NONIONIC SURFACTANTS
`
`EDITED BY
`
`MARTIN J . SCHICK
`LEVER BROTHERS do.
`RESEARCH CENTER
`
`EDGEWATER, NEW JERSEY ‘
`
`196.7
`
`MARCEL DEKKER, INC., NEW YORK
`
`Page 1 of 50
`
`LUPIN EX 1072
`
`LUPIN EX 1072
`
`Page 1 of 50
`
`

`

`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
`
`9%
`
`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.
`
`Fig. 17.4.
`Fig. 17.5.
`Fig. 17.7.
`
`Fig. 17.8.
`
`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.
`
`Table 17.3.
`
`Table 17.9.
`Table 17.12.
`Table 21.1.
`
`M. J. Schick, J. Colfoid Sci'., 17, 801 (1962) (Fig. 1).
`Ibid., 18, 37s (1963) (Fig. 3).
`P. Beeher, ibid., 16, 49 (1961) (Fig. 1).
`Ibid., 17, 325 (1962) (Fig. 2).
`K. Shinoda, T. Nakagawa, B. Tamamuehi, and T. Isen'iura, Colloidal Surfac-
`tants, 1963, p. 140 (Fig. 2.27).
`Ibid., p; 141 (Fig. 2.28).
`M. E. L. McBain and E. Hutchinson, Solubilizati‘on and Related Phenomena,
`1955, p. 169 (Fig. 5.14).
`B. A. Mulley and A. D. Metcalf, J. Colloid Sci, 1'7, 525 (1962) (Fig. 2).
`111121., 1'1, 526 (1962) (Fig. 3).
`K. Shinoda, T. Nakagawa, B. Tamamuchi, and T. Isemura, Colloidal Surfac-
`tants, 1963, p. 142 (Fig. 2.29).
`T. Nakagawa, K. Kuriyama, and H.
`(1960) (Fig. 5).
`W. N. Maclay, ibid., 11, 281 (1956) (Fig. 6).
`M. J. Schick, 171171., 17, 312 (1962) (Fig. 7).
`W. N. Maclay, 175171., 11, 277 (1956) (Fig. 4).
`B. A. Mulley and A. D. Metealf, ibi'd., 19, 508 (1964) (Fig. 6).
`Ibid., 19, 504 (1964) (Fig. 2).
`S. Ross, £61711, 6, 502-504 (1951) (Figs. 1-3).
`B. Maekor, 177171., 6, 492 (1951) (Fig. l).
`E. Mackor and J. H. van cler Waals, 111771., 7, 535 (1952) (Figs. 3 and 4).
`J. F. Danielli, K. G. A._Pa.nkhurst, and A. C. Riddiford, RecentProgress 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, ibid., 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
`
`Page 2 of 50
`
`iv
`
`Page 2 of 50
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`CHAPTER 28
`
`PHYSIOLOGICAL ACTIVITY
`
`OF NONIONIC SURFACTANTS
`
`P. H. Elworthy
`DEPARTMENT OF PHARMACY
`UNIVERSITY OF STRATHCLYDE, GLASGOW, SCOTLAND
`
`Joseph F. Treon
`BIO-MEDICAL RESEARCH DEPARTMENT
`ATLAS CHEMTCAL INDUSTRIES, INC... WILMINGTON, DELAWARE-
`
`Introduction ...................................................... 924
`28.1.
`28.2. Acute Toxicity .................................................... 925
`28.3. Subacute and Chronic Toxicity ...................................... 934
`A. Polyethylene Glycols ............................................ 935
`B. Polyoxyethylene Phenyl or Alkylphenyl Ether Derivatives ............. 936
`C. Polyoxyethylene Alkyl Ethers ..................................... 936
`D. Polyoxyethylene Fatty Acid Esters ................................. 937
`E. Partial Esters of Sorbitan ......................................... 939
`F. Partial Esters of Polyoxyethylene Sorbitan Fatty Acids ............... 940
`G. Other Surfactants ............................................... 941
`H. Tests on Human Subjects ........................................ 941
`I. Some Miscellaneous Effects ...................................... 943
`J.
`intravenous Emulsions ........................................... 943
`28.4. Metabolic Fate ..................................................... 944
`28.5. Effects on the Gastrointestinal Tract .................................. 947
`A. Fat Absorption ................................................ 947
`B. Other Effects
`.................................................. 947
`28.6. Eflects on the Cardiovascular System ..................... ‘............ 947
`28.7. Effects on Blood ...................... .
`. ........................... 948
`A. General ........................................................ 948
`B. Proteins and Lipoproteins ........................................ 948
`C. Triglycerides ............................. i ..................... 949
`D. Cholesterol ..................................................... 950
`28.8. Miscellaneous Pharmacological Effects ................................ 951
`28.9. Effects on Isolated Tissues .......................................... 951
`28.10. Some Effects with Enzymes .......................................... 952
`28.11. Effects on the Eye ................................................. 953
`28.12. Effects on the Skin ..................................... . ........... 954
`A. Irritation ....................................................... 954
`B. Tumor Promotion ............................................... 956
`28.13. Effects on Microorganisms ........................................... 958
`28. 1 4. Phytotoxicity ...................................................... 960
`Appendix A. Toxicity of Ethylene Oxide ................................... 960,
`Appendix B. Toxicity of Propylene Oxide .................................. 961
`References .
`.
`.
`. ............... . .......................................... 961
`
`Page 3 of 50
`
`923
`
`Page 3 of 50
`
`

