`
`EDITED BY
`
`MARTIN J. SCHICK
`LEVER nnomans do.
`RESEARCH CENTER
`
`BDGEWATER, NEW JERSEY ‘
`
`196.’?
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`MARCEL DEKKER, INC., NEW YORK
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`Page1of50
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`LUP|NEX1072
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`LUPIN EX 1072
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`Page 1 of 50
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`COPYRIGHT © 1966 by MARCEL DEKKER, INC.
`
`ALL RIGHTS RESERVED
`
`No part of this book may be reproduced in any form, by
`photostat, microfilm, 01' any other means, without the
`written permission of the publisher.
`
`MARCEL DEKKER, INC.
`95 Madison Avenue, New York, New York 10016
`
`06
`
`LIBRARY OF CONGRESS CATALOG CARD ‘NUMBER 66-22492
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`PERMISSIONS
`
`Academic Press Inc., New York, N. Y.
`
`Fig. 14.11.
`Fig. 14.13.
`Fig. 15.6.
`Fig. 15.8.
`Fig. 17.1.
`
`Fig. 17.2.
`Fig. 17.3.
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`Fig. 17.4.
`Fig. 17.5.
`Fig. 17.7.
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`Fig. 17.8.
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`Fig. 17.9.
`Fig. 17.10.
`Fig. 17.11.
`Fig. 17.28.
`Fig. 17.29.
`Fig. 17.30.
`Fig. 19.12.
`Fig. 19.14.
`Fig. 21.2.
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`Table 17.3.
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`Table 17.9.
`Table 17.12.
`Table 21.1.
`
`M. J. Schick, J. Colloid Sci'., 17, 801 (1962) (Fig. 1).
`Ibid., 18, 378 (1963) (Fig. 3).
`P. Becher, ib1'd., 16, 49 (1961) (Fig. 1).
`Ibid., 1'1, 325 (1962) (Fig. 2).
`K. Shinoda, T. Nakagawa, B. Tamamuchi, and T. Isemura, Colloidal Surfac-
`tants, 1963, p. 140 (Fig. 2.27).
`Ibid., p." 141 (Fig. 2.28).
`M. E. L. McBain and E. Hutchinson, Solubilization and Related Phenomena,
`1955, p. 169 (Fig. 5.14).
`B. A. Mulley and A. D. Metcalf, J. Colloid .S'ci., 1'7, 525 (1962) (Fig.2).
`Ibt'd., 17, 526 (1962) (Fig. 3).
`K. Shinoda, T. Nakagawa, B. Tamainuchi, and T. Isemura, Colloidal Surfac-
`tants, 1963, p. 142 (Fig. 2.29).
`T. Nakagawa, K. Kuriyarna, and H.
`(1960) (Fig. 5).
`W. N. Maclay, ibid., 11, 281 (1956) (Fig. 6).
`M. J. Schick, i'br'd., 17, 312 (1962) (Fig. 7).
`W. N. Maclay, ilJ1'd., 11, 277 (1956) (Fig. 4).
`B. A. Mulley and A. D. Metealf, ib1'd., 19, 508 (1964) (Fig. 6).
`Ibz'd., 19, 504 (1964) (Fig.2).
`5. Ross, r'bz'd., 6, 502-504 (1951) (Figs. 1-3).
`B. Mackor, i'bz'd., 6, 492 (1951) (Fig. 1).
`E. Mackor and J. H. van cler Waa1s,i'br'd., 7, 535 (1952) (Figs. 3 and 4).
`J. F. Danielli, K. G. A._Pa.nkhurst, and A. C. Riddiford, .RecentPr0gre.s's in Sur-
`face Science, 1964, p. 61 (Fig. 2).
`T. Nakagawa, K. Kuriyama, and H. Inoue, J. Colloid Sci., 15, 270 (1960)
`(Table II).
`A. M. Mankowich, I'b1'd., 14, 133 (1959) (Table II).
`S. Ross, ibi'd., 6, 500 (1951) (Table II).
`A. G. Brown, W. C. Thuman, and J. W. McBain, ibid., 8, 502 (1953) (Table 1).
`
`Inoue, J. Colloid Sci., 15, 275
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`Page 2 of 50
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`iv
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`Page 2 of 50
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`CHAPTER
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`PHYSIOLOGICAL ACTIVITY
`
`OF NONIONIC SURFACTANTS
`
`P. H. Elworthy
`DEPARTMENT OF PIIARMAGY
`UNIVERSITY OF STRATHCLYDE, GLASGOW, SCOTLAND
`
`Joseph F. Treon
`B10-MEDICAL RESEARCH DEPARTMENT
`ATLAS CHEMICAL INDUSTRIES, INC", WILMINGTON, DELAWARE
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`Introduction .
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`28.2. Acute Toxicity .
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`28.3. Subacute and Chronic Toxicity .
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`A. Polyethylene Glycols .
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`B. Polyoxyethylene Phenyl or Alkylphcnyl Ether Derivatives .
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`D. Polyoxyethylene Fatty Acid Esters .
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`E. Partial Esters of Sorbitan .
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`F. Partial Esters of Polyoxyethylene Sorbitan Fatty Acids .
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`G. Other Surfactants .
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`H. Tests on Human Subjects . .
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`28.4. Metabolic Fate . . .
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`28.5. Effects on the Gastrointestinal Tract .
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`A. Fat Absorption .
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`B. Other Effects
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`28.6. Efl‘ects on the Cardiovascular System .
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`B. Proteins and Lipoproteins .
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`D. Cholesterol .
