Imerosioal our ofTolgy 24(Supp 375-118 2005, Copyrigh ® Ameria Coleg of Tosi ISSR LO 513102 874K one DoE 10 Tosrosistsomsi170 Final Report of the Safety Assessment of Acacia Catechu Gum, Acacia Concinna Fruit Extract, Acacia Dealbata Leaf Extract, Acacia Dealbata Leaf Wax, Acacia Decurrens Extract, Acacia Farnesiana Extract, Acacia Farnesiana Flower Wax, Acacia Farne: ina Gum, Acacia Senegal Extract, Acacia Senegal Gum, and Acacia Senegal Gum Extract! “These ingredients are derived from various species of the acacia plant Only material derived from Acacia senegal are in eurrent tise according to industry data The concentration at which these ingredients ae reported to be used ranges from 9 0.00014 in tonies, dressings, and other hair-proo arabic Is a techni bic is comprised of various sugars and glucuronic acid residues in in of galactosyl units with branched oligosaccharides is generally recognized as safe as a direct food itive Littl information is available to characterize the extracts of other Acacia plant parts or material from other species Aca- a Fruit Extract was generally described as contain- {ng saponins, alkaloids, and malic acid with parabens and potas- sium sorbate added as preservatives Cosmetic ingredient functions hnave been reported for Acacia Decurrens Extract astringent; skin- conditioning agent—ocelusive) and Acacia Farnesiana Extract (as- tringent), but not for the other Acacias included inthis review Tox- {city data on gum arabie indicates litle or no acute, short-term, ‘or subchronic toxicity Gum arabic Is negative in several geno- toxicity assays, is not a reproductive or developmental toxin, and is not carcinogenic when given intraperitonealy or orally ‘al testing indicated some evidence of skin sensitization with gum arabic The extensive safety test data on gum arabic supports the safety of Acacia Senegal Gum and Acacia Senegal Gum Extract, ‘and it was concluded that these two ingredients are safe as used in cosmetic formulations It was not possible, however, to relate the data on gum arabic to the crude Acacias and thelr extracts from species other than Acacia senegal Therefore, the available data were considered insuflicent to support the safety of Acacia Catechu Gum, Acat Leaf Extract, Acac tract, Acacia Farnesiana Extract, Acacia Farnesiana Flower Wax, ‘Acacia Farnesiana Gum, and Acacia Senegal Extract in cosmetic ing aids Gum name for Acacia Senegal Gum Gum ara Received 15 April 2005; accepted 12 July 2005 ‘Adress comespondence to Wilbur Johnson, Cosmetic Ingredient Review, at CIR, 1101 17th Steet, NW, Suite 310, Washington, DC 20036, USA E-mtil: andersena@cir-safety ong "Reviewed by the Cosmetic Ingredient Review Expert Panel This report was prepared by Wilbur Johnson, Senior Scientific Analyst Writer 75 products The additional data needed to complete the safety as- sessment for these ingredients include (1) concentration of use; the specific chemleal constituents, and clarify the rela- and their extracts and the Acacias ir extracts that are used as cosmetic ingredients; (3) data ‘on contaminants, particularly relating tothe presence of pesticide residues, and a determination of whether Acacia melanoxylon is tused in cosmetics and whether acamelin (a quinone) and mela cacidin (a flavin) are present in the Acacias that are being used; (4) skin sensitization study (ie , dose response to be determined): (6) contact urticaria study at use concentration; and (6) ultraviolet (CV) absorption spectrum; if there is significant absorbance in the LUVA or UVB range, then a photosensitization study may be needed It was also noted that other data may be needed after clarifica- tion of the chemical constituents of the Acacia-derived ingredients INTRODUCTION ‘The Cosmetic Ingredient Review (CIR) Expert Panel began developing a safety assessment of Acecia-derived ingredients in 1996 In 1998, a final safety assessment was issued with the conclusion that the available data were not sufficient to support the safety of these ingredients in cosmetics The needed data included concentration of use; specific chemical constituents, including the relationship between crude Acacias and their ex- tracts and the Acacias and their extracts that are used as cosmetic ingredients; contaminants, particularly relating to the presence of pesticide residues and a determination if Acacia melanoxy- lon is used in cosmeties, and whether acamelin (a quinone) and ‘melacacidin (a flavin) are present in the Acacias that are being used; skin sensitization dose response; contact urticaria data use concentration; and ultraviolet (UV) absorption; if there is signif- icant absorbance in the UVA or UVB range, then a photosensit- zation study may be needed The Panel noted that other studies ‘may be requested after clarification of the chemical constituents of the Acacias In 2000 and 2001, new data were received including use con- centration data on Acacia Senegal and Acacia Senegal Extract;16 information on the composition of gum arabic and various Aca- cig species, UV spectral analyses on Acacia Senegal Gum and Acacia Concinna Fruit Extract, impurities analysis for pesticide residues in gum arabic, human skin tolerance test (skin irita- tion evaluated) on 2% Acacia Concinna Fruit Extact, and hu- ‘man maximization test data on a mascara containing 8% Acacia Senegal Based on this new information, the Panel has prepared this amended safety assessment ‘The terminology with which the cosmetics industry describes these ingredients has changed over the past several years Table | shows the progression of terminology from the mid-1990s to 2004 In some cases (e g , Acacia Concinna Fruit Extract, Acacia Dealbata Leaf Wax, and Acacia Famesiana Gum) the current name for the ingredient (Gottschalck and McEwen 2004) better reflects the source of the plant material The current terminology will be used in this report ‘A key factor in the determination that the current data are sufficient was the finding that gum arabic is the equivalent of Acacia Senegal Gum Accordingly, the following is background information on gum arabic and its relationship to gum produced by the Acacia senegal plant ‘Sudan is the world’s largest producer of gum arabic, and itis the main source of gum in intermational trade Nigeria is the sec- ‘ond largest producer of gum arabic In the Sudan, the term gum arabic is inclusive of two types of gum that are produced and ‘marketed, “hashab” (from Acacia senegal) and “talha” (from Acacia seyal) Gum arabic (hashab) from the Sudan is con- sidered to be of the highest quality, and sets the standard by which other “gum arabies” are judged Acacia senegal intrin- sically produces a high-quality exudate (pale to orange-brown- colored solid) with superior technical performance; and, in the ‘Sudan, the collection, cleaning, sorting, and handling of it up to the time of export is well organized and highly efficient In a ‘wider sense, the name gum arabic often is understood to mean the gum from any Acacia species and is sometimes referred to as “Acacia gum” For example, gum arabic from Zimbabwe is derived from Acacia karroo (Food and Agriculture Organi- zation of the United Nations 1999) Acacia Senegal Gum has bbeen described as the major commercial Acacia gum (Anderson 1988) Although most internationally traded gum arabic comes from Acacia senegal, the term “gum arabic” may not imply a partic~ ‘ular botanical source In a few cases, so-called gum arabie may not even have been collected from Acacia species, but may orig- inate from Combretum, Albizia, or some other genus (Food and Agriculture Organization of the United Nations 1999) In the International Cosmetic Ingredient Dictionary and Handbook, gum arabic is listed as a technical name for Ac: cia Catechu Gum, Acacia Farnesiana Gum, and Acacia Sene- gal Gum (Gottschalck and McEwen 2004) However, since this publication, the Cosmetic, Toiletry, and Fragrance Association (CTFA) determined that gum arabic does not apply t0 Acacia Catecha Gum or Acacia Farnesiana Gum and will no longer be listed in the International Cosmetic Ingredient Dictionary ‘COSMETIC INGREDIENT REVIEW ‘and Handbook as a technicalother name for these ingredients (CTFA 20006) According to CTFA, gum arabic applies tothe dried gummy ‘exudate from branches and stems of Acacia senegal and other Acacia species from Africa, and Acacia catechu and Acacia arnesiana are not Aftican species (CTFA 20006) This definition is similar to the Following definition of Acacia that is found in the National Formulary (United States Pharma~ copeial Convention 2000): Acacia isthe dried gummy exudate fiom the stems and branches of Acacia senegal (Linné) Wilde- now or of other related African species of Acacia (Family Legu- minosae) It has also been described as a complex mixture of calcium, magnesium, and potassium salts of arabic acid Ara- bie acid is a complex of galactose, shamnose, arabinose, and _lucuronie acid (Frutarom Meer Corporation, no date) Gum arabic isa substance that is generally recognized as safe (GRAS) for direct addition to human food under the provisions ‘of Section 184 1330 ofthe Code of Federal Regulations (21 CFR. 184 1330) A report, prepared for the Food and Drug Adminis- tration (FDA), summarizing all available scientific data (1920 to 1972) related tothe safety of gum arabic asa food ingredient has been published (Informatics Inc. 1972) Studies from that report are referenced inthe text ofthis report In a subsequent report (prepared for FDA) evaluating the safety of gum arabic as a food ingredient, the Select Commit- tee on GRAS Substances of the Life Sciences Research Of- fice, Federation of American Societies for Experimental Biology (FASEB), concluded that “there is no evidence in the available information on gum arabic that demonstrates a hazard to the public when itis used at levels that are now current and in the ‘manner now practiced However, itis not possible to determine, without additional data, whether a significant increase in con- sumption would constitute a dietary hazard” (FASEB 1973) ‘The Select Committe also determined that additional exper- iments should be undertaken to evaluate the significance of gum Arabic allergenicity to the poptlation as a whole, and that it ray be advisable to conduct feeding studies in several animal species (including pregnant animals) at dosage levels that ap- proximate and exceed the current maximum daily human intake (see "Noneosmetic Use”) Studies from the 1973 FASEB report are summarized in the text of this report Studies on Acacia Senegal Gum and other species of Acacia (listed in the International Cosmetic Ingredi- ent Dietionaryand Handbook and those not listed) thathave been published since the FASEB report was issued are also included “To ensure that the information in the present report is represen- tative of the published chemistry and toxicity data on species of ‘Acacia, the data presented involve various parts/components of the Acacia tree as well asthe gummy exudate CHEMISTRY Definitions of various ingredients derived from Acacia species in the International Cosmetic Ingredient Dictionary andName ‘Acacia Catecu ‘Acacia Catechu ‘Acacia Concinna Acacia Coneinna Extract ‘Acacia Dealbata Acacia Dealbata Extract ‘Acacia Decurrens Acacia Decurrens Extract Acacia Famesiana Acacia Farnesiana Acacia Famesiana Extract ‘Acacia Senegal ACACIA TABLE n Acacia-derived cosmetic ingredient terminology, description, and function 1993-1997 Terminology (Wenninger and McEwen 1995, 1997) Description lant material erived from Acacia catechu Dried, crushed core of Acacia catechu Plant material derived from Acacia concinna Extract ofthe fut of Acacia concinna Plant material derived from Acacia deatbata Extract ofthe leaves of Acacia dealbata Plant material derived from Acacia decurrens Extract of the acacia, ‘Acacia decurrens Plant material derived from Acacia farnesiana lant material derived from the dried, gummy ‘exudate of the acacia, Acacia farnesiana Extract ofthe flowers and stems of the the ac ‘Acacia farnesiana lant material derived from Acacia senegal ‘Cosmetics function Biological additive Biological additive Not reported Biological additive Not reported Biological additive Not reported Biological additive Not reported Not reported Biological additive Not reported 2004 Terminology (Gottschalck and McEwen 2004) Acacia Catechu Acacia Catechu Gum Acacia Concinna Acacia Concinna Fruit Extract Acacia Dealbata Acacia Dealbata Leaf Extract Acacia Dealbata Leaf Wax Acacia Decurrens Acacia Decurrens Extract Acacia Famesiana Acacia Famesiana Gum Acacia Farmesiana Extract Acacia Famesiana Flower Wax Acacia Senegal Description __Cosmeiies function EU term for Acacia. N/A Catechu Gum Dried, crushed core Not reported of Acacia catechu EU term for Acacia N/A Concinna Fruit Extract, [Extract of the fruit of Not reported. Acacia concinna EU term for Acacia N/A. Dealbata Leaf Extract Extract of the leaves Not reported of the wattle, Acacia dealbata ‘Wax obtained from Skin-conditioning the leaves of agent—emollient; Acacia dealbata skin protectant EUterm for Acacia N/A. Decurrens Extract Extract ofthe acacia, Astringent Acacia decurrens Skin-conditioning agent—Occlusive EU term for Acacia N/A Famesiana Extract, Flower Wax, and Gum, lant material Not reported derived from the dried, gummy exudate of the acacia, Acacia ‘farnesiana Extract of the Astringent flowers and stems of the the acacia, Acacia farnesiana wax obtained from Skin protectant the flowers of Acacia farnesiana EU term for Acacia N/A Senegal Extract, Gum, and Gum Extract, (Continued on next page)8 (COSMETIC INGREDIENT REVIEW ‘TABLE 1993-1997 Terminology (Wenninger and McEwen 1995, 1997) Name Acacia-derived cosmetic ingredient terminology, description, and function (Continued) 2004 Terminology (Goutschatek and McEwen 2004) Cosmetics function Description Cosmetics function Name. Description ‘Acacia senegal Plant material Not reported ‘Acacia Senegal Plant material Not reported derived fiom the Gum derived from the dried, gummy dried, gummy exudate of the exudate of the acacia, Acacia acacia, Acacia senegal senegal ‘Acacia Senegal Extract of the Biological additive Acacia Senegal Extract of the Not reported Extract, flowers and stems Extract flowers and stems of the the acacia, of the acacia, Acacia senegal Acacia senegal Acacia Senegal Extract of the gum Biological additive Acacia Senegal Extract of the gum Not reported Gum Extract, of the acacia, Gum Extract of the acacia, Acacia senegal Handbook are included in Table | (Gottschalck and McEwen 2004) CAS numbers are listed for the following two: Acacia Catechu Gum (CAS no 8001-76-1) and Acacia Senegal Gum (CAS no 9000-01-5) Chemical and Physical Properties Gum Arabic ‘The gummy exudate from the Acacia senegal isa proteina- ceous polysaccharide, with protein contentranging from approx imately 1 5% to 3% for samples from various producing areas, (World Health Organization 1990) (Gum arabic is a white powder that i readily soluble in water, but insoluble in aleohol (Anonymous 1993) Mofecular weights of ~850,000 (Rossetal 1984a, 19846) and ~240,000 (Frutarom “Meer Corporation no date), and a density of 135 to I 49 (Dan- gerous Properties of Industrial Materials Report 1981)have been reported An aqueous solution is acid to litmus (Lewis 1993a) Pazur etal (1986) indicated that gum arabic is composed of p-galactose, rhamnose, L-arabinose, and p-glucuronic acid residues in an arrangement of a main chain of galactosy! units joined by B-D-(1 — 3) linkages and side chains or branched oligosaccharides linked to the main chain by -b-(1 —> 6) link- tages The oligosaccharides may contain terminal rhamnosyl units linked (1 — 3) of terminal erabinofuranosy| units linked (1+ 4) to intemal galactosyl or glucuronosyl units Based on ‘methylation and degradation studies of gum arabic (Acacia sene gal) along with periodate oxidation and other confirmatory re~ actions, the structure for gum arabic shown in Figure 1 was proposed (Informatics Inc. 1972) ‘Gum arabic is almost completely soluble in twice its weight of cold water, and the viscosity of the gum incteases slowly at concentrations up to 25% At concentrations greater than 25%, Acacia senegal the viscosity increases much more rapidly in proportion