`

`924
`
`P. H. ELWORTHY AND JOSEPH F. TREON
`
`28.1. INTRODUCTION
`
`This chapter is a general review of the physiological properties of nonionic
`surfactants. It is mainly'concerned 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 a_few
`large chemical classifications: ethers, esters, and products withaboth 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 (24]).
`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
`US. (13). These are also considered acceptable by the Joint Food and Agri-
`cultural Organization (FAO) of the United Nations and World Health Organiza-
`tion WHO) 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
`
`Page 4 of 50
`
`Page 4 of 50
`
`

`

`PHYSIOLOGICAL ACTIVITY
`
`925
`
`Additives (II). MYRJ 45 [polyoxyethylene (8)* stearate] and MYRJ 52
`[polyoxyethylene (40) stearate] are accepted by FAQ/WHO (H); 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 US. (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
`(NBA) in the US.
`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, which'are manufactured
`with suitable controls to assure their uniformity (11,22—24).
`
`28.2. ACUTE TOXICITY
`
`Since the polydityethylene 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 (4]). 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
`
`L135 0:
`LDso,
`Glycol
`MW
`gflcg
`nimble/kg
`Ref.
`
`
`7
`
`(22)
`13 8
`8.54
`62
`Ethylene
`(27)
`196
`20.76
`106
`Diethylene
`(27)
`147
`22.06
`150
`Triethylene
`(27)
`169
`32. 77
`194
`Tetraethylene
`(27)
`1 12
`31 .64
`282
`Hexaethylene
`(27)
`90
`3 7.41
`404
`Nonaethylene
`(28,30)
`144
`28.9
`200‘I
`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.
`a 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 difi'erence 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 (LD5O) obtained on TERGITOL 15—8—9, which is poiyoxyethylene (9)
`pentadecyl ether, is compatible with the data on polyoxyethylene (10) ethers of
`cety], 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 LDso when
`the product was given orally as a 50 percent 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
`
`Concen—
`Condition,
`tration
`sex,
`species of
`(%) and
`LDSO
`
`Trademark
`animal
`Route”
`vehicle”
`per kg
`Ref.
`
`1.
`
`Polyoxyethylene Alkyl Ethers
`BRIJ 30
