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    POLYETHYLENE GLYCOLS

    Explanation

         Includes polyethylene glycol 200, polyethylene glycol 300,
    polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol
    1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene
    glycol 4000, polyethylene glycol 6000, polyethylene glycol 9000, and
    polyethylene glycol 10 000.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         The G.I. absorption of a series of polyethylene glycols has been
    studied (Schaffer & Critchfield, 1947). Polyethylene glycols having
    average molecular weights of 4000 and 6000 showed no absorption from
    the rat intestine over a five-hour period, while polyethylene glycols
    of 1000 and 1540 molecular weights showed a slight absorption
    amounting to less than 2% of the total dose during the same period.

         When 1 g doses of polyethylene glycols of molecular weight 1000
    (PEG 1000) and 6000 (PEG 6000) were given intravenously to six human
    subjects, 85% of PEG 1000 and 96% of PEG 6000 were excreted in the
    urine in 12 hours. When these two same materials in 10 g doses were
    given orally to five human subjects, none of the PEG 6000 was found in
    the urine in the following 24 hours, whereas about 8% of PEG 1000
    administered was found to excrete in urine within 24 hours (Schaffer &
    Critchfield, 1947).

         When PEG 400 was given intravenously to three human subjects, an
    average of 77% recovery of this material was found in the urine in 12
    hours. However, when the same substance was given orally to the same
    three human subjects, a recovery of between 40 and 50% of the dose was
    determined in the urine in the course of the following 24 hours.
    Single oral doses of PEG 400 were incompletely recovered from urine
    and faeces of rabbits even when collection of excreta was continued as
    long as four days following the dose. Evidence from all these and
    other studies indicate that ethylene glycol is not formed as a
    metabolite of PEG 400 (Schaffer et al., 1950).

         Study of the excretion pattern of 14C-labelled PEG 4000 in rats
    revealed that this compound is so rapidly cleared after an intravenous
    dose of 10 mg (circa 70 mg/kg) that the major portion is excreted via
    the urine in 24 hours while peroral doses pass through the alimentary
    tract with but little absorption in a like interval. The mean
    cumulative, 7-day recovery after I.V. injection by tail vein in rats
    was 81%. Of this, 61% appeared in the urine, none in the exhaled CO2,
    and 20% in the faeces. Peroral administration to rats resulted in a
    mean 7-day cumulative recovery of 86%. Only 4.1% appeared in the
    urine, none in the CO2, and the remainder was eliminated in the
    faeces (Carpenter et al., 1971).

         The renal clearance rates of a series of polyethylene glycols
    ranging from 400 and 6000 molecular weights have been determined in
    the dogs. The PEG 400, 1000, 1540 and 4000 are cleared from the plasma
    at a rate identical with that of creatinine in the normal, lightly
    anaesthetized animals (Schaffer & Critchfield, 1947).

         The polyethylene glycols in general appear to be slow-acting
    parasympathomimetic-like compounds (Smyth et al., 1950). When they are
    given intravenously, they tend to increase the tendency of the blood
    to clot and if given rapidly cause clumping of the cells and death
    occurs from embolism.

         Prolonged skin contact of PEG 1500 and 4000 upon the skin of
    rabbits in dosages of 10 g/kg bw showed no deleterious effects on
    internal organs and little, if any, of the materials was absorbed
    through the skin (Smyth et al., 1950).

    TOXICOLOGICAL STUDIES

    Acute toxicity

    Polyethylene glycol 200 (undiluted)

                                                                        

                               LD50
    Animal          Route      (g/kg bw)     References
                                                                        

    Mouse           Oral       33.90         Union Carbide, 1965
    Mouse           I.P.       11.80         Union Carbide, 1965
    Rat             Oral       28.90         Union Carbide, 1965
    Rat-male        Oral       34.00         Union Carbide, 1965
    Rat-female      Oral       28.25         Union Carbide, 1965
    Guinea pig      Oral       16.90         Union Carbide, 1965
      -female
    Rabbit-male     Oral       14.10         Union Carbide, 1965
                                                                        

    Polyethylene glycol 300 (undiluted)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       31.00          Union Carbide, 1965
    Mouse               I.P.       10.40          Union Carbide, 1965
    Rat                 Oral       31.70          Union Carbide, 1965
    Rat-male            Oral       29.90          Union Carbide, 1965
    Rat-female          Oral       29.20          Union Carbide, 1965
    Rat                 I.P.       17.00          Union Carbide, 1965
    Guinea pig-male     Oral       21.10          Union Carbide, 1965
    Rabbit-female       Oral       21.10          Union Carbide, 1965
                                                                        