to the ‘gum content (Frutarom Meer Corporation no date) UV Absorption ‘An increase in absorbance for Acacia Senegal was observed between 400 nm and approximately 260 nm, reaching a plateau at wavelengths ranging from 270 to ~250 nm A rapid increase in absorbance was observed at wavelengths less then 250 nm (Avon Products, Inc 20002) UV absorption spectra provided ‘on two other lots of Acacia gum (Acacia Senegal) were both, similar to the preceding UV spectral analysis (Avon Products, Ine 20006) Methods of Production Gumarabicis produced when the Acacia tres stressedby in- fection, poor nutrition, heat, o lack of moisture The gum exudes through wounds inthe bark that occur naturally or are purposely ‘made to stimulate production The exudate dries rapidly, is col- lected as hardened drops or tears, sorted, graded, and marketed ‘The gum becomes harder during storage; market preferences exist for both the harder (old) and softer (new) gum (FASEB 1973) According to another source, the removal ofthe bark that ad- heres tothe tears is critical tothe production of quality gum ara- ‘Additionally, in orderto produce quality products, elaborate processes for the preclearng of milled gum andthe cenrifuge- tion and filtration of feed solutions for spray dried gum must be followed The major growing regions for gum arabic are in the Sadan and West Africa, and the Kordofan grade is considered the best (Fratarom Meer Corporation, no date) Gum arabic in solid form is imported from the Sudan Ac- cording to one source, the solid is converted to liquid form andACACIA 9 coon 0 ——— CH G00H 0 et 4-9, Ho }—%0 uh-o, Ho} 4 4 va 4 ey oH ty ) on Hy Ho 4 4 HHO H 4 fi Hon HOW HOW HoH FIGURE 1 Propose stocture for Gum Arabic (Informatics 1972) the preservatives Proxel GXL (0 13%) and sodium benzoate are then added Proxel GXL consists of 20% 1,2-benzisothiazolin- 3-one (BIT) in aqueous dipropylene glycol (Freeman 1984) ‘Crude Acacia Concinna results from the drying and pulver- ization of the pods of Acacia concinna The extract of these pods (Acacia Concinna Fruit Extract) is drawn by cold process- ‘ng (Carlisle International Corporation 1997a) ‘Composition, Analytical Methods, and impurities ‘The following three grades of gum arabie have been noted inthe published literature (1) processed gum arabic recovered by spray-drying from a solution of commercial food grade gum arabic after filtration to remove sand, etc , and after heat treat- ment to effect pasteurization; (2) finely powdered natural gum arabic of poor commercial quality, giving solutions of a dark reddish brown color; (3) finely powdered natural gum arabic of very high quality giving essentially colorless solutions (Strobel etal 1982) Gum arabic has been analyzed by gas chromatog- raphy (Lawrence and Iyengar 1985) and has been identified by microelectrophoresis (Informatics Ine 1972) Powdered gum arabic contains moisture (15% maximum) and insoluble ash (0.5% maximum) ‘The pH of a 10% solution is approximately 4 6 Frutarom Meer Corporation, no date) The following specifications exist for United States Pharmacopoeia, (USP) grade Acacia: loss on érying (15% maximum), total ash (4% maximum), arsenie (3 ppm), lead (0.001%), and heavy metals (0.004%) (United States Pharmacopeial Convention, Iné 2000) FDA has listed Acacia (Gum Arabic) as a direct food addi- tive that meets the specifications of the Food Chemicals Codex (21 CFR 184 1330) The specifications for food grade Aca- cia include arsenic (3 mg/kg maximum), ash, acid-insoluble (0.5% maximum); ash, total (4% maximum), heavy metals (0.002% maximum); insoluble matter (1% maximum); lead (S mg/kg maximum); and loss on drying (15% meximum) Food, ‘Chemicals Codex 1996) ‘Anderson etal (1990) compared the amino acid composition of Sudanese and Nigerian gum arabic Analyses were done on samples collected over a 13-year period for samples from the Sudan and over 9 years for those from Nigeria The data are presented in Table 2 ‘Anderson et al (1991) analyzed gum arabic samples pro- Vided by importers shown in Table 3 All samples conformed to the revised Joint Food and Agriculture Organization of the United Nations/World Health Organization, Expert Committee con Food Additives (JECFA) specification in respect of solubi ity, complete in cold water, acid-insoluble ash, (>0 5%) and matter (> 1%); starch/dextrin (ehsent); tannin (absent); arsenic (©3 ppm), lead (> 10 ppm), heavy metals (>40 ppm) GECFA 1990) A samples were confirmed by nuclear magnetic reso- nance (NMR) spectroscopy to be “good” Acacia senegal ‘Anderson etal (1990) also analyzed the ash from gum arabic samples from these same two countries ‘These data are given in Table 4 West Coast Analytical Service, Inc (1999) analyzed gum arabic for pesticide residues using USP methodology and found no detectable pesticide residues Other food additive specifications for gum atabic from the Food and Agriculture Organization (FAO) ofthe United Nations defined the material asa dried exudate obtained from the stems and branches of Acacia senegal (L ) Willdenow ot Acacia seyal80 (COSMETIC INGREDIENT REVIEW TABLE 2 “The amino acid composition of Sudanese and Nigerian Gum Arabie (Acacia senegal) (Anderson etal 1990) TABLES Cation composition of ash from Sudanese and Nigerian Gum Arabic (Acacia senegal) (Anderson et al 1990) ~ Sudanese samples Nigerian samples Mean residues/1000 Mean resiues/1000 resides (13 years residues (9 years (otal between total between Amino acid 1904 and 1989) 1905 and 1967) Alanine 2743 m4 Arginine 13 1241 Aspartic acid 68413 61 +16 Cystine 244 0 Glutamic Acid 42£10 42415 Glycine S045 5046 Histidine, 4448 4845 Hydroxyprotine 304447 331473, Isoleucine 243 1 Leucine 6647 Cray Lysine 2543 2446 Methionine 242 1 Phenylalanine 3345 2910 Proline +14 5549) Serine 12911 129413 Threonine 6849 e748 ‘Tyrosine 1445 44 Valine 3548 3246 (family Leguminosae), include the following: loss on drying (not ‘more than 15% [105°C, 5 hi] for granular and not more than 10% [105°C, 4 hi] for spray dried material); total ash (not more than 49%), acid-insoluble ash (not more than 0 5%), acid-insoluble ‘matter (not more than 1%); and lead (not more than 2 mg/kg) (FAO 1999) Sudanese samples Mean s1g/g ash unless ‘Nigerian samples ‘Mean ug/g ash unless expressed as ppm expressed as ppm AS years total (9 years total between 1904 between 1905 Cation and 1989) and 1967) Aluminum 190 53 311 + 156" Calcium 256,000 + 34,000 316,000 56,000 Chromium 47422 34426 Copper 52427 66 + 65° Iron 128 4 84 110£33 Lead 6x2 7 Magnesium 38,000 15,000 39,000 15,000, Manganese 100+ 95 s1£27 Nickel +n £17 Potassium 237,000 37,000 221,000 + 43,000 Sodium 9,400 + 4,480 10,200 + 5,200 Zine 24410 40-4 49 Arsenic 1000 plkg) ‘Smith etal (1990), however, found no detectable aflatoxin in either of two samples of gum arabic analyzed using an enzyme- linked immunosorbent assay The assay system was capable of determining aflatoxin in the concentration range of 20 to 200 0 ppb in gum arabic ‘Data from the European Federation for Cosmetic Ingredients (EF /Cl) describes the components of the plant material from various Acacia species While there are some similarities, there re many differences in composition (EF fCI 2000) These data are given in Table 7 Reactivity ‘When Gum Acacia is weakly hydrolyzed by hydrochloric acid at room temperature, pentose is split off (Marrack and Carpenter 1938) Partial acid hydrolysis has also yielded galac- tose and complex sugar acids (Heidelberger etal 1929) Gum Acacia emits acrid smoke when heated 10 decompo- sition (Lewis 19930) Heating a solution of Acacia fora few minutes at 100°C destroys petoxidase (oxidizing agent) present inthe gumand the colored derivatives produced (Gennaro 1990) USE Purpose in Cosmet ‘The functions ofthese ingredients in cosmetics as described inthe International Cosmetic Ingredient Dictionary and Hand- book are given in Table 1 (Wenninger et a 2000) Reportedly. Acacia concinna pods are a useful ir wash, in that they promote hair growth, kill lice, and remove dandruff The active constituents of Acacia concinna pods (saponins, alka- Joids, tannins, and malic acid) are said to have cleansing, stimu- lating, and astringent properties ‘The astringent action provides toning ofthe scalp and conditioning of the hair Additionally, the active constituents are said to offer effective skin and scalp exfoliation (Carlisle Imernational Corporation 19976) Scope and Extent of Use in Cosmetics ‘The product formulation data submitted to the FDA in 2001, indicated that Acacia was used in 33 cosmetic products and that Acacia Senegal was used in 1 cosmetic product (Table 8) (FDA 2001) Neither the species nor the plant part was further delineated in the category “Acacia” It is assumed that Acacia ‘Senegal is Acacia Senegal Gum (Curent concentration of use data are given in Table 8 These data from industry (CTFA 2000a) show the highest concentra tion of Acacia Senegal Gum (9%) in shampoos Acacia Senegal Gum Extract was reported at a concentration of 0.001% in bath soaps and detergents For many uses of these ingredients, i formation regarding use concentration for specific product cate- zgoriesis provided, but the numberof such products is not known, but they must be assumed to be in use ‘Recommended use concentrations of Acacia Concinna Fruit Extract are 05% to 5 0% (Carlisle International Corporation 1997a) and 1 0% to 2.0% fo use in shampoos, hair packs, hair conditioners, and hair rinses (Carlisle Intemational Corporation 1997b) Cosmetic products containing Acacia are applied to most parts of the body and could come in contact with the ocular and nasal mucosne These products could be used on a daily basis, ‘and could be applied frequently over a period of several years Acacias are not included among the substances listed as pro- hibited from use in cosmetic products that are marketed in the European Union (EEC 2001) The European Union terminology‘COSMETIC INGREDIENT REVIEW TABLE 6 ‘Composition and impurities data on Various Species of Acacia ‘Acacia species (parvsource) ‘Analytical method ‘Components Reference ‘Acacia atramentaria and Acacia tortwosa Gas chromatography and Proacacipetalin (cyanogenic Seigler etal (leaves) NMR spectroscopy glucoside) 1983 ‘Acacia albida, Acacia ataxa-cantha, Acacia Jon exchange e-Amino-p-oxalylaminopropionic — Quereshi catechu, Acacia confusa, Acacia coulteri, chromatography acid (neurotoxic lathyrogen) etal 1977 ‘Acacia erubescens, Acacia ferruginea, ‘Acacia galpinii, Acacia hamulosa, Acacia ‘mellifera, Acacia modesta, Acacia nigrescens, Acacia polyacantha, Acacia rowumae, Acacia senegal", Acacia venosa, and Acacia welwitschii (seeds) ‘Acacia aroma (leaves) Gas chromatography and Linamarin and lotaustralin Seigler etal : NMR spectroscopy (cyanogenic glucosides) 1983 Acacia catechut (seed) Thie-layer Aflatoxin By (001 10076 ug/g) Roy and chromatography and Kumari, spectrophotometry 1991 Acacia concinna* (pods) - Highly polar saponin mixture Abul etal “Hydrolysis with alkali yields 5 1997 trterpenoidal prosapogenols ‘oncinnosides A, B,C, and D), 4 glycosides (acadiside, julibroside AA, julbroside A3, albiziasaponin ©), and aglycone, acacic acid lactone Acacia concinna® (fruit) = Kinmoonsides A-C (cytotoxic Tezuka etal saponins) 2000 ‘Acacia farnesiana® (pod, leaf, stem, old __Phytochemical screening Carbohydrates and/or glycosides, Wassel et stem, and flower) reducing sugars, hydrolyzable 1992 tannins, alkaloids and nitrogenous bases, unsaturated sterols, and/or terpenes, and coumarins (all organs) ‘Acacia farnesiana* (pod, lea, old stem, and = Flavonoids (all organs except stem) Wassel etal flower) 192 Acicia farnesiana* (pod, leaf, stem) = CCyanogenic glycosides (in pod, leaf, Wassel etal ‘and stem) 1992 Acacia famesiana® (flower) - Volatiles (ower) Wassel etal 1992 Acacia famnesiana® oil Thin layer Anisaldchyde, benzalcohol, El-Hamid chromatography benzaldehyde, cuminicaleohol, and Sidrak ‘farmesol, cuminicaldehyde, 1970 geraniol, geranyl acetate, jonone, linalool, linalyl acetate, neralidol, terpineol, and methyl salicylate ‘Acacia farnesianat (leaves) - ‘Total soluble phenols ranged from Sotohy etal 10.27% to 35 46% Condensed 1995 tannins ranged from 0 5% to 8 28% ‘on dry matter basis Acacia farnesiana' (leaves) - Cyanogenic glycoside (inamarin or Secor et al Totaustralin may be present) 1976 (Continued on next page)ACACIA 8 TABLE 6 ‘Composition and impmities data on Various Species of Acacia (Continued) Acacia species (partsource) Analytical method ‘Components Reference ‘Acacia tortilis (gum and bark extracts) High-performance liquid Smooth muscle relaxants quaracol A Hagos and chromatography and B (in gum) and (++)fisetinidol Samuelson (in gum and bask) 1988, Acacia georginae (seeds) Extractive and Fluoroacetic acid Oelrichs and chromatographic McEwan procedures 1962 Acacia globulifera (leaves) Gas chromatography and Epiproacacipetalin (cyanogenic Seigler et al NMR spectroscopy slucoside) 1983, ‘Acacia modesta (stem bark, heartwood, and Thin-layer| a-amyzin, betulin, octacosanol and Joshi et al leaf extracts) chromatography e-sitosterol (in stem bark), 1975 ysitsterol and pinitol (in hheartwood); octacosane, hentriacontane, octacosanol, and hentriacontanol (leaves) ‘Acacia mollissima, Acacia confusa, Acacia Amino acid (—)-trans-4-hydroxypipecolic acid Marakesh longifolia, Acacia decu-rence’, Acacia _—_autoanalyzer used etal 1969 dealbata”, Acacia baileyana, and Acacia vertcillata (leaves) "The Acacia species listed in the International Cosmetic Ingredient Dictionary for these ingredients is described in Table 1, where the genus and species names are used to describe all ofthe plant material (eg, ‘gum, extract, ete ) derived from that particular genus/species, dependent of the plant part from which the material is derived ‘The Acacias reviewed inthis report are not included on the ist of ingredients that must not be combined in cosmetic products that are marketed in Japan (Ministry of Health, Labor and Wel- fare [MHLW] 2000s) or on the list of restricted ingredients for cosmetic products that are marketed in Japan (MHLW 2000b) Noncosmetic Use Gum arabic is a substance that is generally recognized as safe (GRAS) for direct addition to human food under the pro- visions of Section 184 1330 ofthe Code of Federal Regulations (CFR) leis approved for use in various food categories atthe following maximum permitted usage levels: 0% (beverage and beverage bases), 5 6% (chewing gum), 12 4% (confections and frostings), 134 (dairy product analogs), 1 5% (fats and oil), 2 5% (gelatis, puddings, and fillings), 46 5% (hard candy and cough drops), 8 3% (nuts and nut products), 6 0% (quiescently frozen confection products), 4 0% (snack foods), 85 0% (soft candy), and 1% (all other food categories) Uses of gum arabie in the various food categories in- clude: emulsifier and emulsifier salt, flavoring agent and ad- juvant, formulation aid, stabilizer and thickener, humectant, surface-fnishing agent, processing id, and texturizer (21 CFR, 184 1330) Gum arabic also listed as One ofthe optional blend- ‘ng ingredients of vanilla powder (21 CFR 169 179) and vanilla- vanillin powder (21 CFR 169 182) ‘The following maximum values for possible daily human intake (g/kg body weight) of gum arabic in the total diet have been calculated for various age groups by the Select Committee ‘on GRAS Substances using data from the National Research ‘Council: 115 mg/kg (0 5 months), 322 mg/kg (610 1} months), 329 mp/kg (12 to 23 months), and 113 mg/kg (2 to 65 + years) (FASEB 1973) At the 3Sth meeting of the JECFA, held in Rome from May 29t0 June 7, 1989, JECFA confirmed its acceptable daily intake (ADD of gum arabic as “not specified” Here, gum arabic (a k a ‘gum Acacia) is defined as the cried gummy exudate from tropical and subtropical Acacia senegal trees ‘ADI “not specified” is applicable toa food substance of very low toxicity, which, on the basis ofthe available data (chemical, biochemical, toxicological, and other), the total dietary intake of the substance arising from its use atthe levels necessary to achieve the desired effect, and from its acceptable background in food does not, inthe opinion of the JECFA, represent hazard to health For that reason, and for reasons stated in individual evaluations, the establishment of an ADI expressed in numerical formis not deemed necessary An additive meeting this criterion ‘ust be used within the bounds of good manufacturing practice, {eit should be technologically efficacious and should be used atthe lowest level necessary to achieve this effect; it should not conceal inferior food quality or adulterstion, and it should not create a nutritional imbalance (ECFA 1990)84 ‘Acacia catechu plant (H-atzlichin 3Hbeta-L-arabopyranoside}--arabinose Semethoxyflavones 4-(4-O-methybalpha->- alncuronosie).