`[polyoxyethylene (4) lauryl
`ether]°
`BRIJ 30
`BRIJ 30
`BRIJ 30
`
`BRIJ 30
`
`Polyoxyethylene (approx. 10)
`lauryl ether
`BRIJ 35
`[polyoxyethylene (23) lauryl
`ether]
`
`BRIJ 35
`BRIJ 35
`
`BRIJ 35
`
`Bikers
`
`Fasted male rat
`
`Oral
`
`Fasted female rat Oral
`Fasted male mouse Oral
`Fasted female
`Oral
`mouse
`
`Nonfasted female Oral
`rat
`
`Mouse
`
`S.Q.
`
`100
`
`100
`100
`100
`
`100
`
`2
`
`8.60 g
`
`(41)
`
`9.07 g
`4.94 g
`7.6l g
`
`(41)
`(42)
`(42)
`
`8.46 g
`
`(42)
`
`0.741.] g (43)
`
`Fasted male rat
`
`Oral
`
`20 (in H10)
`
`8.60 g
`
`(4I,42)
`
`Fasted: female rat Oral
`Fasted female
`Oral
`mouse
`
`20 (in H20)
`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) eetyl
`ether]
`“w
`BRIJ 58
`BRIJ 72
`[polycxyethylene (2) stearyl
`ether]
`
`Fasted male rat
`
`Oral
`
`50 (in H20) >25.l g
`
`(45)
`
`Fasted female rat Oral
`Fasted male rat
`Ora]
`
`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
`Ora]
`
`3.95 g
`25 (in H20)
`40 (in H10) >251 g
`
`BRIJ 72
`
`Fasted female rat Oral
`
`40 (in H20) >25.l g
`
`927
`
`Page 7 of 50
`
`(45)
`(45)
`
`(45)
`(45)
`
`(45)
`Continued
`
`Page 7 of 50
`
`

`

`TABLE 28.2—Caminued
`
`Concen-
`Condition,
`tration
`sex,
`species of
`(‘73) and
`LB”
`
`animal
`Route“
`vehicle”
`per kg
`Ref.
`
`Fasted male rat
`
`Ora]
`
`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 H20)
`
`25.8 g
`3.58 g
`
`(45)
`(41,45)
`
`Fasted female rat Oral
`Fasted male rat
`Oral
`
`25 (in H20)
`25 (in H20)
`
`2.70 g
`3.10 g
`
`(41)
`(45)
`
`Faster! 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 H20)
`
`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)
`(3'7)
`
`(37)
`(37)
`
`Conflnué‘d
`
`Trademark
`
`BRIJ 76
`[polyoxyethylene (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
`[polyoxyethylene (3) tridecyl
`ether]
`SURFONIC TD—30
`
`TERGITOL 15 S 9
`[polyoxyethylene (9) pentadecyl
`ether]
`EMULPHOGENE BC 720”
`(polyoxyethylene tridecy] ether)
`EMULPHOR ON 870“
`EMULPHOR 0N 370d
`EMULPHOGENE BC 840-I
`
`TEXOFOR Ail"
`
`TEXOFOR A4“
`
`TEXOFOR A6“
`
`TEXOFOR 131d
`TERGITOL XD‘
`TERGITOL ){D‘
`
`TERGITOL XH“
`TERGITOL Xl-I‘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
`
`LP.
`
`LP.
`
`LP.
`
`LP.
`Oral
`Skin pene-
`tration
`Ora]
`Skin pene-
`tration
`
`Page 8 of 50
`
`928
`
`Page 8 of 50
`
`