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`28.10. Some Effects with Enzymes .
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`28.l1.Efi"ects on the Eye .
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`28.14. Phytotoxicity .
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`Appendix A. Toxicity of Ethylene Oxide .
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`Page 3 of 50
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`923
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`Page 3 of 50
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`
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`924
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`P. H. ELWORTHY AND JOSEPH F. TREON
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`28.1. INTRODUCTION
`
`This chapter is a general review of the physiological properties of nonionic
`surfactants. It is rnainlyconcerned with their biological, pharmacological, and
`toxicological effects on experimental animals and on human beings, and there
`is less emphasis on bacteriological and phytotoxicological aspects.
`The nonionic surfactants considered in this chapter may be divided into afew
`large chemical classifications: ethers, esters, and products with»-both the ether
`and ester moieties. The ethers may be further subdivided into subclasses:
`(a) polyoxyethylene alkyl ethers, (b) polyoxyethylene phenyl ethers or alkyl
`phenyl ethers, and (0) mixed polyoxyethylene-polyoxypropylene ethers.
`The esters are further subdivided into subclasses (i) polyoxyethylene fatty
`acid esters,'(ii) partial fatty acid esters of polyols and anhydropolyols, and (iii)
`partial fatty acid esters of polyoxyethylene polyols and anhydropolyols.
`Although there exist many types of surfactants, those established as safe for
`human consumption and topical use are few. Acute oral toxicological deter-
`minations are performed on most surfactants regardless of their intended usage;
`this information is valuable even for those products not intended for ingestion,
`since they may be ingested accidentally. Chronic toxicity cannot be postulated
`adequately on the basis of acute toxicity.
`The general principles and procedures for evaluating the safety of food
`additives have been promulgated by the Food Protection Committee (Food
`Nutrition Board) of the National Academy of Sciences-National Research
`Council (2) and by the World Health Organization (9). Suggested detailed pro-
`cedures are given by personnel at the USFDA (3). These include, in addition
`to acute studies, subacute (90~day) toxicity studies, which are considered by
`Lehman (12) of the USFDA as preliminary to 2-year chronic studies in rats and
`dogs, including clinical chemical tests, statistical examination of the data, and
`gross and microscopic examination of the tissues. In. addition, the mode and
`extent of absorption, the route and rate of excretion in the feces, urine, and
`respired air, and the distribution in the blood and tissues of the original product
`and its metabolites are valuable in ascertaining the safety or lack thereof. The
`extent of consideration given to the safety of emulsifiers is illustrated by the
`various official reports on this topic (2-11).
`The nonionic ethers are not generally recognized or used as direct food addi-
`tives. However, certain nonionic esters are acceptable as direct food additives.
`The mono- and diglycerides are Generally Recognized As Safe (GRAS) in the
`U.S. (13). These are also considered acceptable by the Joint Food and Agri-
`cultural Organization (FAO) of the United Nations and World Health Organiza-
`tion WVHO) Expert Committee (11). Furthermore, the SPAN sorbitan fatty acid
`esters and the TWEEN polyoxyethylene sorbitan fatty acid esters’ constitute a
`prominently safe class. The safety of many of these in foods has been accepted by
`the USFDA (14), by Canadian (15), English (16), Japanese (17), and Indian (18)
`regulatory agencies, and by the Joint Food and Agricultural Organization of
`the United Nations and World Health Organization Expert Committee on Food
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`Page 4 of 50
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`Page 4 of 50
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`
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`PHYSIOLOGICAL ACTIVITY
`
`925
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`Additives (11). MYRJ 45 [polyoxyethylene (8)* stearate] and MYRJ 52
`[polyoxyethylene (40) stearate] are accepted by FAO/WHO (1 I); polyoxy-
`ethylene (8) stearate is permitted in unstandardized baked foods in Canada (15)
`and polyoxyethylene (40) stearate is permitted as a direct food additive in de-
`foaming agents in the U.S. (14). Propylene glycol mono- and diesters of fats and
`fatty acids and certain polyglycerol esters of fatty acids also are permitted as
`food additives in the U.S. (19).
`Although not considered a surfactant, per se, certain polyethylene glycols and
`ethylene oxide polymers which may be considered closely related to the poly-
`oxyethylene moiety of certain of the above esters are also permitted in foods (20).
`The considerable use of the nonionics in cosmetic and skin preparations
`necessitates testing for cutaneous toxicity, irritant effects on skin and eye, and
`for induction of allergies (3).
`Today acute and subacute toxicity in more than one species of animals and
`including hemograms, functional tests of certain organs, other clinical chemical
`findings, and histopathology are necessary before the clinical pharmacologist
`can obtain an IND (Investigation of New Drug) for studying the drug in the
`first individual. As the extent of clinical investigation is increased with respect
`to the number of doses to an individual and the number of individuals under
`
`medical surveillance, the extent of studies in the animals with respect to safety,
`metabolism, and functionality are increased. The safety and effectiveness of these
`studies are ascertained by the USFDA prior to the approval of a new drug
`(NDA) in the U.S.
`The mono- and diglycerides and several SPAN and TWEEN products are
`used extensively as surfactant vehicles or emulsifiers in numerous pharmaceutical
`preparations (21).
`The current testing of safety of foods, drugs, and cosmetics requires multiple
`scientific and medical disciplines including toxicology, biochemistry, chemistry,
`pharmacology,
`immunology, genetics, statistics, pathology, clinical pharma-
`cology, and numerous others.
`,
`Although the mono- and diglycerides and the SPAN and TWEEN products
`are not single entities, they are well-defined products, whichare manufactured
`with suitable controls to assure their uniformity (II,22—24).