    Polyethylene glycol 400 (undiluted)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       35.6           Smyth et al., 1941
    Mouse               I.P.       12.9           Union Carbide, 1965
    Rat                 Oral       43.6           Union Carbide, 1965
    Rat-male            Oral       32.6           Smyth et al., 1941
    Rat-female          Oral       32.5           Smyth et al., 1941
    Guinea pig-female   Oral       21.3           Smyth et al., 1941
    Rabbit-male         Oral       22.3           Union Carbide, 1965
                                                                        

    Polyethylene glycol 600 (undiluted)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       35.6           Union Carbide, 1965
    Mouse               I.P.       10.2           Union Carbide, 1965
    Rat                 Oral       38.1           Union Carbide, 1965
    Rat-male            Oral       32.6           Union Carbide, 1965
    Rat-female          Oral       30.5           Union Carbide, 1965
    Guinea pig-female   Oral       28.3           Union Carbide, 1965
    Rabbit-male         Oral       18.9           Union Carbide, 1965
                                                                        

    Polyethylene glycol 1000 (as a 50% solution in water)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       >50.0          Union Carbide, 1965
    Mouse               I.P.       3.1            Union Carbide, 1965
    Rat                 Oral       42.0           Union Carbide, 1965
    Rat-male            Oral       44.7           Union Carbide, 1965
    Rat-female          Oral       32.0           Union Carbide, 1965
    Rat                 I.P.       15.6           Union Carbide, 1965
    Guinea pig-female   Oral       41.0           Union Carbide, 1965
    Rabbit-female       Oral       >50.0          Union Carbide, 1965
                                                                        

    Polyethylene glycol 4000 (as a 50% solution in water)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       >50.0          Union Carbide, 1965
    Mouse               I.P.       10.7           Union Carbide, 1965
    Rat                 Oral       >50.0          Union Carbide, 1965
    Rat                 I.P.       \13.0           Union Carbide, 1965
    Rat-male            Oral       >50.0          Union Carbide, 1965
    Rat-female          Oral       >50.0          Union Carbide, 1965
    Guinea pig-female   Oral       46.4           Union Carbide, 1965
    Rabbit-male         Oral       >50.0          Union Carbide, 1965
                                                                        

    Polyethylene glycol 6000 (as a 50% solution in water)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       >50.0          Union Carbide, 1965
    Mouse               I.P.       5.9            Union Carbide, 1965
    Rat                 Oral       >50.0          Union Carbide, 1965
    Rat                 I.P.       6.8            Union Carbide, 1965
    Rat-male            Oral       >50.0          Union Carbide, 1965
    Rat-female          Oral       >50.0          Union Carbide, 1965
    Guinea pig-female   Oral       >50.0          Union Carbide, 1965
    Rabbit-male         Oral       >50.0          Union Carbide, 1965
                                                                        

    Polyethylene glycol 9000 (as a 50% solution in water)

                                                                        

                                   LD50
       Animal           Route      (g/kg bw)      References
                                                                        

    Mouse               Oral       >50.O         Union Carbide, 1965
    Mouse               I.P.       6.5            Union Carbide, 1965
    Rat-male            Oral       >50.0         Union Carbide, 1965
    Rat-female          Oral       >50.O         Union Carbide, 1965
    Guinea pig-male     Oral       >50.0         Union Carbide, 1965
    Guinea pig-female   Oral       >50.0         Union Carbide, 1965
    Rabbit-male         Oral       >50.0         Union Carbide, 1965
    Rabbit-female       Oral       >50.0         Union Carbide, 1965
                                                                        

    Short-term studies

    Rat

         Various polyethylene glycols have been fed to rats (5 males and 5
    females per dose level at 0, 2, 4, 8, 16 and 24% of the diet) for 90
    days. Criteria studied were = mortality, food consumption, body weight
    gain, liver weight, kidney weight and micropathology of liver and
    kidney. The results were summarized below (Smyth et al., 1955):

                                                                        

                   No effect
    Compound         level          Adverse effect, dose level
                                                                        

    PEG 200           8%            Increase liver weight        (16%)
    PEG 300           4%            Decrease body weight          (8%)
    PEG 400           8%            Decrease body weight         (16%)

    PEG 600           8%            Increase kidney weight and   (16%)
                                      decrease body weight
    PEG 1000          8%            Decrease body weight         (16%)
    PEG 1500          4%            Decrease body weight          (8%)
    PEG 1540          4%            Decrease body weight          (8%)
    PEG 4000          4%            Decrease body weight          (8%)

    PEG 6000          16%           Increase kidney weight and   (24%)
                                      decrease body weight
                                                                        
        Dog

         Polyethylene glycols 400, 1540 and 4000 cause no adverse effect
    upon dogs when fed 2% in the diet for one year (Smyth et al., 1955).