`

`TABLE 28.2—Canrinued
`
`Concen-
`Condition,
`tration
`sex,
`species of
`(%) and
`LDso
`Trademark
`animal
`Route“
`vehicle“
`per kg
`Ref.
`
`
`Rabbit
`
`Skin pene-
`tration
`
`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 H10)
`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)
`
`TERGITOL 15-8-9
`
`.
`2a. Polyoxyethylene Phenyl Ethers
`PYCAL 94"
`PYCAL 94"
`PYCAL 94"
`PYCAL 94d
`PYCAL 94d
`PYCAL 94‘i
`PYCAL 94"
`
`PYCAL 94"
`
`2b. Polyoxyethylene p-t—octylphenyl
`ether
`
`Polyoxyethylene (l) p—t-octyl—
`phenyl ether
`Polyoxyethylene (3) p-t-octyl-
`pheny] ether
`Polyoxyethylene (4) p—t—octyl-
`phenyl ether
`IGEPAL Ca—630
`[Polyoxyethylene (8) isooctyl—
`phenyl ether]
`IGEPAL Cal-630
`Polyoxyethylene (9.7) p-t—octyl-
`phenyl ether
`Polyoxyethylene (12.5) p—t—octyl—
`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"
`20. Polyoxyethylene Nonylphenyl
`Ethers
`
`IGEPAL C0430
`[polyoxyethylene (4) nonyl-
`phenyl ether]
`IGEPAL C0430
`
`Fasted male rat
`
`Oral
`
`Fasted male rat
`
`Oral
`
`Fasted male rat
`
`Oral
`
`Rat
`
`Guinea pig
`Fasted male rat
`
`Oral
`
`Ora]
`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 m]
`
`(33)
`
`1.65 ml
`1.7 g
`
`(33)
`(38,39)
`
`1.8 g
`
`(33)
`
`(39)
`
`(39)
`
`(39)
`
`(39)
`
`(39)
`
`Fasted male rat
`
`Oral
`
`70 (in H20)
`
`28 g
`
`Fasted male rat
`
`Oral
`
`30 (in H20)
`
`2.7 g
`
`Faster} male rat
`
`Oral
`
`70 (in H10)
`
`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——C0ntinued
`
`
`Trademark
`
`
`Condition,
`sex,
`species of
`animal
`
`Concen-
`tration
`(%) and
`LDSD
`Route”
`vehicle”
`per kg
`Ref.
`
`
`TERGITOL NP 14
`{polyoxyethylene (4) nonyl-
`phenyl ether]
`TERGITOL NP 14
`
`TERGITOL NP 27
`[polyoxyethylene (7) nonyL
`phenyl ether]
`TERGITOL NP 27
`
`IGEPAL C0-630
`[polyoxyethylene (8-9) nonyl—
`phenyl ether]
`IGBI’AL CO—630
`TERGITOL TP 9
`[polyoxyethylene (9) nonyl-
`phenyl ether}
`TERGITOL TP 9
`
`Polyoxyethylene (9-10) nonyl-
`phenyl ether
`TERGITOL NPX
`[polyoxyethylene (10.5) nonyl-
`pheny] ether]
`TERGITOL NPX
`
`IGEPAL C0430
`
`[polyoxyethylene (13.5) nonyl-
`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) 1101in-
`pheny] ether]
`TERGITOL NP 40
`
`IGEPAL D1870"
`SURFONIC N—90d
`SURFONIC N—90"
`
`Rat
`
`Oral
`
`4.29 ml
`
`(37)
`
`Rabbit
`
`Rat
`
`Rabbit
`
`Rat
`
`Skin pene-
`tration
`Oral
`
`Skin pene-
`tration
`Oral
`
`Guinea pig
`Rat
`
`Oral
`Oral
`
`Rabbit
`
`Female rat
`
`Skin pene-
`tration
`Oral
`
`M
`
`2.52 ml
`
`(37)
`
`3.67 ml
`
`(37)
`
`1.78 ml
`
`(37)
`
`3 g
`
`(33)
`
`2 g
`2.6 m}
`
`(33)
`(37)
`
`2.8 ml
`
`(37)
`
`100
`
`100
`
`10 (in H30)
`
`1.6 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 (in 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)
`
`50 (in H20)
`H20
`100
`
`31.5 g
`2.58 g
`>8 g
`
`(33)
`(35)
`(35)
`
`Continued
`
`Page 10 of 50
`
`930
`
`Page 10 of 50
`
`