`
`28.2. ACUTE TOXICITY
`
`Since the poly-iiityethylene moiety is an important segment of the TWEEN
`and other products, the acute toxicity of polyethylene glycols is pertinent. The
`acute oral toxicity (LD50 on a gram per kilogram basis) decreases with increasing
`molecular weight (Table 28.1). There is reduced absorption from the gastro-
`intestinal tract as the molecular Weight is increased (41). In the terminology of
`Hodge and Sterner (25,26) for acute oral toxicity, the polyethylene glycols
`would be classified as either “practically nontoxic” or “relatively harmless.”
`
`* The number of oxyethylene units is denoted by (8).
`
`Page 5 of 50
`
`Page 5 of 50
`
`
`
`926
`
`P. H. ELWORTHY AND JOSEPH F. TREON
`
`TABLE 28.1
`
`Acute Oral Toxicity of Some Polyethylene Glycols in Rats
`
`Glycol
`
`MW
`
`I-’])50y
`gflcg
`
`LD5 D!
`mmolefkg
`
`Ref.
`
`_
`
`(2.2)
`13 8
`8.54
`62
`Ethylene
`(27)
`196
`20.76
`106
`Diethylene
`(27)
`147
`22.05
`150
`Triethylene
`(27)
`169
`32.77
`194
`Tetraethylene
`(27)
`1 12
`31 .64
`282
`Hexaethylene
`(27)
`90
`3 7.41
`404
`Nonaethylene
`(28,319)
`144
`28.9
`200“
`Polyethylene
`(28,30)
`106
`31.7
`300“
`Polyethylene
`(28,30)
`82
`32.8
`400“
`Polyethylene
`(30)
`64
`38. 1
`600“
`Polyethylene
`(32)
`35
`51.3
`1250“
`Polyethylene
`
`
`
`
`3600“ > 50” > 14Polyethylene (32)
`
`" Mixture with number-average molecular weight as indicated.
`” All members of a group of 10 rats survived this dosage.
`
`From an academic aspect only, the results are given also on a molar basis.
`Results in animals other than rats may be found in the references cited in
`Table 28.1.
`
`The available data relating to the acute toxicity of the nonionic surfactants
`have been collected in Table 28.2. There is considerable dilference in the acute
`
`toxicity of the various ethers, some of which may be related to the chemical
`structure. In the terminology of Hodge and Sterner (26) the acute oral toxicities
`of these nonionic surfactants would be classified as “slightly toxic,” “ practically
`nontoxic,” or “relatively harmless.” In the case of the cetyl, stearyl, and
`oleyl series of the polyoxyethylene alkyl ethers, for example, BRIJ 50, 70,
`and 90 series, the more hydrophilic products are more toxic when given orally
`to rats than are the lipophilic products. In further support of this concept, the
`toxicity (LD50) obtained on TERGITOL 15-S-9, which is poiyoxyethylene (9)
`pentadecyl ether, is compatible with the data on polyoxyethylene (10) ethers of
`cetyl, stearyl, and oleyl alcohol. In the case of the polyoxyethylene lauryl ethers,
`the sex of the animal was a small factor.
`
`The role that the absorptive state of the animal at the time of intubation and
`the role that the concentration of the product intubated may play is illustrated
`by the results obtained on the polyoxyethylene phenyl ether as given in Table
`28.2. In four comparisons, less PYCAL 94 was required to obtain an LDSD when
`the product was given orally as a 50 per cent solution in water, than when given
`undiluted. Also, in four instances the nonfasted rat was more resistant than the
`
`fasted (16 hr) rat. The absorptive state did not play such a role in the case of the
`polyoxyethylene lauryl ethers.
`
`Page 6 of 50
`
`Page 6 of 50
`
`
`
`TABLE 28.2
`
`Acute Toxicities of Nonionic Surfactants
`
`Trademark
`
`1.
`
`Polyoxyethylene Alkyl Ethers
`BRIJ 30
`[polyoxyethylene (4) lauryl
`ether]°
`BRIJ 30
`BRIJ 30
`BRIJ 30
`
`BRIJ 30
`
`Polyoxyetliylene (approx. 10)
`lauryl ether
`BRIJ 35
`[polyoxyethylene (23) lauryl
`ether]
`
`BRIJ 35
`BRIJ 35
`
`BRIJ 35
`
`Condition,
`sex,
`species of
`animal
`
`Efhers
`
`Route”
`
`Fasted male rat
`
`Oral
`
`Fasted female rat Oral
`Fasted male mouse Oral
`Fasted female
`Oral
`mouse
`
`Nonfasted female Oral
`rat
`
`Mouse
`
`S.Q.
`
`Concen~
`tration
`(%) and
`vehicle”
`
`LD5.,
`per kg
`
`Ref.
