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)