`

`TABLE 28.2—Continued ’
`
`
`Trademark
`
`Polyoxyethylene (20) nonyl—
`phenyl ether
`Polyoxyethylene (9) nonyl~
`phenyl ether
`Polyoxyethylene (9) uonyl—
`phenyl other
`3. Mixed Polyoxyethylene-
`Polyoxypropylene Ethers
`(see PLURONIC Grid)
`PLURONIC L44
`PLURONIC L62
`PLURONIC L64
`PLURONIC P68
`PLURON'IC F68
`PLURONIC F68
`PLURONIC F108
`
`Concen—
`tration
`(%) and
`vehicle“
`
`Condition,
`sex,
`species of
`animal
`
`Golden Shiner
`
`Golden Shiner
`
`Guppy
`
`Route“
`
`Immersion
`in H20
`Immersion
`in H20
`Immersion
`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—] 8 13me (37)
`
`4—5 ppm” (158)
`
`> 20 ppm“
`
`(158)
`
`S g
`5 g
`5 g
`>15 3
`>15 g
`>15 g
`> 37 g
`
`(47)
`(47)
`(47)
`(47)
`(47)
`(47)
`(48)
`
`1. Polyoxyethylene Fatty Acid
`7 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)
`
`LV.
`Oral
`
`Oral
`Oral
`LV.
`
`LV.
`
`I.V.
`
`LV.
`
`Oral
`
`Oral
`
`H20
`
`H20
`
`H20
`
`0.5 g
`64.0 ml
`
`(49)
`(50)
`
`27.0 ml
`>121) ml
`0.25 g
`
`(50)
`(50)
`(49)
`
`0.365 g
`
`(49)
`
`0.87 g
`
`(49)
`
`H20
`
`0.22 g
`
`(49)
`
`>20.0 g
`
`(31)
`
`53.0 ml
`
`(50)
`Continued
`
`Page 11 of 50
`
`