`
`100
`
`100
`100
`100
`
`100
`
`2
`
`8.60 g
`
`(41)
`
`9.07 g
`4.94 g
`7.6! g
`
`(41)
`(42)
`(42)
`
`8.46 g
`
`(42)
`
`0.74.] g (43)
`
`Fasted male rat
`
`Oral
`
`20 (in H10)
`
`8.60 g
`
`(4I,42)
`
`Fasted‘ female rat Oral
`Fasted female
`Oral
`mouse
`
`20 (in H;0)
`20 (in H20)
`
`9.35 g
`4.00 g
`
`(41.42)
`(42)
`
`Nonfasted female
`rat '
`
`Oral
`
`Oral
`
`Skin pene-
`tration
`
`20 (in H20)
`
`7.80 g
`
`(42)
`
`3.26 g
`
`(37)
`
`4.5 ml
`
`(37)
`
`TERGITOL TMN
`[polyoxyethylene (8) trimethyl
`nonyl ether]
`TERGITOL TMN
`
`Rat
`
`Rabbit
`
`BRIJ 52
`[polyoxyethylene (2) cetyl
`ether}
`BRIJ 52
`BRIJ 56
`[polyoxyethylene (10) cetyl
`ether]
`BRIJ 56
`BRIJ 58
`[polyoxyethylene (20) cetyl
`ether]
`*“"
`BRIJ 58
`BRIJ 72
`[polyoxyethylene (2) stearyl
`ether]
`
`Fasted male rat
`-
`
`Oral
`
`50 (in H20) >25.l g
`
`(45)
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`50 (in H20)
`25 (in H20)
`
`22.l g
`3.49 g
`
`(45)
`(45)
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`25 (in H30)
`25 (in H20)
`
`2.46 g
`3.51 g
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`3.95 g
`25 (in H20)
`40 (in H10) >25.l g
`
`BRIJ 72
`
`Fasted female rat Oral
`
`40 (in H20) >25.l g
`
`927
`
`Page 7 of 50
`
`(45)
`(45)
`
`(45)
`(45)
`
`(4.5)
`Cantirrued
`
`Page 7 of 50
`
`
`
`TABLE 28.2——Carttim.red
`
`Condition,
`sex,
`species of
`animal
`
`Route“
`
`C0ncen~
`tration
`(%) and
`vehicle”
`
`LD5o
`per kg
`
`Ref.
`
`Fasted male rat
`
`Oral
`
`25 (in H30)
`
`2.91 g
`
`(45)
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`25 (in H20)
`25 (in H20)
`
`,_2..00 g
`1.92 g
`
`(45)
`(45)
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`25 (in H20)
`100
`
`2.33 g
`25.9 g
`
`(45)
`(45)
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`100
`25 (in H30)
`
`25.8 g
`3.58 g
`
`(45)
`(41,45)
`
`Fasted female rat Oral
`Fasted male 1'at
`Oral
`
`25 (in H20)
`25 (in H20)
`
`2.70 g
`3.10 g
`
`(41)
`(45)
`
`Fasted female rat Oral
`Rat
`LP.
`Male rat
`Oral
`
`25 (in H20)
`
`2.77 g
`0.235 g
`7 ml
`
`(45)
`(46)
`(35)
`
`2 ml
`
`(35)
`
`2.38 g
`
`(37)
`
`25 (in H;O)
`
`1.35 g
`
`(36)
`
`100
`100
`25 or 50
`(in H10)
`Olive oil
`
`Olive oil
`
`Olive oil
`_
`Olive oil
`
`2.25 ml
`2.25 ml
`2.1 g
`
`2.0 g
`(MLD)
`1.5 g
`(MLD)
`1.5 g
`(MLD)
`2.0 g
`11.3 ml
`>20 ml
`
`25 (in H30)
`
`22.4 g
`5.0 g
`
`(33)
`(33)
`(33)
`
`(44)
`
`(44)
`
`(44)
`
`(44)
`(37)
`(37)
`
`(37)
`(37)
`
`Canflnued
`
`Trademark
`
`BRIJ 76
`Epolyoxyethylene (10) stearyl
`ether]
`BRIJ 76
`BRIJ 78
`[polyoxyethylene (20) stearyl
`ether]
`BRIJ 78
`BRIJ 92
`
`[polyoxyethylene (2) oleyl
`ether]
`BRIJ 92
`BRIJ 96
`[polyoxyethylene (10) oleyl
`ether]
`BRIJ 96
`BRIJ 98
`[polyoxyethylene (20) oley]
`ether]
`'
`BRIJ 98
`Polyoxyethylene (20) oleyl ether
`SURFONIC TD—30
`Ipolyoxyethylene (3) tridecyl
`ether]
`SURFONIC TD—30
`
`TERGITOL 15 S 9
`[polyoxyethylene (9) pentadecyl
`ether]
`EMULPI-IOGENE BC 720"
`(polyoxyethylene tridecyl ether)
`EMULPHOR ON 370*
`EMULPHOR ON 3701
`EMULPHOGENE BC 840"
`
`TEXOFOR A2‘
`
`TEXOFOR A4"
`
`TEXOFOR A6‘
`
`TEXOFOR 31¢
`TERGITOL xnd
`TERGITOL X0"
`
`TERGITOL XH“
`TERGITOL X!-I"
`
`Rabbit
`
`Rat
`
`Rat
`
`Rat
`Guinea pig
`Rat
`
`Guinea pig
`
`Guinea pig
`
`Guinea pig
`
`Guinea pig
`Rat
`Rabbit
`
`Rat
`Rabbit
`
`Skin pene-
`tration
`
`Oral
`
`Oral
`
`Oral
`Oral
`Oral
`
`I.P.
`
`I.P.
`
`I.P.
`
`I.P.
`Oral
`Skin pene-
`tration
`Oral
`Skin pene-
`tration
`
`Page 8 of 50
`
`928
`
`Page 8 of 50
`
`
`
`TABLE .‘28.2—Corm'nued
`
`Condition,
`sex,
`species of
`animal
`
`Rabbit
`
`Route“
`
`Skin pene-
`tration
`
`Concen-
`tration
`(%) and
`vehicle“
`
`LD,,,,
`per kg
`
`Ref.