-arabinose 4-hydroxypipecolic acid 5-(beta-p-xylopyranoside)-L-arabinose 7.3,d-tribydioxy-3,8-dimethoxyflavone 7,8,14'-tribydroxyflavonol 7.8.4-tribydroxy-3-methoxyflavone S-methoxyfisetin 9-methoxyflavone-3,4-diones Acacatechin Acetaldehyde Aldobiuronic acid ‘Alpha-amino-beta- oxalylaminopropionic acid Alpha catechin Beta catechin Boron Catecbuie acid Catechutannic acid Cobalt Degalactose glucuronic acid D-xylose Dismino acid Diydrokaempferol Di-catechol L-cpicatechin Fisetin Flavotannin Formaldehyde ‘COSMETIC INGREDIENT REVIEW TABLET Acacia decuneens plant (+)-catechin| 3345 ,T-pentahydroxy-2- phenylchroman 3,34" 7-pentahydroxyfiavin 3emethyl-L-rhamnose 7.3'S-etrahydroxyflava O-L-catechin Acetic acid Aldobionic acid Alpha cellulose Anthocyanidin Anthoeyanitidine Beta carotene Carbohydrates Cellulose D-galacturonic acid Depinetol Fiber Fisetinidin Fructose Gallocatechin Indoleacetic acid L-arabinose L-rhamnose Lignin Mearnsitrin Methanol Methylsalicylic ester Pelargonidin Phlobaphene Phlobaphene anhydride Phioroglucinol Proanthocyanidin Chemicals found in Acacia species (EF fCI 2000) ‘Acacia farnesiana plant (catechol (4)-gallocatecho! Apigenin-6,8-bis-beta- D-glucopyranoside Aromadendrin Aspartic acid Cresols Ellagic acid Ethyl ester Hydroxyacetophenone Isorhamnetin-3 rutinoside Kaempferol Kaempferol-7- galloylglucose Kaempferol-7- slucoside Linamarin Lotaustralin ‘m-digallic acid Methyl gallate Mucilage Myricetin~ ‘methylether-3- rhamnoside N-acetyl-djenkkolie Natingenin-7- slucoside Naringenin-7- shamnoglucoside Pipecholic acid Prunin-O-6'-gallate Quercetin3-0- rutinoside Salicylic acid ‘Tyramine ‘Acacia senegal plant 4-methoxyglucuronic acid ‘Arabic acid Arabinose Ascorbic acid Aspattic acid Beta sitosterot Beta sitosterol--glucose Cysteine Degalactose Deglucoside Dimethyyptamine Ethos Galactoglucuronid acid Glucuronie acid HCN Hentriacontane Hentriacontanol Kaempferol L-arabinose Lthamnose Leucine Magnesium Cctacosanol Peroxidase Potassium Quercetin, Rhamnose Rhamnose hydrate Serine Sitosterol Sodium (Continued on next page)ACACIA 85 TABLE 7 Chemicals found in Acacia species (EF fC1, 2000) (Continued) ‘Acacia catechu plant Acacia decurrens plant ‘Acacia farnesiana plant Acacia senegal plant Gallic acid Protocatechuic acid Gallotannin Robinetin Gamma-catechin Rutin Glucosyluronic acid ‘Xamthophyll Gum Tsocacatechin Isorhamnetin Isovaleraldehyde Kaempferol Leepicatechin L-leucomacluricglycol ether Lrhamnose ‘Magnesium Malate dehydrogenase Manganese Peroxidase Phlobatannin Phosphatase Procyanidin Quervetagerin Quercetin Quereitrin Rutin Silicon Tannin ‘Taxifolin Uronic acid ‘Gum arabie (Acacia Senegal Gum) is used in the pharmaceu- tical industry to stabilize emulsions during the preparation of tablets (Collins etal 1987) It s also used for its demulcent ac- tion in the treatment of throat or gastric inflammation (Gennaro 1990) ‘The therapeutic efficacy of Acacia Catechu in the treatment of lepromatous leprosy has been reported (jha et al 1969) Gum Arabic has also been used in glues, lithographic so- lutions, and matches (tip and binder in striking surface), and polisher and textile finishes (van Ketel 1984) ‘The following uses of Acacia Concinna in folk medicine have been reported A chutney (pungent relish of fruits, spices, and herbs) made of the tender leaves of Acacia concinna, salt tamarind, and chilies is administered for the treatment of bil- ious affections such as jaundice An infusion of the leaves is used in the treatment of malarial fever; it checks flatu- lence and serves as a mild laxative Furthermore, repeated, large doses of a decoction of the Acacia concinna pods act as an emetic and purgative (Carlisle International Corporation 19976) ‘Sucrose, Tannin Uronie acid Valine ‘An intment made from the Acacia concinna pods reportedly is used in the treatment of skin diseases (Carlisle Intemational Corporation 19976) BIOLOGICAL PROPERTIES Absorption, Distribution, Metabolism, and Excretion Gum Arabic ‘The weight gain for rats fed gum arabic at a dietary con- centration of 16% was 75% of that reported for control rats It was determined that approximately 80% of the gum arabie was absorbed (Informatics 1972) Ina study using rats, an apparent decrease inthe caloric value of gum arabic with increasing administered dose was noted Gum arabic was incorporated into the diet at concentrations of ‘5%, 10%, and 17% Digestbility data indicated that up to 80% of the gum arabic was absorbed (Informatics Inc 1972) Following a48 h fast, 20 young male rats were fed 10mg of a ‘mixture consisting of 34% white, powdered gum arabic und 66% cacao butter At 72 h after feeding, the rats were anesthetized86 (COSMETIC INGREDIENT REVIEW TABLES Product formulation data on Acacia and Acacia Senegal Product category (otal formulations in category) (FDA 2001) Concentration of use (CTPA 20002) (9%) Formulations with ingredient (FDA 2001) ‘Acacia Other bath preparations (193) Mascara (187) Other eye makeup preparations (151) Hair tnts 49) Hair color sprays (Aerosol (5) Other hair-coloring preparations (59) Foundations (319) Lipstick (942) Other makeup preparations (186) Body and hand skin care preparations (excluding shaving) (827) Paste masks (mud packs) (269) 2001 totals for Acacia 33 ‘Aca Eyebrow pencil Eyeliner Mascara (187) Powders (dusting and talcum; excluding aftershave talc) Tonics, dressings, and other hair grooming aids Other skin care preparations 2001 totals for Acaci egal Gum Senegal Gum 1 39 05 0.0001 oo ‘Acacia Senegal Gum Extract, Bath soaps and detergents 001 2001 totals for Acacia Senegal Gum Extract and the liver was removed and analyzed for glycogen content The difference in glycogen concentration between control and fed rats was insignificant Therefore, it was concluded that the gum arabic molecule was not metabolized by enzymes ofthe rat digestive tract (Informatics Inc 1972, FASEB 1973) (Other studies have indicated that gum arabic is partially di- gested in the rat In one study, weight gain and feed efficiency \were determined using groups of six ras fed 15% gum arabic for 62 days Feedeefficiency was identical between experimental and control groups However, compared to the control group (mean weight gain = 199 g), rats fed gum arabic had a mean weight gain of 224 g In another study, groups of five rats were pair-fed ‘gum arabic (075 g/day, added to 5 g basal diet) Results indi- cated that the digestibility of gum arabic was 71% (Informatics Inc 1972) Ross et al (1984b) evaluated the metabolism of gum arabic using albino Wistar male rats (3 months old, weights = 350 g) The number of animals used in the study was not stated Two groups of animals were fed Oxoid breeders diet only and Oxoid breeders diet plus 200 g gum arabiclkg ad libitum, respectively, ford weeks Oxoid breeders diet was described as areconstituted diet that allowed the ready incorporation of gum arabic into pellet form Feces were collected during the 24 h period before animals ‘were killed Following ad libitum overnight feeding, the animals ‘were killed using a combination of diethyl ether anesthesia and cervical dislocation and contents from the stomach, small bowel, cecum, and distal colon were removed For rats fed gum arabic in the diet, a white flocculent pre- cipitate typical of gum arabic was detected in contents from the stomach and small intestine, but not from the cecum, distal colon, or inthe feces ‘The fact that precipitable gum arabic was detected along the gastrointestinal (GI) tact as far a the termi- nal ileum, but not in the cecum, suggests thatthe metabolism of ‘gum arabic is mediated by bacteria in the cecum In animals in which the cecum was resected, precipitable ‘gum arabic was detected along the length of the entire residual intestine ‘This observation suggests that in the absence of the bacterial mass resident in the cecum, there is no degradation of ‘gum arabic No precipitate typical of gum arabic was found inACACIA a7 the Gl tract of conteol rats that received the Oxoid bieeders diet only (Ross et al 1984b) ‘A total calotc intake slightly greater than that for starch has ‘been reported for gum arabic in rabbits Evidence of glycoge- resis was also demonstrated in this study Thus, it appears that rabbits are able to utilize gum arabic (FASEB 1973) Ina study involving guinea pigs it was determined that gum arabic was highly digestible (90%) when administered in the diet at a concentration of 15% for 10 days (Informatics 1972) Results of studies in which dogs and rabbits were injected intravenously with gum aiabie indicated that gum arabic or some other product associated with it accumulated in the liver and remained in the tissues for several months Nonlethal effects included serious disturbances in hemoglobin, white blood eels, and serum proteins (FASEB 1973) Using many of the studies summarized above, the Select Committee on GRAS Substances determined in 1973 that gum arabic can be digested to simple sugars However, it was also de- termined that conclusive evidence indicating thatthe intact gum arabic molecule is absorbed under normal conditions was lack- ing (FASEB 1973) It should also be noted that data on the fate of undigested gum arabic in male rats (Ross etal. 19846) have been published since the FASEB report was issued The results of this previously summarized study suggest thatthe bacterial ‘mass resident in the cecum is responsible forthe metabolism of gum arabic Hypotensive Activit ‘Acacia (Not Gum Arabic) ‘Sham et al (1984) evaluated the hypotensive activity of Aca- cia catechu (aqueous extract of branches) using four groups of four anesthetized dogs (males and females; weights = 8 to 12 kg) The right femoral artery and vein were cannulated for blood pressure recordings and intravenous injection After @ 30-min equilibration period, Acacia catechu was injected (bolus injection) into dogs from each of the four groups Doses ranged from <1 to ~2 mg/kg Changes in mean arterial blood pressure (MAP) were recognized as differences between the steady MAP before injection and the lowest MAP after injection “The results were presented as a log dose-response curve ‘Acacia catechu induced dose-related hypotensive responses At high doses, the hypotensive effect lasted approximately 30 min Based on experimentation with various blocking agents, it was determined that this effect was not mediated through a- and - adrenergic, cholinergic, or histaminergic receptors, or related to autonomic ganglion transmission “The hypotensive activity of Acacia catechu (aqueous extract of branches) was also evaluated using four groups of five male Sprague-Dawley rats (weights between 170 and 250 g) accord- ing to the procedure in the preceding paragraph, however, in this experiment, the left carotid artery and jugular vein were cannalated ‘Acacia catechu induced dose-related hypotensive responses inrats over the range of doses tested (1 to 2 mg/kg) It was also determined that the hypotensive responses were not mediated through a- and f-adrenergic, cholinergic, or histaminergic re- ceptors, oF related to autonomic ganglion transmission (Sham. etal 1984) “These same authors reported that, in an in vitro experiment, Acacia catechu induced a dose-dependent relaxation of heli- cal strips of rat tail artery that had been preconstricted with the vasoconstrictors arginine vasopressin and methoxamine, respec- tively In the presence of arginine vasopressin, Acacia catechu as tested at concentrations of 001, 003, and O 1 mg/ml Aca cia catechu was tested at concentrations of 0 1,0 3,and | mg/ml in the presence of methoxamine (Sham etal 1984) Hypocholesterolemic Activity Acacia (Not Gum Arabic) ‘Chaudhari and Hatwalne (1973) determined the hypocholes- terolemie activity of the dried water extract of Acacia catechu, ‘also known as Katha in India They used three groups of 10 male albino rats (weights = 100 to 125 g) One gioup was fed stock. iet thoroughly mixed with 1% cholesterol, anda second group was fed stock diet thoroughly mixed with 1% cholesterol plus (02% katha ‘The control group was fed stock diet only ‘The diets, were fed ad libitum Half of the animals in each group were Killed after 6 weeks of feeding, and the remaining animals were killed after 12 weeks of feeding The cholesterol content of the serum and liver was determined for each rat ‘A progressive increase in serum and liver cholesterol con- tent was observed in animals fed the stock diet supplemented with cholesterol for 6 months In animals fed stock diet supple- mented with cholesterol and katha for 6 months, the elevation of serum and liver cholesterol levels was significantly lower (p = (001) when compared to rats fed stock diet supplemented with cholesterol However, atthe end of 12 weeks, the increase in serum and liver cholesterol concentrations in rats fed stock diet supple- mented with cholesterol and katha was elevated by appro mately 50% when compared to rats fed stock diet supplemented ‘with cholesterol only Tt was also determined that there was sub- stantially less deposition of lipids inthe liver of katha-fed rats Ttwas concluded that katha had hypocholesterolemic activity in this study, and that it helped prevent fatty degeneration of the liver (Chaudhari and Hatwalne 1973) Hypoglycemic Activity Acacia (Not Gum Arabic) Wassel et al (1992) studied the hypoglycemic activity of ‘ethanolic extracts of the pod, leaf, stem, old stem, and flower of Acacia fanesiana L Willd using groups of 11 alloxanized diabetic albino rats (weights = 150 to 200 g) To prevent the development of fatal hypoglycemia during the first 12 h after alloxan administration, a 25% glucose solution (5 to 10 ml) ‘was subcutaneously injected at 2 to 3 h intervals Extract from each plant part (dose = 30 or 50 mg/kg in polysorbate 80) was administered orally to group of 11 rats, and blood samples were taken at 2h post administration Blood samples were collected88 (COSMETIC INGREDIENT REVIEW prior to treatment in order to estimate the noumal blood glucose evel of fasting rats ‘The hypoglycemic activity of ethanolic extracts of Aca cia farnesiana stem and pod was considerable following the ‘administration of a 50 mg/kg dose Acacia farnesiana stern and pod caused 21% and 36% reductions in the normal fasting blood sugar level, respectively (Wassel et al 1992) Effects on Smooth Muscle Acacia (Not Gum Arabic) ‘Wassel et al (1992) also studied the effect of ethanolic ex- tracts of the pod, leaf, stem, old stem, and flower of Acacia far- nesiana L Willd on vterine motility Rat uteri at various stages Of the estrous cycle were suspended in 50-ml baths containing ‘oxygenated Krebs solution, uteri were equilibrated in the solu- ton for at least 90 min Drugs were added to the water bath and ‘were retained until the highest contraction was achieved ‘Normal rhythmic contractions of the isolated uteri were first recorded using @ T isotonic transducer and two channel MD2 oscillograph Subsequently, the plant extracts (in polysorbate 80) ‘were added to organ water baths ata dose of 50 or 75 mg/S0 ml bath ‘The drug used to induce uterine contraction was then re- ‘moved by washing the preparation with fresh Krebs solution “Most of the Acacia farnesiana ethanolic extracts stimulated uterine muscular contraction during the estrous cycle and preg- nancy However, some of the extiacts had a stimulatory effect ‘on uterine contraction, followed by inhibition (ie , leaf extract ‘on non-estrus uteri and pod extract on pregnant uterus) The stem extract of Acacia farnesiana inkibited contraction of the pregnant uterus (Wassel et al 1992) ‘Trivedi etal (1986) evaluated the bronchodilator activity of ‘Acacia farnesiana using the perfused, isolated guinea pig lung ‘The control guinea pig lung