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    FAO Nutrition Meetings 
    Report Series No. 48A 
    WHO/FOOD ADD/70.39




    TOXICOLOGICAL EVALUATION OF SOME
    EXTRACTION SOLVENTS AND CERTAIN 
    OTHER SUBSTANCES




    The content of this document is the 
    result of the deliberations of the Joint 
    FAO/WHO Expert Committee on Food Additives 
    which met in Geneva, 24 June  -2 July 19701




    Food and Agriculture Organization of the United Nations
    World Health Organization


                   

    1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
    Org. techn. Rep. Ser., in press.


    PROPAN-2-OL

    Biological Data

    Biochemical aspects

         When 65-90 ml of CH3CHOH CH3 were administered to 3 dogs, 55-71
    mg per cent. were excreted as acetone, 120-134 mg per cent. were
    excreted unchanged in the urine. 28-29 mg acetone and 63-70 mg
    unchanged material were excreted in the faeces (Kemal, 1937). Dogs
    oxidise iso-propyl alcohol at a rate of 0.001 per cent. per minute and
    this reaction is probably quantitative (Neymark, 1948). I.v.
    administered iso-propyl alcohol disappears from the blood of dogs at
    inconstant rate and much appears in urine, saliva and stomach (Lehman
    et al., 1944). I.v. and i.p. administered propan-2-ol is excreted
    twice as fast by the rat as by the dog (Abshagen & Rietbrock, 1969).
    Dogs absorb it rapidly from the intestine but slowly from the stomach
    and metabolise it at a rate proportional to the concentration
    (Browning, 1965). Instillation of iso-propyl alcohol into isolated
    loops of dog intestine showed that absorption occurs from all
    positions of the G.I. tract and quickly distributes to all tissues and
    the C.S.F. 82% of absorption occurs within 30 minutes (Wax et al.,
    I949). Single oral doses of 4 or 6 g/kg iso-propyl alcohol given to
    rats considerably increase liver triglycerides but cholesterol and
    phospholipids levels are not effected. The blood lipid fractions were
    not affected (Gaillard & Derache, 1966).

         Ingestion of 720 mg iso-propyl alcohol by man produced 335.9 mg
    of iso-propyl alcohol (46.7 per cent.) and 17.1 mg acetone in the
    exhaled air over a period of 3 hours (Hahn, 1937). Iso-propyl alcohol
    is secreted by the salivary glands and by the gastric mucosa in man
    (Juncos & Taguchi, 1968). I.v. injected iso-propyl alcohol in cats,
    rabbits, rats and pigeons was cleared at rates for rabbit, rat and
    pigeon, indicating initial rapid metabolism while the cat appears to
    have a constant rate of metabolism (Lelman et al., 1945). Rabbits
    excrete 10 per cent. of the dosage as glucuronide (Kamil, 1953) and
    excrete acetone in the urine for up to 72 hours after a single large
    oral dose (Morris & Lightbody, 1938).

         Alcohol dehydrogenase probably also converts iso-propyl alcohol
    to acetone and then to acetate, formate, CO2, etc. There is no
    cumulation (Williams, 1959). Iso-propyl alcohol given intragastrically
    to rats, rabbits and cats raised the convulsion threshold thus acting
    as anticonvulsant (Chue et al., 1948).

    Acute toxicity

                                                                                              

                                  LD50           LD100
    Animal         Route          mg/kg          mg/kg          References
                                  body-weight    body-weight
                                                                                          

    Mouse          oral           -              4970           Spector, 1956
                   oral           -              6.0-7.6 ml     Browning, 1965
                   s.c.           -              6000           Spector, 1956
                   s.c.           -              7.6 ml         Browning, 1965
    Rat            oral           5840           -              Spector, 1956
                   oral           6.73 cc        -              Lehman & Chase, 1944
    Guinea-pig     i.p.           -              5 ml           Keil, 1953
    Rabbit         oral           -              5000           Spector, 1956
                   oral           -              10ml           Browning, 1965
                                                                Browning, 1965
                   oral           6.41 cc        -              Lehman & Chase, 1944
                   cutaneous      16.4 cc        -              Spector, 1956
                   i.v.           -              8.2 mil        Oxygenated Solvents, 1964
                                                                Lelunan & Chase, 1944
    Cat            i.v.           -              1962.5         (Spector, 1956 Macht, 1920
    Dog            oral           6.15 cc        -              Lehman & Chase, 1944
                   i.v.           -              5.1 Ml         Oxygenated Solvents, 1964
                                                                (Lehman & Chase, 1944
    Man            oral           -              166 ml         Oxygenated Solvents, 1964
                                                 (estimated)
                                                                                          