`
`2.0 ml
`
`(37)
`
`Oral
`Fasted male rat
`Oral
`Fasted male rat
`Fasted female rat Oral
`Fasted female rat Oral
`Nonfasted male rat Oral
`Nonfasted male rat Oral
`Nonfasted female Oral
`rat
`
`'
`
`Nonfasted female Oral
`rat
`
`100
`50 {in H;,O)
`100
`50 (in H20)
`100
`50 (in H20)
`100
`
`2.00 ml
`1.80 ml
`2.23 ml
`1.26 ml
`4.40 ml
`3.55 ml
`4.45 ml
`
`(42)
`(42)
`(42)
`(42)
`(42)
`(42)
`(42)
`
`50 (in H20)
`
`3.05 ml
`
`(42)
`
`Trademark
`
`TERGITOL 15-S-9
`
`.
`22¢. Polyoxyethylene Phenyl Ethers
`PYCAL 94"
`PYCAL 94"
`PYCAL 94"
`PYCAL 94“
`PYCAL 94“
`PYCAL 94‘
`PYCAL 94"
`
`PYCAL 94”
`
`2b. Polyoxyethylene p-t-octylphenyl
`ether
`
`Polyoxyethylene (1) p-t-octyl-
`phenyl ether
`Polyoxyethylene (3) p-t-octyl-
`phenyl ether
`Polyoxyethylene (4) p—t—octyl-
`phenyl ether
`IGEPAL Ca—630
`[Polyoxyethylene (8) isooctyl-
`phenyl ether]
`IGEPAL Ca-630
`Polyoxyethylene (9.7) p-t-octyl-
`phenyl ether
`Polyoxyethylene (12.5) p-t-octyI-
`phenyl ether
`Polyoxyethylene (16) p-t-octyl-
`phenyl ether
`Polyoxyethylene (16) p-t-oetyl-
`phenyl ether
`Polyoxyethylene (20) p-t-octyl-
`phenyl ether
`Polyoxyethylene (30) p-t-octyl-
`phenyl ether
`TRITON X-405
`[polyoxyethylene (40) p-t-octyl-
`phenyl ether]
`TRITON CF 10"
`2e. Polyoxyethylene Nonylphenyl
`Ethers
`
`IGEPAL C0430
`[polyoxyethylene (4) 11on.yI-
`phenyl ether]
`IGEPAL CO—430
`
`Fasted male rat
`
`Oral
`
`Fasted male rat
`
`Oral
`
`Fasted male rat
`
`Oral
`
`Rat
`
`Guinea pig
`Fasted male rat
`
`Oral
`
`Oral
`Oral
`
`Fasted male rat
`
`Ora]
`
`100
`
`100
`
`100
`
`100
`
`100
`100
`
`100
`
`7.2 g
`
`(38,39)
`
`3.9 g
`
`(38,39)
`
`3.7 g
`
`(38,39)
`
`4.25 ml
`
`(33)
`
`1.65 ml
`1.7 g
`
`(33)
`(3839)
`
`1.8 g
`
`(33)
`
`(39)
`
`(39)
`
`(39)
`
`(39)
`
`(39)
`
`Fasted male rat
`
`Oral
`
`70 (in H,,O}
`
`2.8 g
`
`Fasted male rat
`
`Oral
`
`30 (in H10)
`
`2.7 g
`
`Fasted male rat
`
`Oral
`
`70 (in H,O)
`
`3.6 g
`
`Fasted male rat
`
`Oral
`
`70 (in H30)
`
`21.2 g
`
`Fasted male rat
`
`Oral
`
`70 (in H20) >2.8 g
`
`Male rat
`
`Rat
`
`Oral
`
`Oral
`
`100
`
`100
`
`2.8 ml
`
`(40)
`
`5 ml
`
`(33)
`
`Guinea pig
`
`Oral
`
`100
`
`5 ml
`
`(33)
`
`Continued
`
`Page 9 of 50
`
`929
`
`Page 9 of 50
`
`
`
`TABLE 28.2——C0ntI'nued
`
`
`Trademark
`
`TERGITOL NP 14
`{polyoxyethylene (4) nor1yl—
`phenyl ether]
`TERGITOL NP 14
`
`TERGITOL NP 2.7
`[polyoxyethylene (7) nony1—
`phenyl ether]
`TERGITOL NP 27
`
`IGEPAL CO-630
`[polyoxyethylene (8-9) nonyl-
`phenyl ether]
`IGBPAL CO-630
`TERGITOL TP 9
`Ipolycxyethylene (9) nony]-
`phenyl ether]
`TERGITOL TP 9
`
`Polyoxyethylene (9-10) nonyl-
`phenyl ether
`TERGITOL NPX
`[polyoxyethylene (10.5) nony1-
`phenyl ether]
`TERGITOL NPX
`
`IGEPAL C0-730
`
`[polyoxyethylene (13.5) nonvi-
`phenyl ether]
`TERGITOL NP 35
`[polyoxyethylene (15) nonyl-
`phenyl ether]
`TERGITOL NP 35
`
`IGEPAL C0-880
`[polyoxyethylene (20) many]-
`phenyl ether]
`TERGITOL NP 40
`[polyoxyethylene (20) nouyl-
`phenyl ether]
`TERGITOL NP 40
`
`IGEPAL DJ-970"
`SURFONIC N-90"
`SURFONIC N—90"
`
`Condition,
`sex,
`species of
`animal
`
`Rat
`
`Rabbit
`
`Rat
`
`Rabbit
`
`Rat
`
`Route“
`
`Oral
`
`Skin pene-
`tration
`Oral
`
`Skin pene-
`tration
`Oral
`
`Guinea pig
`Rat
`
`Oral
`Oral
`
`Rabbit
`
`Female rat
`
`Skin pene-
`tration
`Oral
`
`Concen-
`tration
`($3) and
`vehicle”
`
`LD5.;,
`per kg
`
`Ref.