    Monkey

         Polyethylene glycol 200 was administered orally to monkeys
    (Macaca fascicularis) and rats (Sprague-Dawley) for a 13-week period
    at dosage levels of 2 to 4 ml/kg (monkeys) and 2.5 to 5.0 ml/kg (rats)
    per day. Pathological lesions were encountered only in monkeys and
    these consisted of intratubular deposition of small numbers of oxalate
    crystals in the renal cortex. These lesions were not associated with
    other clinical or pathological findings (Prentice & Majeed, 1978).

    Long-term studies

    Rat

         Dosages of 0.06 g/kg/day of PEG 1500 or of 0.02 g/kg/day of PEG
    4000 did not cause any significant adverse effects (mortality,
    frequency of infection, life-span, fluid consumption, body weight
    gain, kidney and liver weights, frequency of size of litters, blood
    cytology, urinary albumen and sugars, occurrence of neoplasm, and
    micropathology) in albino rats when administered in the drinking water
    over a two-year period (Smyth et al., 1947).

         When fed to rats for two years as a part of their diet, PEG 1540
    and 4000 had no effect at a level of 4% and PEG 400 had no effect at a
    level of 2%. In these animals, higher levels of polyethylene glycols
    produced small, nonspecific effects upon growth or minor cloudy
    swelling of the liver (Smyth et al., 1955).

         Groups of 20 male and 20 female rats were fed 4.0, 2.0, 1.0, 0.5
    and 0% of PEG 200 in their diet for two years and observed for food
    consumption, mortality rate, number of infections, life-span, growth
    rate, liver and kidney weights, gross pathological condition of
    organs, blood haematocrit values, and incidence of neoplasms. The
    results indicated that, even at 4.0% dose level, PEG 200 produced no
    significant deviations from the control rats during the two-year
    feeding study (Weil & Smyth, 1956).

    Skin irritation and sensitization

         Although early reports by Smyth et al. (1950) indicated that skin
    sensitization was observed among a few human subjects and in guinea
    pigs tested with certain polyethylene glycols, later studies
    (Carpenter et al., 1971) showed that currently produced materials were
    without irritating or sensitizing properties. However, recent report
    (Fischer, 1978) demonstrated that four patients showed allergic
    reactions to lower molecular weight liquid polyethylene glycols in
    topical medications. Two had immediate urticarial reactions to PEG
    400. Two other patients had delayed allergic eczematous reactions, one
    to PEG 200, and one to PEG 300.

    Comments

         The acute and short-term studies reported are extensive and cover
    a wide range of animal species. Several long-term studies have been
    carried out. Absorption and excretion of this class of compounds have
    been adequately studied.

         Pure polyethylene glycols have essentially similar toxicity, with
    toxicity being inverse to molecular weights. Absorption from the
    gastrointestinal tract decreases with increasing molecular weight.

         A monograph was prepared.

    EVALUATION

    Level causing no toxicological effect

    Rat: 20 000 ppm (2%) in the diet equivalent to 1000 mg/kg bw.

    Estimate of acceptable daily intake for man

    0-10 mg/kg bw.

    REFERENCES

    Carpenter, C. P. et al. (1971) Toxicol. Appl. Pharmacol., 18, 35-40

    Fisher, A. A. (1978) Contact Dermatitis, 4, 135-138

    Prentice, D. E. & Majeed, S. K. (1978) Toxicol. Lett., 2, 119-122

    Schaffer, C. B. & Critchfield, F. H. (1947) J. Amer. Pharm. Assoc.,
         Sci. Ed., 36, 152-157

    Schaffer, C. B., Critchfield, F. H. & Nair, J. H. (1950) J. Amer.
         Pharm. Assoc., Sci. Ed., 39, 340-344

    Smyth, H. F., jr, Seaton, J. & Fischer, L. (1941) J. Ind. Hyg.
         Toxicol., 23, 259-268

    Smyth, H. F., jr, Carpenter, C. P. & Schaffer, C. B. (1947)
         J. Amer. Pharm. Assoc., Sci. Ed., 36, 157-160

    Smyth, H. F., jr, Carpenter C. P. & Weil, C. S. (1950) J. Amer.
         Pharm. Assoc. Sci. Ed., 39, 349-354

    Smyth, H. F., jr, Carpenter, C. P. & Weil, C. S. (1955) J. Amer.
         Pharm. Assoc. Sci. Ed., 44, 27-30

    Union Carbide (1965) Unpublished data

    Wel, C. S. & Smyth, H. F., jr (1956) Unpublished data (Special Report,
         Institute of Industrial Research, University of Pittsburgh)
    


    See Also:
       Toxicological Abbreviations
       POLYETHYLENE GLYCOLS (JECFA Evaluation)