Alcohols by the Isolated Perfused
         Rat Liver, J. Pharmacol. Exp. Ther., 197, 669-674

    Beauge, F. et al. (1974) Pentunbatrons of the Hepatic Metabolism of
         Palmitate-1-14C Induced in Rat by Administration of Propanol,
         Biochimie (Paris), 56 (8), 1157-1160

    Beauge, F. et al. (1979) Comparative Effects of Ethanol in
         n-Propanol and Iso-Propanol on Lipid Disposal by Rat Liver,
         Chem. Biol. Interact., 26, 155-166

    Blanquet, P. R. & Collyn-d'Hooghe, M. (1979) Effect of Cl-C8 n
         Alcohols on the Growth of 3T2 Mouse Fibroblasts, C. R. Hebd.
         Seances Acad. Sci., Ser. D., 288, 449-452

    Browning, E. (1965) "Toxicity and Metabolism of Industrial Solvents",
         Elsevier Publishing Company, N.Y., pp. 332-334

    Canton, J. H. & Adema, D. M. M. (1978) Reproducibility of Short-term
         and Reproduction Toxicity Experiments with Daphnia magna and
         Comparison of the Sensitivity of Daphnia magna with Daphnia
         pulex and Daphnia Circullata in Short-term Experiments,
         Hydrobiologia, 59, 135-140

    Gaillard, D. & Derache, R. (1966) Action de Quelques Alcools
         Aliphatiques sur la Mobilisation de Differentes Fractions
         Lipidiques chez les Rats, Food Cosmet. Toxicol., 4, 515-520

    Giannitsis, D. J. (1977) Alcohols - Histones Metabolic Interactions in
         Intact Human Erythrocytes, Arzneim.-Forsch., 27, 1595-1597

    Gibel, W., Lohs, K. & Wildner, G. P. (1975) Carcinogenic Activity of
         Propanol, 2-Methyl-1-Propanol, and 3-Methyl-1-Butanol, Arch.
         Geschwulstforsch., 45, 19-24

    Gibel, W. et al. (1974) Experimental Studies on the Carcinogenic
         Effect of Higher Alcohols, as Illustrated by 3-Methyl-1-Butanol,
         1-Propanol and 2-Methyl-1-Propanol, Z. Exp. Chir. Forsch., 7,
         235-239

    Golovinskaya, L. I. (1976) Water & Electrolyte Metabolic Disturbances
         in Poisoning by Home Brew and Higher Alcohols, Sud.-Med.
         Ekspert., 19, 33-35

    Hillbom, M. E., Franssila, K. & Forsander, O. A. (1974) Effects of
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         Res. Commun. Chem. Pathol. Pharmacol., 9, 177-180

    Hillbom, M. E., Franssila, K. & Forsander, O. A. (1974) Effects of
         Chronic Ingestion of Some Lower Aliphatic Alcohols in Rats,
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    Hilscher, H. et al. (1969) Toxicity and Mutagenicity of Single Fusel
         Oil Components on Escherichia coli, Acta Bio. Med. Ger.,
         23, 843-852

    Igarashi, K. et al. (1975) Effect of Alcohols on Polypeptide Chain
         Elongation and Aminoacyl-tRNA Formation, J. Biochem. (Tokyo),
         78, 981-987

    Koerker, R. L., Berlin, A. J. & Schneider, F. H. (1976) The
         Cytotoxicity of Short-Chain Alcohols and Aldehydes in Cultured
         Neuroblastoma Cells, Toxicol. Appl. Pharmacol., 37, 281-288

    Lehman, A. J. & Newman, H. W. (1928) Comparative Intravenous Toxicity
         of Some Monohydric Saturated Alcohols, J. Pharmacol. Exptl.
         Therap., 61, 103-106

    Lendle, L. (1928) Beitrag yur Allgemeinen Phaxma-hologie der Narkose:
         Uber die Narkotische Breite, Arch. Exptl. Pathol. Pharmacol.,
         132, 214-245

    Litton Bionetics (1978) Mutagenicity Evaluation of Normal Propyl
         Alcohol in the Mouse Lymphoma Forward Mutation Assay Final Report
         to Celanese Corporation, N.Y., Litton Bionetics, Inc.,
         Kensington, MD 20795