`
`4.29 ml
`
`(37)
`
`‘M
`
`2.52 ml
`
`(37)
`
`3.67 ml
`
`(37)
`
`I00
`
`100
`
`1.78 ml
`
`(37)
`
`3 g
`
`(33)
`
`2 g
`2.6 ml
`
`(33)
`(37)
`
`2.8 ml
`
`(37)
`
`10 (in H30)
`
`1.5 g
`
`(34)
`
`Rat
`
`Oral
`
`2.5 ml
`
`(37)
`
`Rabbit
`
`Rat
`
`Rat
`
`Rabbit
`
`Rat
`
`Rat
`
`Rabbit
`
`Rat
`Rat
`Rat
`
`Skin pene-
`tration
`
`Oral
`
`Oral
`
`Skin pene-
`tration
`Oral
`
`2.0 ml
`
`(37)
`
`25
`
`H30)
`
`2.5 g
`
`(36)
`
`4.00 g
`
`(37)
`
`3.0 ml
`
`(3.7)
`
`25 (in H20) >16 g
`
`(36)
`
`Oral
`
`15.9 g
`
`(37)
`
`Skin pene-
`tration
`
`Oral
`Oral
`Skin pene-
`tration
`
`4.49 ml
`
`(37)
`
`so (in H20)
`H20
`I00
`
`31.5 g
`2.58 g
`>8 g
`
`(33)
`(35)
`(35)
`
`Continued
`
`Page 10 of 50
`
`930
`
`Page 10 of 50
`
`
`
`TABLE 28.2—Com‘inued ’
`
`
`Trademark
`
`Polyoxyethylene (20) nony1-
`phenyl ether
`Polyoxyethylene (9) nonyl~
`phenyl ether
`Polyoxyethylene (9) 11onyl-
`phenyl ether
`3. Mixed Polyoxyethylene-
`Polyoxypropylene Ethers
`(see PLURONIC Grid)
`PLURONIC L44
`PLURONIC L62
`PLURONIC L64
`PLURONIC P68
`PLURONIC F68
`PLURONIC F68
`PLURONIC F108
`
`Concen-
`tration
`(°/U) and
`vehicle“
`
`Condition,
`sex,
`species of
`animal
`
`Golden shiner
`
`Golden shiner
`
`Guppy
`
`Route“
`
`Immersion
`in H20
`Immersion
`ifl H20
`Imrnersion
`in H20
`
`Rat
`Rat
`Rat
`Mouse
`Rat, rabbit’
`Dog, guinea pig
`Rat
`
`Oral
`Oral
`Oral
`Oral
`Oral
`Oral
`Oral
`
`Esters.‘
`
`LDso
`per kg
`
`Ref.
`
`14~l 8 ppm“ (37)
`
`4-5 ppm‘ (158)
`
`> 20 ppm‘
`
`(158)
`
`5 g
`5 g
`5 g
`>15 g
`>15 g
`>15 g
`> 37 g
`
`(47)
`(47)
`(47)
`(47)
`(47)
`(47)
`(43)
`
`1. Polyoxyethylene Fatty Acid
`K Esters
`'
`NOPALCOL 6-L
`[polyoxyethylene (14) mono-
`laurate]
`NOPALCOL 6-L
`MYRJ 45
`[polyoxyethylene (8) mono-
`stearate]
`MYRJ 45
`MYRJ 45
`PEG 400 monostearate
`[polyoxyethylene (9) mono-
`stearate]
`PEG 400 distearate
`[polyoxyethylene (9)
`distearate}
`CARBOWAX 1000 mono-
`stearate
`[polyoxyethylene (23) mono-
`stearate}
`CARBOWAX 1000 distearate
`[polyoxyethylene (23)
`distearate]
`MYRJ 52
`[polyoxyethylene (40) mono-
`stearate]
`Polyoxyethylene monostearate“
`
`Mouse
`
`Mouse
`Rat
`
`Hamster
`Rabbit
`Mouse
`
`Mouse
`
`Mouse
`
`Mouse
`
`Rat
`
`Rat
`
`Page 11 of 50
`
`931
`
`Oral
`
`H10
`
`>25 g
`
`(49)
`
`I.V.
`Oral
`
`Oral
`Oral
`I.V.
`
`LV.
`
`I.V.
`
`I.V.
`
`Oral
`
`Ora]
`
`H20
`
`H20
`
`H20
`
`0.5 g
`64.0 ml
`
`(49)
`(50)
`
`27.0 ml
`> 12.0 ml
`0.25 g
`
`(50)
`(50)
`(49)
`
`0.365 g
`
`(49)
`
`0.87 g
`
`(49)
`
`I-I20
`
`0.22 g
`
`(49)
`
`>20.0 g
`
`(31)
`
`53.0 ml
`
`(50)
`Continued
`
`Page 11 of 50
`
`
`
`TABLE 28.2—Conn'rmed
`
`
`Concen-
`Condition,
`tration
`sex,
`species of
`(‘3/0) and
`LD5o
`Trademark
`animal
`Route“
`vehicle”
`per kg
`Ref.
