THE ORAL TOXICITY AND PATHOLOGY OF POLYOXYETHYLENE DERIVATIVES IN RATS AND HAMSTERS a

Self Cite

Use of polyoxyethylene preparations in a wide variety of food products has aroused considerable interest in the effects which might follow their ingestion in food. On the basis of an evaluation of 48 published and unpublished reports available to it, the Food Protection Committee ( 4 ) of the National Research Council concluded in 1953 that the data "fail t o demonstrate that polyoxyethylene stearates are safe for use in foods under all patterns of dietary consumption and for all segments of the population. " Other publications have mentioned deleterious effects of polyoxyethylene and sorbitan compounds following oral (13,22,29) and parenteral (3,5,14,15,19,22,23,25,27,28) administration to various experimental animals as well as after in vitro use (1, 10, 12,20,21,23).Recently Krehl, Cowgill, and Whedon (16) reported that polyoxyethylene esters fed to rats and cats for varying periods of time did not have deleterious effects. Graham, Teed, and Grice (7) obtained negative results when they fed polyoxyethylene monostearate to rats in a bread diet for one year. Graham and Brice also reported negative results from feeding polyoxyethylene monostearate in a synthetic diet for 32 weeks (6). The observations reported in the present paper involve the feeding of polyoxyethylene preparationsb for a period of 21 weeks in rats and 39 weeks in hamsters. PROCEDUREFour experiments have been completed to determine the effects of moderate and high levels of several polyoxyethylene compounds in the diet. High levels were used in these experiments in conformity with recommended procedures for evaluation of the safety of chemicals in foods (17, 18). I n the first experiment, weanling male rats (Holtznian Rat Company, Madison, Wisconsin), distributed into 4 groups, were fed for 21 weeks on synthetic diets containing 25% levels of lard; cottonseed oil mono-and diglycerides (CMDG) ' ; polyoxyethylene monostearate (PMS No. 1) d ; or polyoxyethylene sorbitan nionolaurate (PSML)". These diets differed only as to the control or test " D a t a were presented originally in Exhibit 365, Ice Cream Hearings, Docket FDC 34A, 1952. These materials were offered on the open market for use in food products. They were mixtures of many chemical compounds and undoubtedly contained traces of unidentified impuritiex. The heterogeneous composition of polyoxyethylene stearates has been discussed at some length in a report issued by the Food Protection Committee ( 4 ) .A commercial equilibrium mixture of mono., di-, and triglycerides prepared by reacting partially hydrogenated cottonseed oil with glycerine. It will be identified subsequently in this paper by the abbreviaiion CMDC.A partial ester of commercial stearic acid and prefabricated polyethylene glycol, which will be identified subsequently in this paper by the abbreviation PMS No. 1.' A partial ester of commercial lauric acid, sorbitan, and mixed polyoxyethylene diols having a n average chain length corresponding to 20 ethylene oxide units per mol of sorbitan. It will be identified subsequently i ...

Section: Resultsmentioning

confidence: 99%

EFFECTS OF FEEDING POLYOXYETHYLENE PREPARATIONS TO RATS AND HAMSTERS^a

Poling

Eagle

Rice

1956

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“…This report further emphasized that no evidence of gross or microscopic pathology attributable to MYRJ 45 was found in other species. Recent reports of work originally presented in 1952 (1,7) indicates adverse effects of MYRJ 45 in hamsters, particularly at 25% level in synthetic diets, including diarrhea, genitourinary bleeding and increased mortality.…”

