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Journal Article•DOI•

The chronic oral toxicology of the polyethylene glycols

Henry F. Smyth1, Charles P. Carpenter1, Carrol S. Weil1•
Mellon Institute of Industrial Research1
01 Jan 1955-Journal of the American Pharmaceutical Association (Elsevier)-Vol. 44, Iss: 1, pp 27-30
TL;DR: This work supports the view that the polyethylene glycols may be considered inert when taken by mouth, and is definitely less toxic by mouth than those of lower molecular weights.
Abstract: Polyethylene glycols were fed in the diet to rats for two years and to dogs for one year.Apparently a compound with a mean molecular weight of 6,000 is definitely less toxicby mouth than those of lower molecular weights.This work supports the view that the polyethylene glycols may be considered inert when taken by mouth.
Citations
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Journal Article•DOI•
Attachment of drugs to polyethylene glycols

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Samuel Zalipsky1, Chaim Gilon1, Albert Zilkha1•
Hebrew University of Jerusalem1
01 Jan 1983-European Polymer Journal
TL;DR: Polyethylene glycol was used as a carrier polymer for the attachment, via end groups, of drugs such as penicillin V, aspirin, amphetamine, quinidine and atropine.

467 citations

Journal Article•DOI•
Laboratory synthesis of polyethylene glycol derivatives

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J. Milton Harris1•
University of Alabama in Huntsville1
01 Aug 1985-Journal of Macromolecular Science-reviews in Macromolecular Chemistry and Physics
TL;DR: Generally applicable laboratory methods for preparing PEG derivatives from the parent PEG and some of its ethers and esters are described.
Abstract: In recent years, derivatives of polyethylene glycol (PEG) have proven valuable in a variety of diverse chemical and biological endeavors. Such applications include peptide synthesis, phase transfer catalysis, pharmaceutical modification, protein and cell purifications, polymer-bound reagents, and binding assays. Because of the great deal of interest surrounding this subject, this review will describe generally applicable laboratory methods for preparing PEG derivatives from the parent PEG. We have largely restricted discussion to this starting material because most research laboratories interested in applications are not equipped to handle complex ethylene oxide polymerizations used in large-scale industrial preparations and because PEG and some of its ethers and esters are the only commonly available polymeric starting materials. For the purpose of this review, PEG is defined as those polyoxyethylenes having hydroxyl endgroups and a molecular weight of 20,000 daltons or less.

357 citations

Journal Article•DOI•
Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products

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Claudia Fruijtier-Pölloth
15 Oct 2005-Toxicology
TL;DR: It is concluded that PEGs of a wide molecular weight range, their ethers, and fatty acid esters are safe for use in cosmetics under the present conditions of intended use and no safety concern with regard to these endpoints could be identified.

344 citations

Cites background or methods from "The chronic oral toxicology of the ..."

  • ...Kidney damage was observed when about 4000 mg/kg bw/d were administered via the drinking water Smyth et al. (1955, 1942) PEG-32 Diet, 2 years Rat (n= 5/sex/group) 2%, 4%, 8%, 16%, 24% in diet 4% (about 3000 mg/kg bw/d): no effect Smyth et al. (1955) PEG-32 Diet, 1 years Dog (n= 2) 2% (about 500…...

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  • ...Reproductive toxicity No notable adverse effects on the reproductio ats occurred in oral studies over three genera ith PEG-6-32 and PEG-75 (Smyth et al., 1947, 1955). eproductive parameters were not influenced in s es with PEG-8 when pregnant Sprague–Dawley nd New Zealand White rabbits (10/group) were do etween gestation days 6 and 17 (rats) or 6 and 18 its) by oral gavage (Gupta et al., 1996)....

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  • ...…8%, 16%, 24% in diet 4% (about 3000 mg/kg bw/d): no effect Smyth et al. (1955) PEG-32 Diet, 1 years Dog (n= 2) 2% (about 500 mg/kg bw/d): no effect Smyth et al. (1955) PEG-75 Diet, 2 years Rat (n= 5/sex/group) 2%, 4%, 8%, 16%, 24% in diet 16%: increased kidney weights; 4% (about 3000 mg/kg bw/d):…...