`
`
`Polyoxyethylene monostearate“
`Polyoxyethylene monostearate“
`NOPALCOL 4-0
`[polyoxyethylene (9) n1ono-
`oleate]
`NOPALCOL 4-0
`NOPALCOL 6-0
`[polyoxyethylene (14) mono-
`oleate]
`NOPALCOL 6-0
`EMULPHOR EL-719
`[polyoxyethylene (40) castor oil]
`BMULPI-IOR EL-719
`2. Partial Fatty Acid Esters of
`Polyols and Anliydropolyols
`- SPAN 20
`(sorbitan monolaurate)
`SPAN 40
`(sorbitan monopalmitate)
`SPAN 60
`(sorbitari monostearate)
`SPAN 60
`SPAN 65
`(sorbitan tristearate)
`SPAN 80
`(sorbitan monooleate)
`Glycerol monolaurate
`3. Partial Fatty Acid Esters of
`Polyoxyethylene Polyols and
`Anhydropolyols
`TWEBN 20
`[polyoxyethylenc (20) sorbitan
`monolaurate]
`TWEBN 20
`TWEBN 20
`TWEEN 20
`TWEBN 20
`TWEBN 20
`TWEEN 21
`[polyoxyethylene (4) sorbitan
`monolaurate]
`TWEBN 2]
`TWEEN 40
`{polyoxyethylene (20) sorbitan
`monopalmitate]
`
`Hamster
`Rabbit
`Mouse
`
`Mouse
`Mouse
`
`Mouse
`Rat
`
`Guinea pig
`
`Male rat
`
`Male rat
`
`Male rat
`
`Rat
`Female rat
`
`Male rat
`
`Rat
`
`Oral
`Oral
`Oral
`
`I.V.
`Oral
`
`I.V.
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`Oral
`
`Oral
`
`Oral
`
`19.5 ml
`> 15.0 ml
`>25 g
`
`(50)
`(50)
`(49)
`
`”'
`
`1.08 g
`>25 g
`
`(49)
`(49)
`
`0.5 g
`70 ml
`
`70 ml
`
`(49)
`(33)
`
`(33)
`
`>20 ml"
`
`(31)
`
`H30
`
`H;O
`H20
`
`H20
`100
`
`100
`
`100
`
`>10 g“
`
`>10 3"
`
`31.0 g
`50 (in H;O) >10 g‘
`
`(31)
`
`(31)
`
`(50)
`(31)
`
`100
`
`>10 ml”
`
`(31)
`
`53.4 ml
`
`(50)
`
`Male rat
`
`Oral
`
`100
`
`>20 ml“
`
`(31)
`
`Rat
`Faster! rat
`Mouse
`Mouse
`Hamster
`Male rat
`
`Fasted rat
`Male rat
`
`Oral
`Oral
`Oral
`I.V.
`Oral
`Oral
`
`Oral
`Oral
`
`100
`H20
`H20
`
`100
`
`100
`100
`
`36.7 ml
`34.7‘
`>25 g
`3.75 g
`18.0 ml
`>10 ml”
`
`(50)
`(357)
`(49)
`(49)
`(50)
`(31)
`
`33.81
`>20 ml”
`
`(357)
`(31)
`
`Continued
`
`Page 12 of 50
`
`932
`
`Page 12 of 50
`
`
`
`TABLE 28.2—C'<mt:'m:ed
` .._.m__
`
`Trademark
`
`Condition,
`sex,
`species of
`animal
`
`TWEEN 40
`TWEEN 61
`[polyoxyethylene (4) sorbitan
`mono téarate]
`TWEE
`60
`
`
`
`Fasted rat
`Female rat
`
`Rat
`
`TW EN 60
`Polyoxyethylene (40) sorbitan
`monostearate
`
`Fasted rat
`Rat
`
`Concen-
`tration
`Wu) and
`vehicle“
`
`100
`
`100
`
`100
`
`LD50
`per kg
`
`Ref.
`
`34.21
`>10 g‘
`
`(357)
`(31)
`
`>20 ml”
`
`(31)
`
`33.83
`> 60.0 ml
`
`(357)
`(50)
`
`Route“
`
`Oral
`Oral
`
`Oral
`
`Oral
`Oral
`
`Female rat
`
`Oral
`
`100
`
`>10 ml"
`
`(31)
`
`Male rat
`
`Fasted rat
`Male rat
`
`Rat
`Fasted rat
`Mouse
`Mouse
`Male rat
`
`Oral
`
`Oral
`Oral
`
`Oral
`Oral
`Oral
`I.V.
`Oral
`
`100
`
`100
`100
`
`100
`H10
`H20
`100
`
`>20 ml"
`
`(31)
`
`36.6’
`>20 ml‘
`
`(357)
`(31)
`
`54.5 ml
`38.0‘
`>25 g
`53.8 g
`>20 ml"
`
`(50)
`(357)
`(49)
`(49)
`(31)
`
`TWEEN 65
`[polyoxyethylene (20) sorbitan
`tristearate]
`TWEEN 81
`[polyoxyethylene (5) sorbitan
`monooleate]
`TWEEN 81
`TWEEN 80
`[polyoxyethy1ene(20) sorbitan
`monooleate]
`TWEEN 80
`TWEEN 80
`TWEEN 30
`TWEEN 80
`TWEEN 85
`Epolyoxyethylene (20) sorbitan
`trioleate]
`
`Fasted rat Oral 100 36.4‘TWEBN 85 (357)
`
`
`
`
`
`
`
`
`
`" I.P., intraperitoneal; I.V., intravenous; S.Q., subcutaneous.
`" 100 per cent indicates undiluted administration.