preparation was treated with saline ‘The unripe pods of Acacia farnesiana were collected and dried atroom temperature The glycosidal fraction ofthe ethyl alcohol extract of coarsely powdered Acacia pods was then isolated, and ‘an aqueous solution of this fraction was tested Doses of 2, 5, and 10 1g of the aqueous solution increased outflow in the isolated lung perfusion preparation, indicating that the glycosidal fraction induced a smooth muscle relaxantef- feet The same doses also increased outflow following histamine (10 2g)-induced contraction, and the bronchodilator effect was not blocked by propranolol (400 4g) These results suggested that the glycosidal fraction exerted a direct relaxant action on the bronchial muscles The investigators noted that tis effect is not mediated through B-adrenergic receptors The vasodilator activity of Acacia famesiana was evaluated in vitro The glycosidal fraction of the ethyl alcohol extract of coarsely powdered Acacia pods was isolated, and an aqueous solution of this fraction was tested The hind limb of dogs was perfused through the femoral artery with oxygenated, defibri nated blood in Ringer's solution Femoral venous outflow was recorded periodically The control preparation was treated with ‘normal saline “The aqueous glycosidal fraction induced vasodilation at doses of 2,5, and 10 jg (increases in blood flow/min of 21 4,20 86, and 24 3, respectively, n = 5) Vasodilation was not blocked following the addition of any of the following agents chlor- phenaramine maleate (20 1g), atropine (20 4g) 01 propranolol (400 jog) Study results indicated that the glycosidal fraction of Acacia fanesiana had a smooth muscle relaxant effect The investigators noted that this effect was not mediated through cholinergic or Hy receptors (Trivedi etal 1986) Anti-Inflammatory Activity Acacia (Not Gum Arabic) ‘The anti-inflammatory activity of Acacia farnesiana was evaluated in vitro The glycosidal fraction of the ethyl alcohol extract of coarsely powdered Acacia pods was isolated, and an aqueous solution of this fraction was tested The effect ofthis, fraction on chemically induced edema of the rat hind paw was, evaluated according to the method of Winter et al (1962) The slycosidal fraction inhibited carrageenin and formaldehyde i duced inflammation of the rat hind paw in vivo (% inhibition of 38 2 and 26 26, respectively; p < O01, n = 10) It was, concluded that this fraction has @ promising anti effect (Trivedi etal 1986) Oxidative Phosphorylation Gum Arabic Bachmann etl (1978) administered gum arabic twice daily to groups of four rats (weights = 100 to 110 g) at concentra- tions of 1%, 2%, and 10%, respectively, 5 days per week for 4 weeks The test substance was suspended in distilled water and administered orally ata dose volume of © 2 ml/100 g body ‘weight; control rats were given equal volumes of distilled water ‘The actual doses of gum arabic administered were 2 x 20,2 x 40, and 2 x 200 mg/ke/day Groups of four rats were killed by cervical dislocation 16 h after administration of the lst dose Following maceration and homogenization, heart and liver tochondria were isolated by differential centrifugation Electron transfer reactions (oxygen consumption) and oxidative phospho- zylation were measured polarographically The hydroxylation of biphenyl was chosen as the assay system for measuring mixed function oxidases of hepatic cell endoplasmic reticulum Dose-dependent uncoupling of oxidative phosphorylation was the primary effect on cardiac and hepatic cell mitochon- Arial fonction The damage to cardiac mitochondria progressed 1s dosing continued However, hepatic cell mitochondrial fune- tion seemed fo have gradually retuned to normal during the fourth week of dosing At the highest administered dose (2 x 200 me/kg/day) marked uncoupling of oxidative phosphorylation was observed inthe heart and liver after2 days of dosing Partial recovery was reported for cardiae mitochondria after the first week of dosing; however, the same degtee of uncoupling Was noted up othe end ofthe experiment Hepatic cell mitochondria were said to have recovered slowly asthe experiment progressed Guim arabic alsoACACIA, 89 ‘caused a progressive inhibition ofthe biphenylhydioxylase sys- tem in the hepatic microsomal fraction (Bachmann etal 1978) Lutz et al (1978) considered these results and investi- gated whether comparable biochemical effects of gum arabic (USP grade) could also be demonstrated in vivo The mes- surement of maximal aminopyrine demethylation as expired CO; was deemed a suitable approach for this investigation, ‘which was conducted using female rats ofthe ZUR SIVZ strain (weights = 152 to 180 g) Oral dosing with 10% (w/v) gum arabic had no effect on the in vivo demethylation of, 4-dimethyi[*C)-aminoantipyrine (Lutz.et al 1978) Antimicrobial Activity ‘Acacia (Not Gum Arabic) ‘The antimicrobial activity of ethanolic extracts of plant or -gans from Acacia farnesiana was evaluated Extuacts were made fiom the following plant parts: the pod, lea, stem, old stem, and flower Bactetia and yeast were cultured and filter paper disks were impiegnated with 10 il of each extract Each disk (one extract per disk) was then dried and placed on the surface of the inoculated agar medium, and cultures were incubated for 48 h and obsetved for zones of inhibition All plant extracts were inhibitory to Bacillus subtilis and Staphylococcus aureus Ad- ditionally, most ofthe extracts were inhibitory to Sarcina lutea, Pseudomonas aeruginosa, and Escherichia coli The plant ex- tracts had no effect on Mycobacterium phleior Candida albicans (Wassel et al 1992) ANIMAL TOXICOLOGY ‘Acute Oral Te Gum Arabic In an acute oral toxicity study using rabbits (weights and strain not stated), an Acacia Gum LDsp of 80 g/kg was reported (Dangerous Properties of Industrial Materials Report 1981) ity Acacia (Not Gum Arabic) Letizia et al (2000) conducted a study in which the acute oral toxicity of Acacia Famesiana Extract (from flowers) was ‘evaluated using ten rats (strain notstated) The test substance was administered atadose of 5 0 g/kg, and animals were observed for 14 days Necropsy was performed at the end of the observation petiod ‘An LDsp of greater than5 Og/kg was reported Signs observed in animals during the study included chromorhinorrhea in five or more animals and isolated instances ofthe following tachypnea, chromodacryorthea, ptosis, lethargy, piloerection, emaciation, ataxia, and respiratory noise Necropsy findings for the only animal that died included abnormalities of the lungs, kidneys, liver, spleen, and gastrointestinal uact (Letizia etal 2000) ‘The Societe Bertin (1987) reported an acute oral toxicity study in which Cire Essentielle Cassie (uade name for Aca- cia Farnesiana Flower Wax) was evaluated using groups of five rats (males and females) of the OFA Sprague-Dawley 1OPS stiain Mean weights for male and female test animals were 219 60 g and 183 60 g, tespectively Control mean weights were 2240 g (males) and 18380 g (females) The animals were all approximately the same age (ages not stated) A sin- le 10 ml/kg, dose of the product was administered orally to each animal, and followed by a 14-day observation period Con- trol animals were dosed with com oil (10 ml/kg) The animals were killed at the end of the observation period and necropsy performed ‘Significant changes in general condition (weight changes in- cluded) ot behavior between test and control animals were not observed None ofthe animals died and no test substance-related organ lesions were observed ‘The test material was classified as innocuous atthe dose administered (Societe Bertin 1987) Biogir $A. Conseil Recherche (1990a) also reported the acute oral toxicity of Cire Essentielle de fleurs de Mimosa (trade name for Acacia Dealbata Leaf Wax) ina suspension with paraf- fin oil using five male (178 3 +9 8 g) and five female (172.8 59 g) rats of the OFA Sprague-Dawley strain (SPF) The ani- ‘als were 2 months old. single oral dose of 2 g/kg (10 mikg) of the product was administered to each animal by gavage, and dosing was followed by a 14-day observation period Feeding resumed at 4h post dosing Atthe end f the observation period, the animals were killed and gross necropsy performed ‘Weight gain was described as normal and no deaths were reported Additionally, none of the animals had overt signs of central nervous system or neurovegetative system toxicity, and no lesions of organs examined were noted at necropsy The min- imal lethal dose was greater than 2 pkg (Biogir SA Conseil Recherche 1990a) Acute Dermal Toxi Acacia (Not Gum Arabic) ‘The acute dermal toxicity of Acacia Famesiana Extract (from flowers) was evaluated using 10 rabbits (strain and weights not stated) A single dose of 5 0 g/kg was administered dermally to each animal, and observations were made over a period of 14 days Gross necropsy was performed at the end of the obser- vation period Signs observed during the study were as follows: lated instances of lethargy, diarthea, ptosis, and nasal dis- charge (yellow) Gross observations at necropsy were normal for each animal An LDso of greater than 5 0 g/kg was reported (Letizia et al 2000) Skin irritation reactions observed in this study are included in the section on Skin Iitation Tater in the report text Acute Intraperitoneal Tos Gum Arabic Ina study using dogs (number and weights not stated), the inaperitoneal injection of 4 8 g/kg gum arabic did not induce toxicity However, the same dose killed dehydrated dogs (highest no-effect level = 1 9 g/kg) (FASEB 1973) ity90 COSMETIC INGREDIENT REVIEW Short-Term Oral To» Gum Arabic Informatics Inc (1972) reported a study in which diets con- taining Gum Arabic were fed to 133 guinea pigs Except for one diet containing 20% gum arabic, all ofthe diets contained 15% ‘gum arabic The animals were fed for periods ranging from three tonnine weeks No toxic effects resulted fiom the administration of gum arabic Groups of rats (number and weights not stated) were fed 15% ‘gum arabic inthe diet fou 62 days A cathartic effect was noted ‘Weight gain, feed efficiency, hematological findings, and organ weights were normal (World Health Organization 1974) Anderson et al (1984) fed three groups of three male Albino Wistar rats (weights = 140 to 160 g) diets containing 1%, 4%, ‘and 89% (w/w) gum arabic (Acacia Senegal Gum), respectively daily for 28 days A fourth group served as the negative con- twol At necropsy, hepatic and cardiac tissues were obtained for electron microscopy and microsomal P.450 assays No discernible ultrastructural differences were observed be- tween the livers of test (all dietary groups) and control rats; par- ticularly, the mitochondria were normal Also, no discernible ultrastructural differences were found between the hearts of test (all dietary groups) and control rats. Particularly, both the ap- pearance and concentration of the mitochondria and myofibrils ‘were identical in this comparison The results of assays of hep- atic microsomal protein and cytochrome P-450 for each dietary ‘group indicated thst gum arabic did not eause inductive effects The investigators noted that when induction by active agents (eg ,phenobarbitone) takes place, cytochrome P-450 values are increased by several-fold within a few days (Anderson et al 1984) Anderson et al. (1986) fed 10% (w/w) gum arabic (Acacia Senegal Gum) daily for 45 days to Wistar albino rats (99 to 120 g) The number of rats in the study was not stated The rats were then killed by cervical dislocation while under ether anes- thesia Portions ofthe jejunum, ileum, and cecum were excised ‘and the ultrastructure of each Was evaluated using transmission electron microscopy 'No abnormalities in organelles were observed within cells of the jejunum, ileum, or cecum of rats fed gum arabic Ad- pur sosop anos soy pazaisuos ‘pansy “pouad Kop-91 1980 Kjpaadat (ts) Asnoauemnaqas parsofuy ydno3p Bid eautns Q] yo sds omy, inpaoaid sy, as TEU (panama) sssuodsax eaBojounurt, GATAVL 1qe wnt pei poo} wou, panuap sea sped ‘yo 240 “(wa ‘Jo wonessaouoo PON STOU pass) akg wag Jo sope8 2am, wonnyos sieay 49) Lwonnos wiwoy wn aL worms wiv LIN 3 2ouBgRS A,ons oho wip ‘Kopuny jo stud woud 01 Atordon pnd (Su gp) eM wey ewOrTUEAUOD pur 2as-LI9D 261 28HNOW pur uosuony [a uvaa x (rors) 9861 18 HONS ‘p01 0¢ Jo sdnoss ¢ (a zvaa x trots) oigesy wn elite ‘oF ob o¢ Jo sdnows go sodas was2yrp and son (lag) ——_(o8ews wrvoy) Da ervad * tortaeso)) orgesy wing) 961 18 eons [our g.019 jo sda018 ¢ Jo sojdusos wasp ant anges wun (uu oor se vorenussu0> weoues WOU! ‘9861 wosnaiag, ‘pu [oqong oa) 90 oenstunupe aenseBenUL a avg) Sie wan YM paso Ayemay— EEL g Fo sdnosT om, panos) MARAY tN 9596 (COSMETIC INGREDIENT REVIEW ‘The inflammatory response was described as minimal in 1 2-week-old germ-ftee and conventional guinea pigs In the 7= month-old conventional animals, the responses were much more severe than that noted for 12-week-old germ-fiee animals This comparison was made because 7-month-old germ-free animals ‘were not available ‘The inflammatory response to Acacia was most severe inthe conjunctiva and the subconjunctival tissues were relatively free of inflammatory changes. Swelling of superficial epithelial cells of the central cornea and necrosis of a few of these cells we1e also obsei ved The severity of inflammatory responses was cor- related with serum y-globulin concentitions The extent of the inflammation induced by Acacia paralleled y-globulin concen- trations in germ-free guinea pigs more closely than in conven ‘ional guinea pigs (Aronson and McMaster 1972) Gum Arabic Five guinea pigs (weights = 300 to 450 g) were passively sen- sitized with 2 ml of anti-Gum Acacia rabbit serum via intraperi- ‘oneal injection At24 t0 36 h post injection, an intravenous dose ‘of a homologous gum (1 mg) was administered to each animal, and the animals were observed for signs of anaphylaxis Three guinea pigs died 2 to 3 min after intravenous administation, nd the remaining two slowly recovered from shock during the following 2 to 3h (Partridge and Morgan 1942) Rice (195d4a) evaluated the effect of Gum Acacia (species not stated) on complement and antibody production using two groups of 10 guinea pigs (strain not stated; weights = 600 to 1000 g) The animals were injected subcutaneously with gum arabic (7% solution, 5 ml) on alternate days prior to and dur- ing immunization; gum arabic was injected repeatedly over period of seven weeks After 2 weeks of dosing, the animals ‘were bled and injected intraperitoneally with 1 ml of Brucella abortus vaccine Theee additional injections of this vaccine were ‘made 4 days (2-mil injection), 8 days (3 ml), and 21 days (3 ml) later ‘The guinea pigs were bled again one week after the third and fourth doses of vaccine, and all sera were titrated for hemolytic complement and for agglutinative and complement-fixing ac- tivity with Brucella abortus antigens Surviving animals were retested for 6 weeks, bled again, injected with a fifth dose of vaccine, and bled for a fourth time 7 days later Twenty guinea pigs of comparable weight were included in each of the control ‘groups (immunized and non-immunized) 'A sharp decline in complement titers was noted in both groups of guinea pigs injected with Gum Acacia Following seven in- Jections, only 2 of 18 surviving guinea pigs had complement titers over 1000 units per ml (minimum titer = 455) After 14 injections, one of the remaining animals had a titer that ap- proached normal (minimum titer = 385) During the ensuing period, a rise in complement titer to over 1000 units per ml ‘was noted for five guinea pigs and complement titers below '500 units were noted for eight guinea pigs, the reason for these changes in titer was undetermined In addition to the reductions in complement titer noted in the two groups, antibody and total serum protein production were also reduced Tt was determined that no deleterious effects on antibody production resulted, as judged by the development of agglutinative and complement- fixing activity in the serato the bacterial antigen Brucella abortus (Rice 1954a) Rive (1954) also evaluated the effect of Gum Acacia (species, not stated) on complement and antibody production using four rabbits (weight range = 1800 to 