`

`TABLE 28.2—Continued
`
`
`Concen-
`Condition,
`tration
`sex,
`species of
`(9/0) and
`LDso
`Trademark
`animal
`Route“
`vehicle”
`per kg
`Ref.
`
`
`Polyoxyethylene rnonostearatr,ll
`Polyoxyethylem monostearate"
`NOPALCOL 4-0
`[polyoxyethylene (9) mono-
`oleate]
`NOPALCOL 4-0
`NOPALCOL 60
`[polyoxyethylene (14) mono-
`oleate]
`NOPALCOL 6-0
`EMULPHOR EL-719
`[polyoxyethylene (40) castor oil]
`BMULPHOR EL-719
`2. Partial Fatty Acid Esters of
`Polyols and Anhydropolyols
`, SPAN 20
`(sorbitan monolaurate)
`SPAN 40
`(sorbitan monopalmitate)
`SPAN 60
`(sorbitau 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
`[polyoxyethylene (20) sorbitan
`monolaurate]
`TWEBN 20
`TWEEN 20
`TWEEN 20
`TWEEN 20
`TWEEN 20
`TWEEN 21
`[polyoxyethylene (4) sorbitan
`monolaurate]
`TWEEN 21
`TWEEN 40
`Epolyoxyethylene (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
`
`H10
`H20
`
`H20
`100
`
`100
`
`100
`
`> 10 g“
`
`>10 3‘1'
`
`31.0 g
`50 (in H20) >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;};
`>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‘ontinued
`____._—._____—___.—__—_.m—-———-——-———
`
`Concen-
`Condition,
`tration
`sex,
`LDso
`(%) and
`species of
`Trademark
`animal
`Route“
`vehicle”
`per kg
`Ref.
`
`
`TWEEN 40
`TWEEN 61
`[polyoxyethylene (4) sorbitan
`mono téarate]
`TWEE
`60
`[pol oxyethylene (20) sorbitan
`, onostearate}
`TW‘ EN 60
`Polyoxyethylene (40) sorbitan
`monostearate
`
`
`
`Fastcd rat
`Female rat
`
`Rat
`
`Fasted rat
`Rat
`
`Oral
`Oral
`
`Oral
`
`‘
`Oral
`Oral
`
`100
`
`100
`
`100
`
`34.21
`>10 3'
`
`(357)
`(31)
`'
`
`>20 ml"
`
`(31)
`
`33.81
`> 60.0 ml
`
`(357)
`(50)
`
`Female rat
`
`Oral
`
`100
`
`>10 ml"
`
`(31)
`
`100
`
`100
`100
`
`100
`H10
`H20
`100
`
`>20 ml“
`
`(31)
`
`36.61
`>20 ml“
`
`(357)
`(31)
`
`54.5 ml
`38.0J
`>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
`[polyoxyethylene (20) sorbitan
`monooleate]
`TWEEN 80
`TWEEN 80
`TWEEN 80
`TWEEN 80
`TWEEN 85
`Epolyoxyethylene (20) sorbitan
`trioleate]
`(357)
`36.41
`100
`Oral
`Fasted rat
`TWEBN 85
`
`Male rat
`
`Fasted rat
`Male rat
`
`Rat
`Fasted rat
`Mouse
`Mouse
`Male rat
`
`Oral
`
`Oral
`Oral
`
`Oral
`Oral
`Oral
`LV.
`Oral
`
`“ I.P., intraperitoneal; LV‘, 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 LP. to rats
`5 and 10 glkg 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 g/kg (51).
`‘Pollution of water with a polyoxyethylene octylphenol adduct at a concentration of 3 ppm killed
`rainbow trout after 24—hr exposure (I59).
`J 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 polyoxyethylene 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).
`up
`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 LD50. For example, the LD50 for the hydrolyzed polyol
`from SPAN 85 when given intravenously to 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
`gikg 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 (4?). Gross and
`microscopic alterations of the tissues were not observed with the ingestion of
`the SPAN and TWEEN products (3]).
`
`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 50-19%
`(110-lb) person. The World Health Organization (1]) lists, without regard for the
`specific food, the acceptable daily intake zone of emulsifiers for man according
`to certain'chemical 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 a]. (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 level of 0.2 per cent and 1 female
`monkey at the level of 0.5 per cent by Blood for 3 years produced no toxic
`effects (57).
`When diethylene glycol was fed to rats at dietary levels of 1, 2, and 4 per cent
`for a 2-year period, toxic eflects were observed by Fitzhugh and Nelson (53).
`Growth was retarded at all three levels. Bladder stones, in some instances,
`followed by bladder tumors (papilloma), were observed at the 2 and 4 per cent
`dietary levels. Kidney and liver lesions Were observed in some of the rats.
`Although it cannot be stated unequivocally, it is rather likely that the diethylene
`glycol employed by Fitzhugh and Nelson contained more ethylene glycol than
`the diethylene glycol employed later by Weil et a]. (58).
`More recently, Weil et a1. (58) fed rats on a diet of Purina Laboratory Chow
`containing diethylene glycol; their commercial diethylene glycol was low in
`ethylene glycol, containing 0.031 per cent. In the rats fed a 4 per cent concentra-
`tion of diethylene glycol by Wei] et a1. (58) bladder stones and a tumor were
`formed, but at 2 per cent neither stones or tumors resulted. Stones and a few
`tumors resulted in recipient rats that were never fed diethylene glycol but which
`received implantscof either a calcium oxalate stone or a glass bead, or which
`were sham-operated. Bladder tumors were never developed without the preceding
`or concurrent presence of a foreign body. It was concluded that diethylene glycol
`is not a primary carcinogen, but when fed in very high concentrations is the
`cause of some urinary blad