mentioning

confidence: 99%

EFFECT OF POLYOXYETHYLENE‐8‐MONOSTEARATE (MYRJ 45) ON LIVER FUNCTION IN PATIENTS CONVALESCING FROM HEPATIC DISORDERS^a

Kruesi

Itallie

1956

Manuscript received Nay 26, 195B) Ti1 recent years synthetic emulsifiers of the polyoxyethrlene type have found a wide range of uses in the food and pharmaceutical industries (8,9). Such emulsifiers also have been administered to patients with steatorrheas of various kinds in an attempt to promote intestinal absorption of fat and fat-soluble vitamins ( 4 ) .The toxicology of some of these partial ester emulsifying agents, such as polyoxyethylene-20-sorbitan monooleate (TWEEN" 8 0 ) and polyoxyethylene-8-monostearate (MYRJ" 45) , has been studied extensively in experimental animals and human subjects (2, 3, 5, 6). Kranitz et al. have reported that the oral administration of TWEEN 80 in doses of 4.5 to 6.0 g. per day to more than 100 human subjects for periods up to four pears was unattended by clinical evidence of damage to liver, kidneys or heinatopoietic system ( 5 ) . Preston and associates have found a similar absence of toxic effects of sorbitan monostearate (SPAN" 60) polyoxyethylene-20-sorbitan monostearate (TWEEN 60) and of MYRJ 45 in relatively short-term studies involving administration of these substances to infants and children (10).Studies on certain polyoxyethyleiie stearates, including MYRJ 45, were reviewed i n 1953 by the Food Protection Committee of the Food and Nutrition Board of the National Research Council (11). This report concluded from the then available evidence that the safety of MYRJ 45 for use in foods had not been fully established owing principally to the findings of urinary calculi and mild liver changes in rats and hamsters fed high dietary levels for prolonged periods. This report further emphasized that no evidence of gross or microscopic pathology attributable to MYRJ 45 was found in other species. Recent reports of work originally presented in 1952 (1, 7) indicates adverse effects of MYRJ 45 in hamsters, particularly at 25% level in synthetic diets, including diarrhea, genitourinary bleeding and increased mortality.Reports of other studies, however, have described chronic feeding experiments with rats in which bread containing 15% of polyoxyethylene monostearate (MYRJ 45) on a flour basis (10.25 per cent as fed in the diet) (2, 3 ) or purified diets containing up to 207% (6) induced no specific pathology. The latter report concluded on the basis of both nutritional and histopathologic evidence "that no reasonable doubt exists concerning

“…Parenthetically it may be noted that hamsters, which normally mature as early as 28 days of age and have a short gestation period, are extremely sensitive to vitamin E shortage (10,17,22). Nevertheless, Eagle and Poling refer to work by Wissler et al (4,26) in which the hemmiderosis is attributed to increased iron absorption via the cecum. Since there is no organ in the human equivalent to the cecum of the rat or hamster in structure and in function, the occurrence of hemosiderosis via the cecum in these animals has no relation to human physiology, and therefore is probably of no significance.…”

Section: Discussionmentioning

confidence: 94%

THE RESPONSE OF HAMSTERS TO A NATURAL‐TYPE DIET CONTAINING EMULSIFIERS^a

Oser¹,

Oser²

1957

With the wide acceptance by the food industry of polyoxyethylene (8) stearate (Myrj 45) and other surface-active, partial fatty acid esters as emulsifying agents, considerable attention has been directed t o the study of the nutritional value and safety of these compounds (1,2,3,7,8,12,13,14,20). Although most studies emphasize the innocuous effects of Myrj 45 when ingested in experimental diets at extremely exaggerated dosage levels, Schweigert e t al. (23,27), employing purified diets, reported some deleterious effects in hamsters. The hamster is a relative newcomer among experimental animals for prolonged nutritional studies and much remains to be elucidated of its nutritional requirements and normal physiology ( 5 ) . I n addition, it is known t o be less uniform in its responses than the rat and is subject to many transmissible diseases (18, 22, 28). It therefore seemed of interest t o reevaluate the hamster response to high levels of Myrj 45 under conditions where the basal diet consisted of natural rather than "purified" ingredients. Although the results of these studies were largely negative insofar as demonstrating toxicity was concerned, it seemed warranted to record our observations because of the recent publication (4,19) of apparently contradictory findings which were originally reported a t the Ice Cream Hearings (25) before the Administrator of the Federal Security Agency in 1952.The basic composition of the diet fed in our hamster experiments is the same as that used in long-term studies of the nutritional effects of a large series of emulsifiers in rats ( 1 5 ) . It was formulated t o resemble the American dietary in respect to the proportions of protein, fat, and carbohydrate present and the proportions of protein and fat derived from animal and vegetable sources, while a t the same time satisfying the known nutritional requirements of either rats or hamsters. The test materials were incorporated at the expense of the wheat and corn mixture in the ratio in which the latter appear in the diet (i.e., 2 : l ) .Two studies were conducted. In the first, diets including equivalent levels of Myrj 45 (polyoxyethylene (8) monostearate) were compared with those containing a hydrogenated vegetable oil (Primex), diglycerides and monoglycerides from meat fats and vegetable fats (sold commercially as "Esterine"), and cottonseed oil monoglyceride ("Myverol 18-85"). The test materials were fed at graded dietary levels ( 0 , 5, 10, and 15%) in successive periods of 2 or 4 weeks' duration, the levels being the same for all materials a t any given period.Because of the observation of increased kidney weights and somewhat lower weight gains in the Myrj 45 hamsters compared with those fed "This investigation was supported by a grant from the Atlas Powder Company, Wilmington, Delaware. 273