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  • ...…at a level of 2% (about 1000 mg/kg bw/d) Smyth et al. (1955) PEG-8 Diet, 1 year Dog (n= 4) 2% of PEG-400 (about 500 mg/kg bw/d): no adverse effects Smyth et al. (1955) PEG-32 Diet; drinking water, 90 days Rat (n= 5/sex/group) 2%, 4%, 8%, 16%, 24% in diet 4% in diet (about 3000 mg/kg bw/d): No…...

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  • ...No notable adverse effects on the development of rats occurred in oral studies over three generations with PEG-6–32 and PEG-75 (Smyth et al., 1947, 1955)....

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Journal Article•DOI•
PEGylated Proteins: Evaluation of Their Safety in the Absence of Definitive Metabolism Studies

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Rob Webster1, Eric Didier, Philip Harris, Ned Siegel, Jeanne Stadler, Lorraine Tilbury, Dennis A. Smith •
Pfizer1
01 Jan 2007-Drug Metabolism and Disposition
TL;DR: Assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.
Abstract: During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.

336 citations

Cites background from "The chronic oral toxicology of the ..."

  • ...In chronic oral toxicology studies in the rat, PEG1500 (0.06 g/kg/ day) and PEG4000 (0.02 g/kg/day) did not cause any significant adverse effects after 2 years’ administration (Smyth et al., 1955)....

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  • ...PEGs have a descriptor associated with them that represents the mean molecular weight of the molecule (i.e., PEG200 has a molecular weight of 200) (Smyth et al., 1955)....

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  • ...In chronic toxicology studies in nonrodent species there were no adverse events in dogs that received PEGs ranging from 400 to 4000 molecular weight (2% in diet) for a year (Smyth et al., 1955)....

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  • ...%) to rats, no effects were observed (Smyth et al., 1955)....

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  • ...Experiments with PEG400 showed no effect at doses of 2% in diet, with higher doses showing nonspecific effects on growth and cloudy swellings in the liver (Smyth et al., 1955)....

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Journal Article•DOI•
Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation

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A Attar, M Lémann1, Anne Ferguson1, M Halphen1, M C Boutron1, B Flourié1, E Alix1, M Salmeron1, F Guillemot1, S Chaussade1, A M Ménard1, J Moreau1, G Naudin1, M Barthet1 •
Western General Hospital1
01 Feb 1999-Gut
TL;DR: Low dose PEG 3350 was more effective than lactulose and better tolerated in chronic constipation and clinical tolerance was similar in the two groups, but flatus was less frequently reported in the PEG group.
Abstract: Background—Polyethylene glycol (PEG) 3350 is a non-absorbable, nonmetabolised osmotic agent used in lavage solutions for gut cleansing. Aims—To compare the eYcacy of PEG and lactulose in chronic constipation. Methods—A total of 115 patients with chronic constipation entered a multicentre, randomised, comparative trial. They initially received two sachets containing either PEG (13 g/sachet) or lactulose (10 g/sachet) and were given an option to change the dose to one or three sachets/ day, depending on response. Results—Ninety nine patients completed the trial. After four weeks, patients in the PEG group (n=50) had a higher number of stools and a lower median daily score for straining at stool than patients in the lactulose group (n=49). Overall improvement was greater in the PEG group. Clinical tolerance was similar in the two groups, but flatus was less frequently reported in the PEG group. The mean number of liquid stools was higher in the PEG group but the diVerence was significant only for the first two weeks. There were no serious adverse events and no significant change in laboratory tests in either group. At the end of the study, the number of sachets used by the patients was 1.6 (0.7)/day in the PEG group and 2.1 (0.7)/day in the lactulose group. Sixty one patients completed a further two months open study of one to three sachets PEG daily; there was no loss of eYcacy and no serious toxicity. Conclusion—Low dose PEG 3350 was more eVective than lactulose and better tolerated. (Gut 1999;44:226‐230)

248 citations

Cites background from "The chronic oral toxicology of the ..."