    
         The acute toxic effects of iso-propyl alcohol are similar to
    those of ethyl alcohol but it is 1.5 to 2 times as toxic as ethyl
    alcohol (Browning, 1965). Sublethal doses produced no delayed toxic
    effects in rats, rabbits and dogs (Lehman & Chase, 1944). 5 rats
    injected s.c. daily with 0.23 cc/kg iso-propyl alcohol for 1 week
    showed slight parenchymatous hepatic degeneration (Abreu et al.,
    1944). Reversible fatty changes have been reported in the liver of
    mice after repeated inhalation (Weese, 1928).

    Short-term studies

    Rat. Seven groups of 5 male or 5 female rats received in their
    drinking water either 0 per cent. (male and female), 0.5 per cent.
    (males), 1.0 per cent. (females), 2.5 per cent. (males), 5.0 per cent.
    (females) or 10 per cent. (males) iso-propyl alcohol for 27 weeks. All
    animals at the 10 per cent. level died within 7 to 28 days. The
    females at 1 per cent. and 5 per cent. showed no gross abnormalities
    but there was some depression of growth and body-weight compared with
    controls. Two male rats at the 0.5 per cent. and 3 at the 2.5 per
    cent. level died from causes not related to the test substance. Growth

    and bodyweight was reduced during the first 13 weeks but increased
    during the remaining 14 weeks to exceed controls. Gross and
    histopathological examination of brain, pituitary, lung, heart, liver,
    spleen, kidneys and adrenals showed nothing of note related to the
    test substance (Lehman & Chase. 1944).

         In another experiment 8 rats received a 5 per cent. solution of
    iso-propyl alcohol as drinking water for 9 months. All drank less than
    controls. All showed some 23 per cent. reduction in body-weight
    compared with controls and developed noisy breathing after several
    months. When put on tapwater after 9 months all rats gained weight
    over the next 30 days. Noisy breathing disappeared (Boughton, 1944).

    Mouse. Three groups of 10, 27 and 49 mice of different strains
    received 20 or more s.c. injections of 0.025 ml iso-propyl alcohol
    over periods of 5 to 9 months. No difference was observed in the
    tumour incidence of tests and controls. Three groups of 36, 41 and 47
    mice of different strains were exposed to iso-propyl alcohol 5 days a
    week 7 hours a day by inhalation over 5 to 8 months. There was no
    significant difference in tumour incidence between test animals and
    controls (Weil et al., 1952).

    Cat. One cat was given 15.20 cc per cent. iso-propyl alcohol daily
    over 13 days. After each dose the cat became stuporous but recovered
    after some hours. At autopsy there was evidence of sub-acute gastritis
    and enteritis and some cloudy swelling of the kidneys. No eye signs
    were noted (Fuller & Hunter, 1927).

    Rabbit. Five rabbits were given 5, 10 or 15 cc iso-propyl alcohol
    daily over 28 days. The animals lost weight and at autopsy showed
    gastritis and enteritis (Fuller & Hunter, 1927).

    Chicken. One bird was given 10, 15 and 20 cc iso-propyl alcohol
    daily over 28 days. There was weight loss but recovery occurred after
    termination (Fuller & Hunter, 1927),

    Monkey. One monkey was given 13 doses of 5 cc 50 per cent.
    iso-propyl alcohol over 19 days. Mild intoxication and loss of
    appetite occurred. The eyes showed some temporary congestion. The
    animal survived but remained in poor health (Fuller & Hunter, 1927).