    Litton Bionetics (1978) Mutagenicity Evaluation of Normal Propyl
         Alcohol in the Ames Salmonella/Microsome Plate Test Final Report
         to Celanese Corporation, N.Y., Litton Bionetics, Inc.,
         Kensington, MD 20795

    Macht, D. (1920) A Toxicological Study of Some Alcohols with Special
         References to Isomers, J. Pharmacol. Exptl. Therap., 16, 1-10

    McNerney, J. M. et al. (1962) Report on Rangefinding Toxicity Testing
         on Normal Propanol, Industrial Hyg. Foundation of America, Inc.,
         Mellon Institute, Pittsburgh, PA

    Mikheev, M. I. & Frolova, A.D. (1978) Toxico Kinetics of Certain
         Representatives of a Homologous Series of Alcohol, Gig. Sanit.,
         6, 33-37

    Munch, J. C. & Schwartze, E. W. (1925) Narcotic and Toxic Potency of
         Aliphatic Alcohols Upon Rabbits, J. Lab. Clin. Med., 10,
         985-996

    Rietbrock, V. N. & Abshagen, U. (1971) Pharmacokinetics and Metabolism
         of Aliphatic Alcohols, Arzneim.-Forsch., 21, 1309-1319

    Ross, D. H. (1976) Selective Action of Alcohols on Cerebral Calcium
         Levels, Ann. N.Y. Acad. Sci., 273, 280-294

    Rumsby, M. G. & Finean, J. B. (1966) The Action of Organic Solvents on
         the Myelin Sheath of Peripheral Nerve Tissue. II.
         J. Neurochem., 13, 1509-1511

    Saito, M. (1975) Metabolism of Lower Alcohols, Nichidai Igaku
         Zasshi, 34, 569-585

    Slobozhanina, E. I. et al. (1975) Effect of Aliphatic Alcohols on the
         Structure of Erythrocyte Membranes, Vestsi Akad. Navuk B. SSR
         Ser. Biyal. Navuk, issue 4, pp. 44-48

    Smyth, H. F. jr, Carpenter, C. P. & Weil, C. S. (1954) Range-finding
         Toxicity Data, Arch. Ind. Hyg. Occup. Med., 10, 61-69

    Stock, K. & Schmidt, M. (1978) Effect of Short-chain Alcohols on
         Adenylate Cyclose in Plasma Membranes of Rat Adipocytes,
         Naunyn-Schmiedeberg's Archiv. Pharmacol., 302, 37-43

    Stolzenberg, S. J. & Hine, C. H. (1979) Mutagenicity of Hologenated
         and Oxygenated Three-carbon Compounds, J. Toxicol. Environ.
         Health, 5, 1149-1158

    Strange, A. W., Schneider, C. W. & Goldbort, R. (1976) Selection of C3
         Alcohols by High & Low Ethanol Selecting Mouse Strains and the
         Effects on Open Field Activity, Pharmacol. Biochem. Behav.,
         4, 527-530

    Thore, A. & Baltscheffsky, H. (1965) Effect of Lower Aliphatic
         Alcohols on Mitochondrial Structure, Acta Chem. Scand., 19,
         1975-1985

    Treon, J. F. (1963) In: Patty, F. A. ed. "Industrial Hygiene and
         Toxicology", Vol. II, n-Propyl Alcohol, Interscience
         Publications, Wiley & Sons, Inc. N.Y. pp. 1434-1435

    Teshke, R., Hasumura, Y. & Lieber, C. S. (1974) Biochem. Biophys.
         Res., Comm., 60, 851

    Vatsis, P. K. & Schulman, M. P. (1975) Oxidation of Alcohols by Mouse
         Hepatic Microsomes, The Pharmacologist, 17, 241

    Weese, H. (1928) Vergleichende Untersuchungen Uber die Wirksamkeit
         und Griftigkeit der Dampfe Niederer Aliphatischer Alkohole,
         Arch. Exptl. Pathol. Pharmacol., 135, 118-130

    World Health Organization (1980) WHO Evaluation of Certain Food
         Additives, Twenty-third Report of the Joint FAO/WHO Expert
         Committee on Food Additives, WHO Techn Rep. Ser., No. 648
    


    See Also:
       Toxicological Abbreviations