  • ...Chronic toxicity studies have been carried out in animals with PEG 1540 and 4000 being mixed in the food over a two year period without any signs of toxicity....

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References
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Journal Article•
Experimental methods used in determining chronic toxicity; a critical review.

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J. M. Barnes, F. A. Denz
01 Jun 1954-Pharmacological Reviews
TL;DR: In their final report to the U. S. Congress, the Delaney Committee investigating the "Use of Chemicals in Food and Cosmetics" expressed their conviction that "chemicals have been utilised in and on the food supply of the Nation without adequate and sufficient testing of their long-range injurious effects".
Abstract: In their final report to the U. S. Congress, the Delaney Committee investigating the "Use of Chemicals in Food and Cosmetics" expressed their conviction that "chemicals have been utilised in and on the food supply of the Nation without adequate and sufficient testing of their long-range injurious effects" (76). They recommended legislation to ensure that the public was safeguarded by making it compulsory to have adequate tests carried out before an article reached the market. A possible sequel to such legislation would be the adoption of some standard form of toxicity testing. Such a danger was recognised by at least one expert who gave evidence before this Committee when he stated (p. 749) "Investigations of this type make heavy demands upon the general technical knowledge and experience of the investigator whose interest in a problem and whose ingenuity in approaching it should not he thwarted by the necessity of adhering to a stereotyped procedure for the sake of obtaining uniform data on toxicity for comparative purposes," and (p. 757) ". . . I would not wish to be bound by anybody's specifications as to what is necessary to establish the facts with reference to the safety of this or that" (164). This is valid criticism of any stereotyped toxicity test. A second criticism is that the conventional type of chronic toxicity test is not the best way of providing safeguards against human poisoning. The assessment of a toxic hazard can be properly based only on some knowledge of the fate and behaviour of a compound after its introduction into the body. A study of the absorption, distribution and elimination of a compound might take longer and prove more exacting than a routine feeding test. But such work would lead logically to biochemical and physiological studies. This approach would be scientific in contrast to the empirical method of chronic toxicity tests. The criteria used in the routine type of feeding or inhalation tests are complex and little understood. A disturbance of growth or fertility or even an increased mortality adds little to our knowledge of the mode of action of a toxic material. The value of such criteria is further depreciated by the fact that they are apparently so insensitive as indices of poisoning. With some knowledge about the behaviour of a compound in laboratory animals, it becomes possible to consider means of finding out how the same compound behaves when given to man. Only when some information of this kind is available would it be worth considering that the results of long-term feeding experiments in animals have any bearing on the problem with regard to man. There would appear to be a much bigger place for the subacute type of test on animals in order to find out just what biological processes are disturbed. Tests of longer duration have little value until something is known about the mode of action of a compound, so that the effects of such an action can, if desired, be studied specifically over long periods. Into this category would fall the tests carried out for carcinogenicity. The value of routine long-term feeding tests as measures of administrative expediency is not a question for discussion here. The use of such an experimental approach should not be confused with a scientific attack on a difficult problem.

86 citations

Related Papers (5)
The toxicology of the polyethylene glycols

[...]

01 Jun 1950-Journal of the American Pharmaceutical Association
Henry F. Smyth, Charles P. Carpenter, Carrol S. Weil
The absorption and excretion of the solid polyethylene glycols (“Carbowax” compounds)

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01 May 1947-Journal of the American Pharmaceutical Association
C. Boyd Shaffer, Frances H. Critchfield
Response of dogs to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and sensitization.

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01 Jan 1971-Toxicology and Applied Pharmacology
Charles P. Carpenter, M.D. Woodside, Edwin R. Kinkead, J.M. King, L.J. Sullivan 
Measurements of Intestinal Permeability Using Low Molecular Weight Polyethylene Glycols (PEG 400): II. Application to normal and abnormal permeability states in man and animals

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01 Aug 1977-Gastroenterology
V.S. Chadwick, Sidney F. Phillips, Alan F. Hofmann
Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol.

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10 Jun 1977-Journal of Biological Chemistry
Abraham Abuchowski, T. van Es, Nicholas C. Palczuk, Frank F. Davis