2650 g) This experimentis from the study summarized in the preceding paragraph The rabbits were injected subcutaneously with a 7% solution of Gum Acacia (10 ml) every other day for 4 weeks All rabbits were bled on the 15th day and immunized with | ml Brucella abortus vaccine ‘The vaccine was also injected 4 and 8 days later in 2-ml and 3-ml volumes, respectively The rabbits were bled again seven days after the third dose of vaccine Untreated rabbits (immunized) and nonimmunized rabbits served as controls In contrast to the effects noted in guinea pigs in the preced- ing study, Gum Acacia did not appreciably lower complement activity The authors concluded that no deleterious effects on antibody production resulted, as judged by the development of agglutination and complement-fixing activity in the sera to the bacterial antigen Brucella abortus (Rice 1954a) In another study, Rice (1954b) evaluated complement titers in guinea pigs (strain and weights not stated) that were either actively or passively sensitized to a7% solution of Gum Acacia Ten guinea pigs were injected subcutaneously with 16 doses (S ml per dose) of a 7% Gum Acacia (species not stated) solution over a period of 16 days The animals were actively sensitized after 7 doses, and the nine survivors were bled, challenged, and rebled in 3 weeks Signs of asphyxia were reported for one ofthe nine survivors; this animal survived for more than 3h The other guinea pigs became excited shortly after challenge, running around wildly and squealing (shock signs); two eventually died An additional 10 guinea pigs that had received 11 injections of Gum Acacia solution were passively sensitized, bled, and challenged 48 later ‘Typical respiratory signs developed; none of the animals died No significant decline in serum-complement activity was detected in animals challenged shortly after passive sensitization or in actively sensitized Gum Acacia-treated guinea pigs; how- lever, a decline in this activity was noted Additionally, in both sensitized groups, initial excitement followed by fatigue and ‘weakness were the most striking clinical signs (Rice 19540) Silvetteetal (1955) reported that anaphylactic shock resulted in each of the 12 guinea pigs sensitized via intra-abdominal injection of 160 mg Acacia with Freund’s complete adjuvant (FCA) (2 ml of emulsion containing two parts 20% Acacia) ‘Ten guinea pigs died Two additional guinea pigs were sensi tized via intra-abdominal injection of 160 mg Acacia with FCA. (2 ml of emulsion containing two parts 20% Acacia) This Aca- cia sample was from another lot The animals were challenged ‘intravenously with 60 mg Acacia ! month later Typical anaphy- Tactic death was reported for both guinea pigsACACIA 7 “The results of this experiment as well as addtional experi rents (abbits and guinea pigs) in this study collectively indi- cated that four different lots of Gum Acacia were equally f- fective as immunizing, sensitizing, and anaphylactogenic and desensitizing antigens, based on the results of cross-precpitin tests and cross-anaphylaxis experiments (Slvete etal 1955) Antibodies directed against gum arabic (species not stated) have been isolated using. affinity chromatography on AH Sepharose 4B containing gum arabic ligands These antibodies ‘were induced in rabbits immunized with gum arabic in FCA. It was determined tat the antibodies were ant-carbohydrateani- bodies with specificity for certain eabobydhate units of the gum auabic The results of chemical modification and inibition ex- periments indicated that 4-a-L-arabinofuranosyl-o-glucuronic acid tits ofthe polysaccharide were the majo: immunodeter- rinant groups (Pazur etal 1986) ‘Blood group antigens have been demonstrated in sum arabic (species not slated) The following substances were identified using an agglutinin inhibition test of mild hydrolyzed gum ara- bic: B, C (of ABO blood group system) and H substances (of H blood group system) and Le* (Lewis* antigen, in Lewis blood group system) The results ofa revised latex agglutination tech- rique indicated the presence of P and S (of MN blood group system) as well asthe substances mentioned in the preceding statement Elution processes, using sensitized and agglutinated latex of kaolin particles, resulted inthe identification of B, H, and Le! substances in gum arabic: the elution ofanti-P and anti-S didnot occur (Matsuzawa 1968) [Narita (1985) reported the isolation of high-tter anti-Gum Arabic sera obtained from rabbits injected with gum arabic (species not stated) The antisera had cross-reactivity withthe Lewis® antigen (Le), as measured by both a single diffusion tube tes and the Ouchterlony test (Narita 1985) Strobel etal (1982) evaluated the allergenicity of three grades of gum arabic using female CBA mice (6 weeks old; six to eight mice per group) The grades of gum arabic tested were 2 follows (1) processed gum atabic recovered by spray-drying from a solution of commercial food grade gum arabic after fi- tration to remove sand, etc , and after heat treatment to effect pasteurization; (2) finely powdered natural pum arabic of poor ‘commercial quality giving solations ofa dark red-brown color, (3) finely powdered natural gum arabic of very high quality, giving essentially colorless solutions “The gum exudates were dissolvedin0 15 MNaClataconcen- tration of 4 mg/l by incubation at 37°C for 16h The resulting solution was sterilized by irradiation ‘The mice were immunized by injection of the antigen (0 1 mg in 005 ml of FCA) into the left hind footpad At 21 days after primary immunization, delayed-type hypersensitivity was measured using skin est In this test, the antigen (0 1 mg dissolved in 0 15 M saline in vol- ‘ume of 0 05 mi) was injected intradermally into the plantar side ofthe right footpad of anesthetized mice Using s micro caliper, footpad thickness was measured in triplicate immediatly be- fore intradermal injection and 24 later For contol, footpad swelling was measured before and after antigen injection into the footpad of nonimmunized mice, and before and after saline injection ito the footpad of immunized mice All mice were killed one week after the skin tests The animals were bled and scium sepatated and decomplemented ‘Theinttadermal injection of antigen nto nonimmunized,con- trol mice four mice per antigen) did not induce significant foot padswellingat2+h Similay, the intradermal injection of saline into immunized control mice did not cause a significant increase in footpad thickness However, compared tothe contol, signif. icant positive responses were noted in mice of the test groups (p_< 01) indicating an antigen-specific hypersensitivity re- section for all ree gum atabie specimens that were tested. A compatison of results for the three grades of gum arabic indi- cated that footpad swelling in mice immunized and tested with the dark, red-brown grade was significantly greater (p = 005) when compated tothe colorless grade (Strobel etal 1982) Strobel and Ferguson (1986) studied the immunologieal ac- Lvity of gum arabic (species not stated) using two groups of eight female BDF! [(CS7BL16] x DBA/2)F,) mice (6108 weeks old) A finely powdered sample of gum arabic was dissolved in 0115 M saline at a concentration of 400 mg/m! Each of eight mice was then dosed with gum arabic (80 mg) by intragastric adminisuation Control mice were dosed with saline At 7 days post dosing, the mice were immunized by injecting a saline solution of 100 jeg gum arabic emulsified in an equal volume of FCA (otal volume injected = 005 ml) into the left hind footpad Control mice were immunized with 0 15 M saline in FCA Prior to and 3 weeks after immunization all mice were bled and decomplemented sera were tested for ani-Gum Arabic antibod ies by a micro-ELISA (enzyme-linked immunosorbent assay) technique Delayed:-type hypersensitivity was also measured (skin test) at 3 weeks post immunization The mice were anesthetized and 0-1 mg gum arabic (in volume of 005 mil) was injected intrader- rally into the right footpad Footpad thickness was measured in triplicate immediately before intradermal injection and 24 h later As controls, footpad swelling Was measured before and af- te1 gum arabic was injected into the footpad of saline/adjuvant- immunized animals, as well a before and after saline was i {ected into the footpad of mice immunized with gum arabic Footpad swelling was negligible in both control groups An- tibodies were not detected inthe serum of mice that were bled before systemicimmunization Serumantibodies were identified in five of eight control (Saline prefed) mice after systemic im- ‘munization However, antibodies were not detected in the serum of mice that were prefed with gum arabic Regarding delayed- {ype hypersensitivity, a similar pattem was noted Positive skin tests weie reported for all saline-prefed mice However, fot pad swelling in mice prefed with gum arabic was significantly suppressed ‘Test results indicated that systemic immunological hhyporesponsiveness (oral tolerance) developed in mice that were {ed gum arabic (Strobel and Ferguson 1986)98 (COSMETIC INGREDIENT REVIEW Suobel (1986) evaluated the immunogenicity, cross- reactivity, and nonspecific irritant properties of gum arabic (Aca- cia Senegal Gum) using male mice (6 to 8 weeks old) of the [(CS7BLI6] x DBA/2F;] (BDF\) strain Nonspecific irritant ‘properties were assessed in the foot pad swelling test using con- {rol groups of nonimmunized mice Immunogenicity was evalu- ated in an in vivo footpad swelling test, and cross-reactivity was assessed by secondary antibody tesponse ‘The following gum arabic samples (identified as samples A, B,C, D, and E) wete tested in each experiment (1) Sample ‘A (sodium arabate) sesulted fiom the neutralization of sample C with sodium hydroxide (2) Sample B resulted fiom three successive precipitations of sample C fiom aqueous solution with acidified ethanol (3) Sample C, gum arabic, was a water- soluble polysaccharide containing rhamnose, atabinose, glu- ccutonie acid, and galactose (4) Sample D was defined as pow- dered food grade natural gum arabic (5) Sample E was obtained by exhaustive ethanolic extraction of sample D In the nonspe- cific footpad swelling test, five groups (six to cight mice per group) of nonimmunized male mice were injected intradermally ‘with the five samples, respectively ‘Sample A did not induce significant swelling at 24 h, how- ever, samples B, C, and D increased, but only slightly, nonspe- cific swelling (p < 05) Sample E induced the greatest extent of footpad swelling These results (footpad swelling) were in- icative of a nonspecific iritant effect Tn a second experiment, five groups (30 to 40 mice per group) of mice were immunized with the five gum arabic sam- ples (200 jeg per sample), respectively inthe left hind footpad Each gum arabic sample was emulsified in FCA prior to immu- nization Control mice (30 to 40 mice) were immunized with saline in FCA. At 21 days post immunization, the presence of delayed-type hypersensitivity (specific cell mediated immunity) ‘was measured in the footpad swelling skin test ‘All gum arabic samples were immunogenic in this test In ceach case, intradermal challenge after immunization caused a significant increase in footpad thickness at 24 h In the test for cross-reactivity, blood samples were obtained from mice that had been immunized and tested (footpad swelling test) 3 weeks after immunization Antibodies were assayed by an ELISA. ‘Assay results indicated that antigens were shared between all of the samples, except for sample E Mice immunized with sample A had significant reactions when tested with samples A, B,C,and D The greatest nonspecific swelling was produced by samples B and C (Strobel et al 1986) GENOTOXICITY Gum Arabic Both in vitro and in vivo studies on the mutagenicity of gum arabic described as gum arabic, Acacia, or Gum Acacia are sumnmatized in Table 10 Although a few positive results are described, most studies were negative for genotoxicity UV Damage Repair Acacia (Not Gum Arabic) Jain etal (1987) evaluated the effect of Acacia arabica on [UV-induced damage in the WP.2 strain of Escherichia colt Cul- tures were inadiated with UV light (1 5 Sim*/s) for 15 s, with intermittent sting The bark of Acacia arabica was extracted with methanol and the extract was added to cultures ata con centration of 5 mg/plate The revertants and viable cells were counted after incubation fortwo days at a temperature of 37°C Compated to contro cultures exposed to UV light (mean number of revertants per plate = 216), the mutagenic activity of UV light was reduced in cultures dosed with Acacia arabica ‘extiact The mean numberof revertants per plate in test cultures was 34 The survival for control and test cultures was 100% and 70 6%, respectively The investigators stated that the decrease in UV-induced mutagenicity inthe presence of Acacia could have been due to some enzymatic action that reverted the formation of pyrimidine dimers (Jain etal 1987) Effect on Genotoxi Gum Arabic ‘The effect of 3% gum arabic (solvent) on the mutagenicity of 4-nitroquinoline-N-oxide was evaluated using results from the bone marrow micronucleus assay Based on an analysis of time- response and dose-1esponse data on 4-nitro-quinoline--oxide, twas determined that the mutagenicity ofthis chemical was six times greater in gum arabic when compared totes results for the chemical in DMSO When the mutagenicity of other chemicals, such as mitomycin C, was evaluated using different solvents, no solvent effect on mutagenicity was observed The investigators concluded that no clear relationship existed between the solvent used and the mutagenicity observed (Katz et al 1981) ‘of Other Agents Carcinogenicity Gum Arabic No evidence of carcinogenicity was noted in rats dosed in- tuaperitoneally with gum arabic (1 75% or 7% in saline or wa ter) three times per week for up to 15 weeks Based on the data presented, it was difficult to ascertain the size of the dose ad- ‘ministered The doses administered were on the order of several hundred mg/kg Also, no evidence of carcinogenicity was found in a similar study using mice (doses injected not stated) (FASEB 1973) Gum arabic gruel was injected intramediastinally (single dose) into five (0 5 ml dose of test substance) and 10 (1 ml dose) guinea pigs The animals (strain not specified) ranged in weight fiom 220 t0 450 g and were 4 to 10 months old Neoplasms were not observed in any of the guinea pigs either at necropsy or at ‘microscopic examination of tissue On the average, the animals survived from 1200 to 1490 days (Tlolka-Pluszezyk 1970) Melnick et al (1983) studied the carcinogenicity of gum arabic using 4-week-old F344 rats (50 males, 50 females) and(980d pau uo pamapuo.y) ppaasasqo sound aseyieue younouge ‘unayap ony, 2ams0d se payisse> asuodsoy Lb TONON pur JPAXEY mnoyutn 40 tyoqerou 2661 "1 w0810z i S1uDBEINU ON, snow 30 1661 119 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mice (50 males, 50 females) in a 2- year chronic study Both male and female rats were divided into high- and low-dose gioups Low-dose animals were fed ‘gam arabie at a concentration of 25,000 ppm in the diet and high-dose animals were fed 50,000 ppm Test diets were fed for 103 consecutive weeks, followed by | {0 2 weeks of feed- ing of the basal diet Control mice (50 males, 50 females) and rats (50 males, 50 females) were fed the basal diet only accord- ing to the same schedule Mosibund animals and animals that survived to the end of the study were killed using carbon diox- ide and neciopsied Tissues were preserved for histopathologic evaluation ‘Changes in mean body weight for male and female rats were comparable to those of the respective contiol groups throughout the study Slight decreases in body weight (7% to 13%) were ‘observed in female rats Compared to conuols, consistent dif- ferences in mean body weight were noted for female mice of the high dose group (50,000 ppmin diet) No significant differences \ere found in survival between experimental mice or rats when ‘compared to the respective control groups Neoplasms were observed only in male rats, and were diagnosed as malignant lymphomas or leukemia/lymphoma ‘The incidences of malignant lymphomas for control, low-dose (25,000 