`" Figures in parentheses after polyoxyethylene represent, to the best of our knowledge, the number of
`E0 groups per molecule of product.
`_
`" Owing to lack of data on chemical composition, products are not defined chemically beyond general
`classification.
`‘
`'’ Weightfvolumg,
`3' Rabbits given 0.1 and 1.0 g/kg PLURONIC F68 LV. showed no toxic symptoms. Given I.P. to rats
`5 and 10 gfkg resulted in the death of a few animals (47).
`" All members of a group of rats survived this dosage, which was the largest administered.
`" Polyoxyethylene adducts of stearic and ricinoleic acids (MW 600 and 2700, respectively) were tolerated
`by rats up to doses of 16 gfkg (51).
`‘Pollution of water with a polyoxyethylene octylphenol adduct at a concentration of 3 ppm killed
`rainbow trout after 24-hr exposure (I59).
`4 All members of a group of 10 (5 male and 5 female) rats survived.
`
`933
`
`Page 13 of 50
`
`Page 13 of 50
`
`
`
`934
`
`P. H. ELWORTHY AND JOSEPH F. TREON
`
`In the case of the polycxyethylene p-t-octyl phenyl ether series, the acute oral
`toxicity in the fasted male rat appears to increase somewhat when the average
`number of moles of ethylene oxide increases from 1 to about 10; thereafter, the
`toxicity decreases slowly until 20 moles are obtained; between 20 and 30 moles
`the acute toxicity decreases sharply. A somewhat similar relationship also obtains
`with the polyoxyethylene nonylphenyl ethers. This effect has been suggested to
`be due to a decreased absorption of the longer chain (39).
`....a
`By comparing Tables 28.1 and 28.2, it can be seen that the conversion of a
`polyethylene glycol into its phenyl ether gives a considerable increase in toxicity;
`this is particularly apparent when the LD50 value of nonaethylene glycol is
`compared with those for polyoxyethylene nonyl- and octylphenyl ethers con-
`taining roughly the same number of oxyethylene units. The corresponding
`change in acute toxicity does not occur with the ester derivative.
`In general, the acute oral toxicities of the esters (Table 28.2) are less than those
`of the ethers.
`
`Although not employed for intravenous purposes, it is of interest to note the
`extremely large dosage of the hydrolyzate from certain of the partial fatty acid
`esters of polyols and anhydropoiyols and their polyoxyethylene derivatives are
`necessary to obtain an LD5o. For example, the LD50 for the hydrolyzed polyol
`from SPAN 85 when given intravenously t.o fasted female mice is between 15
`and 20 gfkg of body weight, with all the members of the group surviving at
`15 g/kg; in the case of fasted female mice, the LD50 values (I.V.) for the hydro-
`lyzed polyol from TWEEN 60 and TWEEN 80 were, respectively, 18.8 and 19.2
`gfkg of body weight; in the case of fasted female rats, these values were, respec-
`tively, 24.9 and 25.7 g/kg of body weight (45). The acute oral toxicities of the
`hydrolyzed polyol from TWEEN 60 and TWEEN 80, when given orally to
`fasted female rats were, respectively, 47.5 and 42.2 g/kg of body weight (45).
`No significant gross pathology was reported from autopsies on rats killed
`with SURFONIC N90 (35). TRITON CF10 caused death of rats by progressive
`weakness and no convulsive phenomena were involved (40). The PLURONIC
`products L44, 62, and 64 gave depression, prostration, and death by respiratory
`paralysis. Autopsies showed symptoms of massive vascular dilation with dis-
`tention produced by the hydrogogue effect of these substances (47). Gross and
`microscopic alterations of the tissues were not observed with the ingestion of
`the SPAN and TWEEN products (31).
`
`28.3. SUBACUTE AND CHRONIC TOXICITY
`
`An individual may ingest a food additive such as a nonionic emulsifier every
`day (1,5,52). An estimate of the maximum practical limit of such from foods is
`0.75 g/day/person (52), which is equivalent to 0.015 g/kg/day for a 5'0-kg
`(110-lb) person. The World Health Organization (11) lists, without regard for the
`specific food, the acceptable daily intake zone of emulsifiers for man according
`to certainchemical classifications. The acceptable unconditional amount that
`
`Page 14 of 50
`
`Page 14 of 50
`
`
`
`PHYSIOLOGICAL ACTIVITY
`
`935
`
`may be ingested in the food varies for the various classes from 0.020 to 0.125
`gfkg/day. The U.S. also permits certain emulsifiers in food, usually according to
`a specified amount in a particular food, and according to functionability and
`safety. Justification of a food additive is both on the basis of safety and function-
`ability with respect to technological improvement. Food additives must, there-
`fore, pass rigid tests of safety usually involving metabolism and “lifetime”
`studies in certain species of animals.
`
`A. Polyethylene Glycols
`
`This section is not intended to be comprehensive, but to outline some salient
`features of polyethylene glycols. Furthermore, the monomer and lower polymers
`are not intended as direct food additives.
`Oxalate bladder stones were observed among rats which were fed on dietary
`levels of 1 and 2 per cent of ethylene glycol for 2 years by Morris et al. (55).
`When ethylene glycol was incorporated into the diet of rats for 2 years by Blood
`(56) some oxalate calculi were observed in the kidneys of the females at 4 per
`cent and the males at
`1 per cent; the 0.1 per cent level was considered a
`“no-effect level” for all pertinent parameters. The addition of ethylene glycol
`to the diet of two male monkeys at the lev.el of 0.2 per cent and 1 female
`m