    Dog. Following a single i.v. injection of either 2.56 or 3.84 ml
    iso-propyl alcohol, three dogs were given fluid containing 1-4 per
    cent. iso-propyl alcohol during one month and then kept on 4 per cent.
    alcohol for a further six months. The dogs became inebriated once a
    day but then recovered. One dog lost weight over 7 months and died on
    retesting with i.e. injection of iso-propyl alcohol. At autopsy no
    evidence of pathological changes were seen. Only the animal which died
    showed some evidence of renal tubular necrosis and central
    haemorrhages in the brain. A second dog also showed a few capillary
    haemorrhages in the brain (Lehman et al., 1945). In another experiment
    one dog was given 30 cc or 50 per cent. iso-propyl alcohol daily over
    10 days. The animal uncoordinated for 10 minutes but developed

    tolerance later. No ophthalmological changes were seen (Fuller &
    Hunter, 1927).

    Reproduction studies

    Rat. Six female and three male rats were given 2.5 per cent,
    iso-propyl alcohol in their drinking water for 80 days and then mated
    on 6 occasions. Four litters with 44 pups were produced as the F1
    generation. 13 F1 females produced 11 litters with 66 pups as the F2
    generation. The growth rate of the second generation when given 2.5
    per cent. iso-propyl alcohol as drinking water was no different from
    controls on water. There was some growth depression of the F1
    generation if given iso-propyl alcohol during the early post natal
    period only (Lehman ef al,, 1945).

    Special studies

         0.05 or 0.1 ml of undiluted iso-propyl alcohol were injected into
    the yolk sac of fertile hens eggs and subsequently incubated.
    Hatchability was reduced to 35% and 15% of normal but no deformities
    were noted in the chicks (McLaughlin et al., 1963). 19.5, 39 and 78
    mg/egg injected into the yolk sac prior to incubation resulted in
    hatches of 65, 35 and 5% of normal respectively (McLaughlin ef al.,
    1964).

         0.05 ml of iso-propanol was injected into fertile hens eggs and
    reduced the survival of embryos to 24% (Walker, 1967).

         Fertile hen eggs injected with 0.05 ml after 5 days incubation
    resulted in a 33% hatch. Unincubated eggs immersed for 2/3 their
    length for 10 seconds in 50%, aq. v.v. iso-propyl alcohol were
    unaffected, but 5 day incubated eggs treated similarly showed a 50%
    reduction in hatchability (Clegg, 1964).

         0.05 ml of iso-propanol was injected into fertile hens eggs and
    reduced the survival of embryos to 24% (Walker, 1967).

    Human observations

         4 subjects received either single doses of 0.1, 0.25, 0,5, 1, 2,
    2.5, 5, 10  20 g or 3 times 5 g iso-propyl alcohol acetone was found
    in the urine and the expired air but it accounted only for a few per
    cent. of intake (Kemal, 1927).

         Five men drank 30 ml of 50 per cent. iso-propyl alcohol daily on
    three consecutive days after various test doses one month previously
    and two females drank one dose of 30 ml of 50 per cent. iso-propyl
    alcohol. The immediate effects were a fall in B.P. and dizziness. Five
    experienced headaches. No untoward effects on vision were noted.
    Acetone occurred in the urine within 24 hours and disappeared after 24
    hours (Fuller & Hunter, 1927). Inhalation of 400 ppm is irritating
    mildly but is regarded as the TLV (Browning, 1965). Groups of 8 men
    drank 0, 2.6 mg/kg or 6.4 mg/kg iso-=propyl alcohol daily for six

    weeks. No significant changes occurred in the chemical or cellular
    composition of blood and urine, liver function tests remained
    unaffected, there were no ophthalmological changes (Wills et al.,
    1969).

         Ingestion by man of 22.5 ml produced no exhilaration, but
    dizziness, salivation, flushed face, muscular and nervous disturbance
    and prolonged headache (Thompson, 1938). Acute intoxication has been
    reported to cause myopathy, renal failure and haemolytic anaemia
    (Juncos & Taguchi, 1968). The TLV is 400 ppm (Amer. Conf. Gov, Ind.
    Hyg., 1969).

    Long-term studies

         None available bat a 2-year study in rats at levels of 0, 0.31
    per cent., 0.625 per cent., 1.25 per cent. and 2.5 per cent. in the
    drinking water is being carried out at BIBRA in the United Kingdom.