ppm gum arabic), and high-dose (50,000 ppm gum ara- bic) experimental groups of male rats were as follows: 4/50 (low-dose), 1/50 (high-dose), 8/50 (concurrent controls), and 31/1066 (historical controls) Compared to the concurrent con- {rol group, a significant decrease (p < 05) in tumor incidence was observed in the high dose group, and this was the only statistically significant finding for this neoplasm ‘The incidences of neoplasms classified as leukemia lymphoma in control, low-dose (25,000 ppm gum arabic), and high-dose (50,000 ppm gum arabic) groups of male rats ‘were: 19/50 (low-dose), 16/50 (high-dose), 18/50 (concurrent controls), and 238/1066 (historical controls) Compared to concurrent controls, no statistically significant differences were observed in the incidence of tumors ofthis type No significant changes were observed in the incidence of primary neoplasms in mice that were fed gum arabic in the diet at concentrations of 25,000 or $0,000 ppm Based on the preceding results, the investigators concluded that gum arabic was not carcinogenic in F344 rats or B6C3F, mice of either sex (Melnick et al 1983) Cocarcinogenicity Gum Arabic ‘Vogel and Zaldivar (1971) studied the cocarcinogenicity of Gum Acacia using male rats of the Buffalo strain (6 to 10 weeks (old) Thirty-four rats were exposed to fission neutrons (single exposure of 300 to 364 rads; whole-body irradiation), followed by three intraperitoneal injections (0.5 ml per injection) of a 7% solution of Gum Acacia in 0 85% sodium chloride weekly for 23 weeks (COSMETIC INGREDIENT REVIEW A second test group (30 rats) was irradiated after treatment with Gum Acacia according tothe same procedure Three groups ‘of rats served as controls: one of the control groups (SO rts) was exposed to fission neutrons only Two additional conttol groups consisted of 40 rats injected intraperitoneally with 7% Gum Acacia only (according to test group protocol) and an untreated control group of 79 rats No significant neoplasm incidence was present in the two control groups However, the survival time for the 40 control 1a injected with Gum Acacia (5548 + 39.4 days, n = 30) \was significantly shortened when compared to untreated controls, (6692 + 19 0 days, n = 58) Increases in hepatic, gastric, and intestinal neoplasms were noted in the first test group (34 rats; neutron exposure followed by Gum Acacia injections), when compared to the group of SOrats exposed to fission neutrons only Except for gastric neoplasms, these differences in neoplasm incidence were considered small and probably not significant It is important to note that no gastric neoplasms were observed jn the 50 rats exposed to fission neutrons only, whereas, 20% of the 34 test rats had gastric cancers No explanation for this difference was given Tissues of 28 of the 34 test rats in this group were subjected to complete histopathological analysis after necropsy Similarly (compared to fission neutrons control group), no gastric neo- plasms were noted in the group of 30 rats treated with Gum ‘Acacia and then exposed to fission neutrons The investigators sated that this finding could have been due tothe small number of rats (n = 14, compared to n = 28 in other test group) sub- jected to complete histopathological examination after necropsy ‘The authors stated that the data presented in this study sug- gest that Gum Acacia might be considered a “potentiator” for carcinogenesis (Vogel and Zaldivar 1971) ‘Gum arabic has been reported to increase the number of metastases in mice injected intraperitoneally with Ehrlich as- cites carcinoma cells The carcinoma cells were injected 6 or 24 hrafter the mice were injected intravenously with gum arabic, However, under some conditions, ascites tumor formation was inhibited (Osswald 1968) REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Gum Arabic ‘Studies on the reproductive and developmental toxicity of ‘gum arabic are summarized in Table 11 and discussed below ‘The antifertlity activity of Gum Acacia (1 ml in wates) was evaluated using 10 female rats (strain and weights not stated) ‘The test substance was administered by stomach tube daily for a period of 5 days after mating After performing laparotomy ‘on anesthetized dams, the numberof fetuses was counted on the 10 day of pregnancy The average number of implants per rat was 78 The peicentage of rats with no implant was 0 (Sabir ‘and Razdan 1970) Ina study by the Food and Drug Research Laboratories (1972), the teratogenicity of gum arabic was evaluated using six(280d n2u wo pomaywoy) ajoko srayso Jo as sansooxd Suuinp Tuneut Aq pomoijog *s9yofo srs 9 Jo pouiad 12n0 Iona TUN Bp “(QuoUEde usop soye sajofo senso Jo wontanp wut-poys) 219% sansa pan tu soBueyp 1ueaguudis oN sdnos yo ase seunsooud Sump soyeut ‘nts Bumpus Kg powoytoy ‘0K Goce ost snsys9 om) Jo potsed s9n0 SPU} | uoon0g si8t0m) ‘1 fjfeo paisisiunupe siseay wing ayy ——-—STH UL a|PUIO zo skyposy | usamnoq siyfto%) oy wroB9y TN Hp TBI AITEIO pasoq, sg aTEUIY IMPY ese sjg0m z1 Jo 20140} 01 S41 w20mi0g 8461 wHeFog sojowy pawantun yi poreu pur system) suqgae ppuv weKesouBu9x kop 82 405 Sop Steso posop sajeyy ug aunyyeHT9 —wioBOY ND ayy Booz skep ay nog wo2mi09 20} (Ju! 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suonenuaoue> Kxeaip pay sdn03 (Soyeu ane) ‘yer Soqwweqy-ondiesds 21 Beer 60iz us2mi9g SHZTOM jo sye0% | uwaaaaaq siyston plo sy22m 9) sve [ett YEIAD'LD Aojmecr-ansesds, 03 20g waemag siyBtom fsynuow 6~) sw ¥aao:89, Aoymoq-andeidg, ‘yeas 9¢ sys (urens yaa) epuapy-2mn0489 lo-yaous-p Jo snus aigesy wn 8 oiger uum snoanbre a4 onnyos a1geze und snoanbe 4g cain eouag wiae2y) siqaay tung 105106 groups of mated adult female albino CD-1 outbred mice Three of the test gioups consisted of 22 to 23 mice per group end re- ceived doses of 16, 75, and 350 mg/kg, respectively, on days 6 through IS of gestation Doses were administered by oral intuba- tion The fourth test group of 31 mice was dosed with gum arabic (1600 mgfkg) according to the same procedure Sham-treated mice (28) served as negative controls, and positive-control mice were dosed with aspirin (150 mg/kg) Mean body weights for the test groups ranged from 30 to 397 g and weie 31 2 g and 318 g fox negative and positive contiols, respectively ‘On day 17, all dams were placed under anesthesia and ce- sarean section was performed The numbers of implantation sites, resorption sites, and live and dead fetuses were recorded ‘The wogenital tract of each dam was examined in detail for anatomical normality Gross examinations for the presence of, ‘extemal congenital abnormalities were performed on all fe- tuses Detailed visceral examinations employing 10% magnifi cation were performed on one-third of the fetuses from each Titer ‘The remaining two-thirds were examined for skeletal defects The administation of gum arabic to pregnant mice at doses up to 1600 mg/kg had no clearly discernible effect on nidation for maternal or fetal survival The numbet of sbnormalities ‘observed in either soft or skeletal tissues of fetuses from test ‘groups did not differ from the number occurring spontaneously, in shamtreated controls, ‘As partof this study, groups ofits, rabbits, and hamsters were {dosed with gum arabic according tothe following modifications of the above test procedure: doses (indicated above) were admin- istered to hamsters (gestation days 6 through 10), rats (gestation days 6 through 15), and rabbits (gestation days 6 through 18) (Cesarean sections were performed earlier on hamsters (day 14) ‘and later on rats (day 20) Positive-control rats and hamsters re ceived a higher dose of aspirin (250 mgrkg) Rabbits were dosed ‘with gum arabic in corn oil (8, 37, 173, and 800 mgrkg, respec tively), cesatean sections were performed on day 29 Rabbits were injected with human chorionic gonadotropin (day 0) and ntificially inseminated Mean weights for the dams tested were 1s follows: 200 to 216 g (24 rats per group), 104 6 to 1184 g, {21 to 24 hamsters per group), and 2.01 to 243 kg (15 rabbits, per group) ‘The administration of gum arabic, in corn oil, to pregnant rabbits at doses up to 37 mg/kg (highest dose tested = 800 mg/kg) had no clear effect on nidation or maternal or fetal sur- vival The number and types of abnormalities observed in fe tal soft or skeletal tissues from this group did not differ from the number occurring spontaneously in the sham-treated con- trols Of the four test groups of rabbits (15 dams pei group), the ‘number of survivors per dose group was reported as follows: 13 rabbits (8 0 mg/kg dose group), 15 rabbits (370 mg/kg), 12 rabbits (173 0 mglkg), and 9 rabbits (800 0 mg/kg) In 173 and 800 mg/kg dose groups, maternal death was preceded by severe bloody diarrhea, urinary incontinence, and anorexia At necropsy, hemorchage in the mucosa of the small intestines was, (COSMETIC INGREDIENT REVIEW the only gross pathological finding (Food and Diug Research Laboratories 1972) ‘Akbarsha and Manivannan (1993) studied the reproductive toxicity of Gum Acacia using «wo groups of five male albino tats of the Wistar strain (4 months old; weights between 180 and 200 g) The test substance was administered orally (dose = 1 ml) to the first group daily for 24 days The second group was, dosed (dose = 1 ml) daily for 48 days Rats in both groups were necropsied 24 h after the last dose ‘The testis, epididymis (divided into caput and cauda), semi- nal vesicle, ventral prostate, and coagulating gland were excised, homogenized, and centrifuged The supernatant was used for de- termination of total protein and acid phosphatase (ACPase) and alkaline phosphatase (ALPase) activities. Supernatant obtained from the testes was also used for the deteimination of glycogen and cholesterol, and lactate dehydrogenase (LDH) activity ‘The authors stated that increased glycogen and LDH in the testis are both consequences of spermatogenic arrest, and that decreased ACPase and increased ALPase activities in the testis also ueflect the suppression of spermatogenesis They concluded that Gum Acacia did not suppress spermatogenesis inthis study (Akbarsha and Manivannan 1993) Huynh etal (2000) used gum arabic as the vehicle controlina study evaluating the effect oftriptolide(deterpene triepoxide) on spermatogenesisin adult male Sprague-Dawley rts (12 animals, 90 days old) Control males were fed 30% gum arabic inthe diet daily for $2 days Males in the test group were each fed triptolide at a daily dose of 100 g/kg body weight Male and female rats (two females per male) were housed together during the feeding period, afier which pregnancy rates were determined ‘The presence of sperm in morning vaginal smears was used to determine whether or not mating was successful Any male that impregnated at least one of the females was considered fertile AIL 12control males were fertile, whereas all males fed triptolide in the diet were sterile Collins et al (1987) evaluated the teratogenicity of gum ara- bic (Acacia Senegal Gum) using groups of 4-week-old Osborne- ‘Mendel (FDA strain) rats Beginning at 13 weeks prior to mat- ing, the rats were fed gum arabic at concentrations of 1%, 2%, 4%, 7 5%, or 15%, respectively Another group of ras was fed a control diet Control and test diets were also fed throughout ‘mating and gestation After mating was confirmed, females were placed in groups of 41 to 47 The dams were killed on day 20 of gestation (One female rat (1% dietary group) died during the study Ex- ternal observations ofthe dams were unremarkable One female (7 5% dietary group) did have a cystic ovary and one had lung nodules (15% dietary group) Sporadic nonsignificant increases in body weight were observed in all experimental groups ‘The percentage of pregnant females was approximately the same in all experimental groups and controls Mean numbers cf corpora lutea and implants per female were also similar to contol values, and the average number of viable fetuses was lar in all groups No effect was seen in any group withACACIA respect to the mean number of viable males and females ‘Three liters were totally zesorbed, one litter from the control, 1%, and 4% dietary groups Gum arabic in the diet had no effect on the percentage of females with atleast one resorption or with atleast ‘wo resorptions The numbers of early and late deaths, singly or ‘combined (as average percentage of resorptions), were similar toccontrol values ‘The feeding of gum arabic had no effect on mean fetal body weights and crown-rump lengths The ingestion of gum aa- bie also had no effect on the distribution of fetuses by sex A significant decrease in mean female body weight in the 1% di- etary group was noted, however, this observation was deemed ‘random occurrence ‘The significant inctease in the length of females in the 4% and 7 5% dietary groups was not considesed biologically significant ‘The investigators stated that because of the large group of animals in this study, small variations in erown-rump length can resultin significant effects Similar numbers of runts were noted among male and female fetuses from all dietary groups, with the ‘exception of no runts among male fetuses in the 1% and 15% dietary groups Regarding external variations in live fetuses, spina bifida ‘and exencephaly were observed in two fetuses from the con- ‘ol group No other terata were observed, and the external vari- ations were distributed randomly Similar numbers of fetuses ‘with hemorrhages were observed in all dietary groups ‘The mean numbers of sternebral variations per litter var- ied from 418 (4% gum arabic dietary group) to 5.09 (15% dietary group) in experimental groups, and the mean number of sternebral variations per litter in the control group was 5 21 ‘The variations included reduced ossification and bipartite, miss- ing, and malsligned sternebrae No dose-related increases were found with respect to any ofthe observed stemebral deficiencies, and no significant differences were found between experimental ‘and control groups The significant decrease inthe average num- ber of fetuses with one of more sternebral variations per litter that was observed in the 49% and 7 5% dietary groups was con- sidered a random occurrence Thus, the ingestion of gum arabic did not affect the incidence of liters with fetuses with sternebral variations ‘Skeletal ossification deficiencies were observed in bones other than sternebrae, however, no dose-related differences were ‘observed between experimental and control groups with respect to any variation Furthermore, no dose-related effect was found ‘on the incidence of variations, fetuses with variations, or litters affected in any of the dietary groups Also, no dose-related effect was observed on the incidence of any type of soft-tissue variation Mostof the softtissue variations involved the kidneys Additionally, the incidence of soft tissue variations in fetuses from experimental and control groups was similar The mean numbers of soft tissue variations per liter ranged from 0 30 (15% dietary group) to 0 82 (7 5% dietary group), and the mean was 076 per litter in the control group (Collins etal 1987) 107 Schardein et al. (1965) administered a 10% aqueous Acacia solution by gavage to (wo groups of nine Litle Dutch strain mated female rabbits (average weight = 2 1 kg) at doses of 1 26 and 1 5 mig, respectively Doses were administered on day 0 and the following 6 days (7 doses per female) Nine untieated rabbits served as negative contiols Blastocysts were removed fiomthe uterine hors at 65 days of age, preparedas fat mounts, and then evaluated ‘The number of fertile rabbits with blastocysts recovered (cight of nine rabbits) in the 1 26 and 1.5 ml/kg dose groups ‘was the same as that noted for the untreated control group ‘The ‘mean numbers of blastocysts per rabbit were as follows un- treated controls (5 3 1 2), 26 ml/kg dose group (7 0 17), and 5 mivkg dose group (5 4 22) Normal microscopic vari- ations in blastocysts were reported for test and control groups “These variations included minor trophoblastic vacuolation, to- phoblastic degeneration granules, and trophoblastic knob for- mations (Schardein etal 1965) ‘Morseth and Thara (1989) studied the teratogenicity of a ‘5% solution of gum arabic (powder) in distilled water using 36 female Cri CDBR rats (~9 months old) for which mating had been confirmed Body weights on gestation day 0 ranged from 207 to 314 g The solution was administered by gavage ‘once daily (S mivkg/day) on gestation days 6 through 17 The dams were necropsied on day 20 of gestation Fetuses were subjected fo extemal (303 fetuses) visceral (102 fetuses), and skeletal (201 fetuses) examinations Extemal variations were not observed in any of the fetuses evaluated; however, external malformations, brachygnathig and rugimentary/shor tail, were observed in one fetus Visceral vari- ations included only two fetuses with increased renal pelvic cavitation At skeletal evaluation, one fetus had brachygnathia, tail shorvudimentary, abnormal fusion of sternebrae, and verte- bral anomaly with/without associated rib anomaly The external, visceral, and skeletal malformations observed were unrelated to dosing with Acacia (Morseth and Ihara 1989a) ‘Morseth and Ihara (1989b) evaluated the effect of a 5% so- Ition of gum arabic (powder) in distilled water on fertility and ‘general reproductive performance using 30 male (6 weeks old; weights = 1819 t0 2263 g) and 30 female (10 weeks okt, ‘weights = 2109 t0 3099 g) Sprague-Dawley Crl CDBR rats ‘The solution was administered (oral intubation) to male and fe- male rats once daily (5 mi/kg/day) for 63 days prior to mating, throughout the mating period, and until the animals were killed Male rats were killed after the females had littered The oral dosing schedule for female rats was daily for 14 days prior to ‘mating, throughout the mating period, and through gestation day 19 or day 21 of lactation Fifteen female rats were killed on day 20 of gestation, and the remaining females were allowed to raise their neonates to day 22 postpartum ‘No abnormal estrous eycles that were considered treatment related were observed in any ofthe females Twenty-nine of the 30 females became pregnant, the male fertility index was 97% ‘Mean viability and mean weaning indices were 96% and 98%,108 cosmeric respectively No external, skeletal, or Soft ‘were observed (Morseth and Iara 1989b) ‘The reproductive toxicity of 5% Gum Acacia was evaluated using nine male Syrian golden hamsters (8 weeks old, w. £80 to 100 g) The males weie mated with female Syrian golden hamsters in order to confirm fenility Subsequently, the males ‘were dosed (oral gavage) with 5% Gum Acacia (dose volume 01 mi/10 g body weight) daily for 54 days ‘The animals were killed 3 days after the last dose As determined by analysis of testis sections, spermatogenesis was reported for all hamsters Al of the hamsters produced morphologically normal sperm, which were also observed in the epididymis (Walleret al 1983) Yegnanarayan and Joglekat (1978) studied the amifeutitity effects of 4% Gum Acacia in a series of five experiments using ‘male and female rats and female rabbits of the Haffkine strain Inthe first study, six male albino rats (weights = 175 to 225 g) were tested The rats were dosed oually daily for 28 days using ‘a rubber catheter Beginning on the first day of feeding, males ‘were mated (one male to wo females) with females for 12 weeks Females were replaced each week of feeding Additional groups of females were mated with control males dosed with saline ‘according tothe same procedure Vaginal smears were examined daily for the presence of spermatozoa Pregnant females were surgically observed on the tenth day of pregnancy ‘The number of inseminated females (73) was the same in experimental and control groups The total number of pregnant females in experimental and control groups was 24 and 37, re- spectively, but this difference was not statistically significant In the second experiment, the effect of 4% Gum Acacia on the estrus cycle and mating was evaluated using fertile female albino rats (Weights = 150 to 200 g) The experiment was di vided into two phases In the first phase (short-term treatment), 456 Gum Acacia was administered orally to 10 female rats over 4 period of two estrus cycles, beginning on the day of proestrus ‘The females were mated singly with males during the proestrus phase of the third estrus cycle In the second phase (long-term treatment), 4% Gum Acacia was administered orally to six fe- male rats over a period of six estrus cycles, beginning in the proestrus phase Mating was allowed in the proestrus stage of the seventh estrus cycle In both the first and second experimen tal phases, control females dosed with saline were mated with males according to the same procedures, respectively Results for the first and second phases of this experiment indicated no significant differences in mating (number of females insemi- nated) between experimental and control groups Additionally, for both phases, no significant changes were observed in the duration of estrus cycles after dosing ‘The third experiment, for determining anti-implantation ef- fects, involved 10 fertile rats (weight range from 150 to 200 g) that were mated in proestrus singly with fertile males. Females were dosed orally with 4% gum arabic on days I to 7 of preg: nancy The animals were allowed to deliver normally and litter sizes were recorded Ten control females dosed with saline were ‘mated according to the same procedure. No statistically signif- 1e malformations INGREDIENT REVIEW icant differences were observed in average litter sizes between experimental and control groups, indicating that fetal resorption id not occur in liters of rats dosed with 4% gum arabic ‘The fourth experiment was performed to determine any postimplantation effect of 4% gum arabic using ten fertile rats (weights = 150t0200 p) Female rats were dosed orally with 4% gum arabic on days 10 to 16 and the number of pups delivered ‘was deteimined The rats were observed for vaginal bleeding, indicative of abortifacient activity during pregnancy Control fe= rales were dosed with saline according to the same procedure One of 10 experimental rats did not have a litter All control females had liters No statistically significant differences were ‘observed in the number of pups delivered between experimental and control groups Inthe fifth experiment, the aniovulatory potential of 44%Gum ‘Acacia was evaluated using adult female rabbits (number not stated, weights = I 102 kg) The rabbits were dosed orally with 49 gum arabie for 2 days Copper acetate (4 mg/kg) was then injected into the maiginal ear vein in order to induce ovulation ‘AL48 h pos injection, laparotomy was performed fresh bleed- ;ng points on the ovaries were indicative of ovulation Control sabbits were pretreated with saline according to the same proce- dure prior tothe injection of copper acetate After the injection of copper acetate, bleeding points on the ovaries were observed in all control and experimental rabbits Therefore, the authors concluded that 4% Gum Acacia did not have an inhibitory effect on ovulation (Yegnanerayan and Joglekar 1978) ‘A 1 equeous suspension or mucilage prepared from gum arabic had no lethal effects on fetuses of NMRI mice injected intrapertoneally (Single injection oF series of five injections), subcutaneously (five injections), or administered orally (ive times) between the 11th and 15th day of gestation (Frohberg eral 1969) ‘The embryotoxicty of 1% Gum Acacia was evaluated using ten Charles Foster rats (90 days old; weights = 200+ 20.) The test substance was administered daily at a dose of 50 mgfke/day ding the period of organogenesis The fetuses were delivered by cesarean section on day 20 of gestation, fixed in Bouin's solution, and examined for visceral and skeletal defects None ‘of the fetuses had gross or visceral defects (Sethi etal 1989) CLINICAL ASSESSMENT OF SAFETY Absorption, Distribution, and Excretion Gum Arabic ‘The FASEB (1973) review stated that there was no evidence of the absorption of intact gum arabic found in a study using infants. Twenty-two infants, 10 15 months old, were fed gum arabic (15 to 20 g pet day) in milk No urinary excretion of pentose or significant excretion of gum atabie was observed in the stools Ina nephrotic patient, 20% of the gum arabic injected intra- venously over a period of 6 weeks was excreted in the urineACACIA Other studies involving patients with nephrosis indicated that intravenously injected Gum Acacia, oF some product associated ‘with it, accumulated in the liver and remained in the tissues for several months Serious disturbances in hemoglobin, white blood cells, and serum proteins, all nonlethal effects, were noted (FASEB 1973) Rosset al (1984s) evaluated the excretion of gum arabic and its effect on glucose absorption and routine hematological and ‘biochemical measurements infive healthy male volunteers (30 t0 55 years old) All subjects were free of signs of gastrointestinal disease The study was divided into two time periods, a 7-day control pesiod that was followed by a 24-day treatment period “After an overnight fast, glucose (50 g in 200 mil H0) was fed to ‘each subject on the first day of the conttol period During the 24- day treatment period, gum arabic (25 g in 125 ml 7% dextrose) ‘was ingested daily by each subject Urine was collected on I day cof the control period and on 1 day during the 3rd week of the tucatment period Complete 5-day fecal collections were made ‘on days 2 10 6 of the control period and on days 16 to 20 of the treatment period Pooled stool slurry samples from the five subjects were centrifuged A precipitate typical of gum arabic was not detected in fecal specimens collected before or after the ‘administration of gum arabic “The marked increases in breath hydiogen production noted after gum arabic ingestion were indicative of bacterial break- down of gum arabie in the cecum and colon after 3 weeks of ‘administration Additional study results are summarized in the following paragraph No significant differences in the mean concentration of serum lipids (phospholipids and triglycerides) were noted before and after gum arabic ingestion However, a significant decrease in serum cholesterol (0 39 mmoV/L reduction; p < 05) was noted ‘Also, no statistically significant differences were observed be- ‘ween the mean blood glucose concentration (control) and the ‘lucose concentration after the administration of gum arabic ‘Similarly, no significant differences were found in the mean insulin concentration before versus after gum arabic ingestion) ‘Alanine aminotransferase and aspartate aminotransferase activ- ities were significantly reduced (p < 0025; p < 001) after ‘gum arabic ingestion; however, both mean values were within the normal limits forthe population Of the 13 biochemical mea- surements that were estimated in the plasma, these reductions in plasma enzyme concentrations represented the only noted significant changes (Ross et al 1984a) Short-Term Oral To Gum Arabic Five healthy male subjects (30 to 55 years old) ingested 25 g ‘gum arabic (Acacia Senegal Gum) daily for 21 days Toxic ef- fects were not observed during the 21-day period, breath hydro- ‘gen concentrations incieased only after chionic administration ‘The fact that gum arabic was not recovered from the feces sug- gest that itis degraded extensively in the human colon (Anderson 1986) y 109 Short-Term Intravenous Toxi Acacia (Not Gum Arabic) ‘Acacia was administered to nine patients with nephrotic edema over periods up t08 weeks The test substance was admin- istered intravenously, and total doses ranged from 80 to 325 g ‘No signs ot symptoms of hepatic enlargement or any other com- plications were observed Five ofthe patients excreted 5 5% to 38% of a single dose in the urine during periods ranging from 10 to 30 days, sespectively (World Health Organization 1974) Skin Irritation Acacia (Not Gum Arabic) ‘The skin irritation potential of Acacia Farnesiana Extract (from flowers, 40% in petrolatum) was evaluated in a 48-h closed:-patch test using 30 healthy male and female volunteers Skin ivtation was not observed (Letizia etal 2000) ‘Shaligram and Vakil (1990) evaluated the skin iritation po- tential of Acacia Concinna Fruit Extract (2% in carageenan base [pH of 6 to 7] or 2% in a shampoo [pH of 7 to 8)) in a use {est involving 30 normal subjects. The carageenan base and the shampoo, both without the fruit extract, served as controls. The application procedure was described as a routine half head (wet surface) application of Acacia Concinna Fruit Extract (in car- rageenan base or in shampoo) The respective controls were applied to the other half of the head (wet surface) Application of test and control materials was followed by rinsing with warm water at 10 to 15 min post exposure The scalp of each subject, was evaluated for signs of imitation (erythema, edema, or any other reaction) at 24 and 48 h post application Neither Acacia Concinna Fruit Extract (2% in carrageenan co 2% in shampoo base) nor the controls induced skin irritation (Shaligram and Vakil 1990) Skin Ser Gum Arabic Ivy Laboratories (2000) evaluated the skin sensitization po- tential of a mascara containing 8 0% Acacia Senegal in a max- imization test using 28 healthy adult volunteers (males and females, 18 1049 years old) Twenty-five subjects completed the study because three withdrew for reasons that were unrelated the test procedure During the induction phase, approximately 0.1 ml of 0 25% aqueous sodium lauryl sulfate (SLS) was ap- plied (under an occlusive patch) to each subject Patches were applied to the upper outer arm, volar forearm, orto the back for 24h After patch removal, 1 mlof the mascara was applied (un- der an occlusive patch) to the same site on each subject Patches remained in place for 48 h, except for weekend applications in which the contact period was 72) Sites were observed for signs of irritation atthe time of patch removal If skin initation was not observed, an occlusive patch con- taining 0 25% aqueous SLS was applied to the same test site for 24h An occlusive patch containing the test substance was then applied tothe same site for 48h The preceding patch application izationpanunuoosip ‘aunsodxo soye wwowaunsout ‘uonouny Suny pur smoers feat 4861 “18 Sousa 24 {yo suuay Ut Kropaepsns Ssas8 01g iydoseq ueuiny pue sisor youd ‘su¥aq 99jj09 parsbo1 1809 01 post iqear siqese wing “sayo9 SunquLp 10ye ‘und pu 2ayj00 01 uonwzntsuss jong —_paouatiadyo sivapr suonovar o8s2qTe ‘un spear pro-avae-co stoned ¢ ut yses/Burqay “swwaned sigesy wing sigan win 8L61 ‘wus patean wo29q poy stone ydsuen Koupry st pioeoy 219] squow 1, wonwado puooas sae pe Aro@uns aye uonnyos aurpes 15% ‘Asains sisenueydoy2 ze6r ‘wou Sutsanooas uneBeyy pur winikeyy, 949 Jo worenstumupe snousaenuy yey plo-eax-1z vroeay aeqaiouioy (9 os) auyes ut sey ‘Areuourjnd Zot 91 999 Jo uouwsstuupe snouaKeNUY ‘gan waned oop bow (pauodas (20 09s) aures ur iseay 49 stmoydtaAs yoy) 430.280 "4° Kq pamorjoy asop puoseg ——sueupenb saddn 143 ‘uonnjos viseoy Jo uonENSTUTUIpE (as0p/3 970) umumests Srup ay) ur sseur rejnpou sey ze61 eT snouaaeiut Aq parezaj2ooe 1eaq] JO Sosop oat Jo uonDafur snoouRMDANE —_YHLM ayew plo-wak-g/, eioeoy SUBIR ‘suns, ‘ansodxa jo parenyeao siuanieg orpmis ‘unos/aumpa2cig ustpaisuy ‘eowDy Jo soroads so4po pu aigeay wm UO SuOdaL ast) TL aTaVL 0‘PROT [oa wer ssot quis pu uaysy>qy ‘PR6r weueai| r6I PURE S61 21M 161 ‘Te 19 souyog, 8661 “Te Yost ‘iquie wind snoanbe 2401 Jo Runsay ypreg “o1qee umn 0} aunsodso saye pauasiom ages wd snoonbe ——euzz2a ‘ot tp uo (sored Sunud {gol 0: uonovas so red aantsog 1809.01 pasn)aiqese wn 01 aunsode sae nd snoanbe 9367 0 won2eat ++ 91 pauopad sso yorea “gol tun snoanbe 9g pe 31 1 wHRIaI-+ 2m wo SOK Z 0} Ae HM O aMSOR pooped (sroqumey> wary) 80 yore sages urn oy uononar ++ go aq) Uo argese un oy amnsOo powsoyrad 1801 uonwznisuas smvak g 01 p = amsodya yo uonemp afviany ouoore [Adoxdost pur wioeoy Kouds ng Suuemuos @unuud-s0}09 ur pasn) Aeads 0 aunsodx pouuopied sso) snooueinaeur pu snosuin> wodoy{“srqere wun ZummneI409 ‘eads 198910 0) aunsodso 0} anp eunpsy ‘i901 snogueinoenut pu youd ug {mo} se suonenua.400 te p: suonotar axnisod peonpt ‘uonoefut auapenur puv yorog our BIOBOY Paying “wouuomtaus Asor>ey woyy snp ‘apnis 6; vonzsay aanisod KIpoyRYy Jo woNeTeY OF anp eUNSE peIyoUO pauuoyied sisay ‘puig2s9 purey Jo, ‘ons sw96-z qo soruudowpy pio-se2h-py (impon pee 20490) Aso} Buss20030 uma jo sod cp uyise un siojuud 9yeur 2 