    Comments

         A human study extending over six weeks points to a tolerated
    daily intake of about 350 mg/day for adults. However, the
    establishment of an ADI will have to await the outcome of long-term
    oral studies now in progress in rats.

    Tentative Evaluation

         The use of this solvent should be restricted to that determined
    by good manufacturing practice, which is expected to result in
    residues unlikely to have any toxicological significance. It is
    recognized that the results of studies now in progress may permit a
    more extensive food additive use.

    REFERENCES

    Abreu, B. E. Auerbach, S. H. Thuringer, J. M. & Peoples, S. A. (1944)
    J. Pharm. exp. Ther., 80, 139

    Abshagen, U. & Rietbrock, N. (I9G9) Naunyn-Schmiedeberg's Arch.
    exp-Path. Pharmak., 264, 110

    Amer. Conf. Gov. Ind. Hyg. (1969) Threshold limit values for 1969

    Browning, E. (1965) The Toxicity and Metabolism of Industrial
    Solvents Elsevier, Amsterdam

    Boughton, L. L. (1944) J. Amer. Pharm. Assn., 33, iii

    Chu, N., Driver, R. L. & Hanzlik, P. J. (1948) J. Pharm. Exptl.
    Ther., 92, 291

    Clegg,D. J. (1964) Food Cosmet. Toxicol., 1, 717

    Fuller, H. C. & Hunter, B. (1927) J. Lab. Clin. Med., 12, 326

    Gaillard, D. & Derache, R. (1966) Fd. Cosmet. Toxicol., 4, 515

    Hahn, E. (1937) Biochem. Z.,  292, 148

    Juncos, L. & Taguchi, J. T. (1968) J.A.M.A., 204. 732

    Kamil, I. A. (1953) Biochem. J 53, 129

    Keil, R. (1953) Die Pharmamzie, 518

    Kemal, H. (1927) Bioch. Zschr., 187, 461

    Kewal, H. (1937) Z.physiol. Chemie, 246, 59

    Lehman, A. J. & Chase, H. F. (1944) J. Lab. Clin. Med., 29, 561

    Lehman, A. J., Schwerma, H. & Richards, E. (1944) J. Pharm. exp.
    Ther.,82, 196

    Lehman, A. J., Schwerma, H. & Richards, E. (1945)J. Pharm. exp.
    Ther.,85, 61

    Macht, D. I. (1920) J. Pharmac. Expt. Therap., 16, 1

    McLaughlin, J. Jr., Marliac, J.-P., Verrett, M. J., Mutchler, M. K. &
    Fitzhugh, O. G. (1963) Toxic. Appl. Pharmacol 5, 760

    Mclaughlin, J. Jr., Marliac, J.-P., Verrett, M. J., Mutchler, M. K. &
    Fitzhugh, O. G. (1964) Amer. Ind. Hyg. Ass. J., 25, 282

    Morris, H. J. & Lightbody, H. D. (1938) J. Ind. Hyg. Toxicol., 20,
    428

    Neymark, M. (1938) Skand. Arch. Physiol., 78, 242

    Oxygenated Solvents (1964) Handling Manual, Section XI

    Spector, W. S. (1956) Handbook of Toxicology, ed. by W. B. Saunders
    & Co.

    Thompson, W. G. (1938) cited by Morris & Lightbody, J. Ind. Hyg.
    Toxicol (1938)120, 428

    Walker, N.E. (1967) Toxic. Appl. Pharmacol., 10, 290

    Wax, J., Ellis, F. W. & Lehman, A. J. (1949) J. Pharm. exp. Ther.,
    97, 229

    Weese, H. (1928) Arch. Exper. Path. Pharmak., 135, 118

    Weil, C. S., Smyth, H. F. Jr. & Nale, T. W. (1952) A.M.A. Arch.
    Indust. Hyg., 5, 535

    Wills, J. H., Jameson, E. M. & Coulston, F. (1969) Toxicol. appl.
    Phamacol., 15, 560

    Williams, R.T. (1959) Detoxication Mechanisms. Chapman & Hall,
    London
    


    See Also:
       Toxicological Abbreviations