4 raymud pjo-rwas-¢¢ siqeze wn igeay wn, sv) atgery wn aiqery wap pioway win, aiqeay wn (29439 arexpyoqres winpos ‘qua parzesixa) oesy tun (suuoy paguind ue apnis) Brow nL2 sequence was 1epeated for a total of five induction exposures, after which a 10-day nontreatment period was observed Piiot to challenge patch application, a new site on the opposite arm, forearm, or side of the back was pretreated for 1 h with 5% aqueous SLS (0 1 ml under occlusive patch) A single challenge patch (ocelusive patch) was then applied to the same site for 48 b Reactions were scored at 1 and 24 h after patch removal according to the following scale 0 (aot sensitized) to 3 (song sensitization [large vesiculobullous reaction]) ‘Sensitization reactions were not obscived at 1 or 24 h after challenge patch removal It was concluded that, under the con- ditions ofthis test, the mascara containing & 0% Acacia Senegal did not possess a detectable contact-sensitizing potential, and, hhence, is not likely to cause contact sensitivity teactions under normal use conditions (Ivy Laboratories 2000) Acacia (Not Gum Arabic) Letizia et al (2000) evaluated the sensitization potential of Acacia Farnesiana Extract (from flowers, 4% in petrolatum) in & ‘maximization test using 30 healthy male and female volunteers ‘The test substance was applied, under occlusion, to the same site on both forearms of each subject throughout induction The induction phase consisted of a total of five 48-h exposures (on alternate days) Prior to application of the initial induction patch, the test site was pretreated with 5% aqueous SLS, undes occlusion The induction phase was followed by a 14-day nontreatment period, after which a challenge patch was applied (48 h) to new sites ‘on each subject Challenge patch applications were preceded by 30 min applications of 2% aqueous SLS, under occlusion, on the left side Challenge sites on the right side were not pretreated ‘A fifth challenge site (petrolatum applied) served as the control Tt was concluded that none of the reactions observed could be classified as a significant skin irritation or allergic reaction (Letiaia et al 2000) Case Reports Gum Arabic Gelfand (1949) reported allergic disorders in 10 subjects (7 males, 3 females; 11 1055 years old) who had ingested various ‘gum-containing foods Gum arabic was among the gums present in each food ingested Some of the allergic symptoms reported included bronchial asthma, generalized urticaria, and vasomo- tor thinitis Allergic symptoms were not observed upon removal ‘of suspect gum-containing foods from the diet, and symptoms ‘were reproduced when clinical trials were repeated Positive skin reactions (test procedure not stated) to gum ara~ bic were observed in each of the 10 subjects The results of setologic studies (sera from four subjects) indicated that gum arabic was the dominant gum antigen in two subjects and that tragacanth and karaya were the dominant gum antigens in the remaining two subjects The serological studies included pas- sive transfer tests in serial dilutions and neutralization studies (COSMETIC INGREDIENT REVIEW It was determined that gum arabic and other vegetable gums could cause alleigic disorders by ingestion in sensitive subjects, (Gelfand 1949) Raghuprasad etal (1980) reported cross-reactivity between ‘Gum Acacia and gum wagacanth ina 24-year-old patient who de- veloped sensitization to Quillaja bark (Quillaja saponaria) dust, ‘which resulted in shinitis and asthma The CIR Expert Panel has previously evaluated the safety of Tragacanth Gum in cosmetics, ‘and concluded that this ingredient is safe in the present practices of use and concentiation (Elder 1987) Specific immunoglobu- lin E(gB) to pulverized Quillaja bark, gum arabic, and gum tuagacanth were measured according to @ modification of the radioallergosorbent test (RAST) Each of the three antigens (20 mg/ml) was coupled directly to methyl cellulose disks that had been activated previously by cyanogen bromide dissolved in acetonitrile. Results were expressed as percent binding. ‘The amount of radioactivity bound by the patient's serum was ‘compared with control sera from healthy, nonallergic volunteers (number not stated) not known to be exposed to Quillaja bark «dust The mean percent binding of IgE to Quillaja bark in patient sera was 22 4%, compared to 3 2% for the control Compared to negligible binding in control sera, significant binding was reported for gum arabic (32.5% binding) and gum tragacanth (30 8% binding) (Raghuprasad et al 1980) ‘Additional case reports on gum arabic and other species of Acacia are summarized in Table 12 Although two fatalities are reported, neither related to gum arabic and most case reports involve sensitization reactions SUMMARY ‘This safety assessment includes the following ingredients, de- rived from Acacia, that are listed in the Jncernational Cosmetic Ingredient Dictionary and Handbook Acacia Catechu Gum, ‘Acacia Concinna Fruit Extract, Acacia Dealbata Leaf Extract, Acacia Dealbata Leaf Wax, Acacia Decurrens Extract, Acacia Famesiana Extract, Acacia Farnesiana Flower Wax, Acacia Far- nesiana Gum, Acacia Senegal Extract, Acacia Senegal Gum, and Acacia Senegal Gum Extract, Gum arabic is another name for Acacia Senegal Gum Gum arabic is generally recognized as safe for direct addition to food. for human ingestion Acacia Senegal Gum has been described as the major commercial Acacia gum Gum arabic is produced when the Acacia tree is siressed by infection, poor nutrition, ‘eat, oF lack of moisture ‘The gum exudes through wounds in the bark that occur naturally or are purposely made to stimulate production Gum arabic is composed of p-galactose, L-rhamnose, L- arabinose, and p-glucuronic acid residues in an arrangement of a main chain of galactosyl units joined by 8-p-(I —r 3) linkages and side chains or branched oligosaccharides inked to the main chain by B-p-(1 ~> 6) linkages It has also been described as a complex mixture of calcium, magnesium, and potassium salts of arabic acid Arabic acid is a complex of galactose, rhamnose, arabinose, and glucuronic acidACACIA, ‘Aflatoxin has been reposted as animpurity in Acacia Catechu, but not in gum arabic Acacia Gum (Acacia Senegal) di not contain detectable pesticide residues, Qualitative information is available on the components that maybe found in ingredients derived from various Acacia species and plant parts This information indicates a few similarities and many differences in constituents Quantitative or serniquantta- tie data wete not available ‘Theprineipal UV absorbance of gum arabic occurredat wave- lengths below 240 nm At wavelengths above 240 nm, the UV absorbance was not significant "Acacia Decurtens Extract and Acacia Faresiana Extact are described as a cosmetic astingent, and Acacia Decurrens is also described as a skin-conditioning agent—ocelusiv, al- though none ofthese are reported tobe in current use. Cosmetic functions of the other Acacia-derved ingredients included in this review are not deseribed Product formulation data submit- ted tothe FDA indicated that Acacia was used in 22 cosmetic products—no information is available to further describe the species or plant part Cosmetic use concentration data supplied by the cosmetics industry indicated maximum use concentra- tions of 9¢ in shampoos for Acacia Senegal Gum and 0.001% for Acacia Senegal Gum Extract, in bath soaps and detergents ‘Recommended use concentrations of Acacia Concinna Fruit Extract are | 0% to 2 0% for use in shampoos, hair packs, hair concitionets, and hair rinses, although no uses have been re- ported to FDA ‘The weight gain for rats fed gum arabic at a dietary con- centration of 16% was 75% of that reported for control rats Approximately 80% of the gum arabic was absorbed Results| from other studies involving ras suggest that the metabolism of gum arabic is mediated by bacteria inthe cecum Results of studies in which dogs and rabbits were injected intravenously with gum arabic indicated that gum arabic or some other product associated with it accumulated in the liver and remained in the tissues for several months Nonlethal effects included disturbances in hemoglobin values, white blood cells, and serum proteins Based on absorption and metabolism studies an expert anal- ysis determined that gum arabic is capable of being digested to Simple sugars It was also determined that conclusive evidence indicating thatthe intact gum arabic molecule is absorbed under normal conditions was lacking Tn an in vitro assay, dose-dependent uncoupling of oxidative phosphorylation was noted in groups of rats dosed orally with ‘gum arabic up t 10% twice daily for 4 weeks, but comparable biochemical effects were not observed in vivo ‘An acute oral LDsp of 8000 mg/kg was reported for Acacia ‘Gum in rabbits The acute oral LDso for Acacia Famesiana Ex- tract (from lowers) in rabbits was >5 0 g/kg A minimal lethal dose of >2 g/kg (10 ml) for Acacia Dealbata Leaf Wax in a suspension with parafin oil was reported in an acute oral tox- icity study involving rats None of the animals died, and no test substance-elated lesions of organs examined were noted at 13 necropsy Similarly, in another study, no deaths or test substance- related, o1gan lesions were reported following the oral adminis- tration of Acacia Farnesiana Flower Wax ata dose of 10 ml/ke, nan acute dermal toxicity study of Acacia Farnesiana Extract (from flowers) involving rabbis, an LDs» of >5.0 ghkg was reported ‘Gum arabic did not cause any abnormal changes in serum chemistry parameteis 01 induce toxicologically significant le- sions in ats that received oral doses daily for 28 days. Gum ar bic was also administered to rats in four other short-term oral tox- icity studies Collectively, test concentrations ranged from 1% to 20% and study durations ranged from 28 day’ to 9 weeks No significant or discernible ultrastructural differences were found between tissues (heat, liver, small intestine) of contol rats and test rats, hematological findings were normal Gum arabic was nontoxic, even atthe highest concentration tested ‘One of three dogs injected intravenously (32t0 3 injections) with gum arabic over a period of 76 days died ‘The range for the {otal cumulative dose was 15 7 0.477 pfkg. and death occurred atthehighest dose (47 7 g/kg) Anenlarged liver was observed in the animal that died, and the cause of death was not determined Enlanged livers and swollen kidneys were also observed in dogs that received doses ranging from Ito 2 g/kg, In subchronic (13 weeks) oral toxicity study on Acacia Senegal Gum, the only reatment-related alteration noted in rats at necropsy was cecal enlargement in animals ofthe highest dose (14 pfxsiday) groups Electron microscopic findings for samples of livers and kid- neys from groups of five ras fed diets containing 0.5% to 3.5% ‘w/w Acacia Senegal Gum daily or 91 days were negative Mito- chondria and nuclei were ultrastructurally normal in appearance and internal structure ‘The administration ofa single dermal dose of Acacia Farme- siana Extract (from flowers, 5 0 g/kg) to rabbits induced moder- ate erythema and edema Undiluted Acacia Deslbata Leaf Wax, was clasified as a non-itrtant after application, under occlusive patches, to scarfied skin of albino rabbits for 24 h. Undiluted ‘Acacia Famesiana Flower Wax was classified asa slight iritant ‘hen tested according to a similar procedure ‘A 20 0% solution of Acacia Famesiana Extract in methanol (from flowers) did not induce phototoxicity in SKHthairless mice ‘Anaphylactic signs in guinea pigs injected intraperitoneally (nid challenge reactions) or intravenously (strong challenge re- actions) with Acacia solution have been reported No signs of anaphylaxis were observed in rabbits injected intravenously (no challenge reaction) with Acacia solution In rabbits and guinea pigs injected with 7% Gum Acacia solution, no deleterious ef- feets on antibody production resulted Mouse footpad swelling test results indicated a significant increase in footpad thickness (compared to controls) in mice immunized by injection of gum arabic in saline and Freund’s ad- juvant Antigen-specific hypersensitivity reactions were noted Ina similar test, footpad swelling was significantly suppressed14 (compared to controls) in mice dosed orally with gum arabic and:then immunized by injection of gum arabic in saline and Freund's adjuvant In another tes, intadermal challenge after immunization of mice with Acacia Senegal Gum caused a sig- nificant increase in footpad thickness Gum arabie was not mutagenic in numerous in vitro mu- tagenicity tests using Salmonella typhimurium, Saccharomyces cerevisiae, and Bacillus subtilis bacteial strains In an in vito cytogenetics assay, though results were classified as slightly pos- itive, gum arabic did not induce definite abnormal anaphase fig- uues in diploid human embryonic lung (WI-38 fibroblasts The mutagenicity of gum arabic was also evaluated in numerous in vivo assays, the results of which were mostly negative Statistically significant positive results were noted in one of the three dominant lethal tests (rat assay, but notin two mouse assays) that weie performed Further testing in the mouse her- itable translocation test yielded negative results In acute and short-term in vivo cytogenetics assays (rats), though no signif- icant positive responses were observed, there may have been a slight positive response It was stated that further tests and 4 detailed statistical evaluation are needed in order to confirm this possibility There were no statistically significant findings, jn mouse chromosomal aberrations and sperm-head morphol- ‘ogy assays. Negative results were also reported in micronucleus, tests (mouse bone marrow smears) and other in vivo assays, No evidence of carcinogenicity was observed in rats dosed intraperitoneally with gum arabic (1 75% or 7 0% in saline or ‘water three times per week for upto 15 weeks In another study, tumors were not observed in guinea pigs injected intramediasti- nally with 0 1 ml of a gruel of gum arabic (single dose) ‘The carcinogenicity of gum arabic was also evaluated using 4-week-old F344 and 4-to S-week-old B6C3F; mice Low-dose animals were fed gum arabic at a concentration of 25 g/kg in the diet and high-dose animals were fed 50 g/kg for 103 weeks ‘Neoplasms were observed only in male rats, and were diagnosed as malignant lymphomas or leukemis-lymphoma Compared to controls, no significant increases were observed inthe incidence of ther type of neoplasm either of the two test concentrations; ‘gum arabic was classified as noncarcinogenic in rats and mice Oral administration of gum arabic (1 ml) did not cause antifer- tility effects in female rats or the suppression of spermatogenesis, inmale rats Gurn arabic was not teratogenic when edministered orally to mice at doses up to 1600 mg/kg, Oral doses of gum. arabic up to 1600 mg/kg also wete not teratogenic in rats and hamsters, and oral doses up t0 800 mg/kg were not teratogenic inrabbits No effects on ferility or ovulation (4% gum arabic), or any abnormal variations in blastocysts (10% gum arabic) were found in rabbits Gum arabic, at a concentration of 15%, failed to in- duce teratogenicity or other teproductive effects in female rats Gam arabic (5%) also did not cause abnormal sperm develop- rmentin hamsters Embryotoxicity was not notedin mice injected {ntraperitoneally with a 1% aqueous suspension ox mucilage pre- pared from gum arabic COSMETIC INGREDIENT REVIEW No evidence of absorption of intact gum arabic was found in 22 infants fed gum arabic in milk In a patient with nephrosis, 20%6 of the gum arabic injected intravenously was excreted in the urine over a period of 6 weeks Gum arabic was not detected in feces specimens collected from five male volunteers before ‘or after administration of the gum Toxic effects were not observed in five male subjects who ingested 25 g of gum arabic daily for 21 days ‘In a 48-h closed patch test, Acacia Famesiana Extract (from flowers, 4 0% in petilatum) did not induce skin imitation in any of the 30 subjects tested In an “in-use test.” skin irritation was not observed in any of the 30 subjects tested with Acacia Concinna Fruit Extract (2% in natural base {such as carageenaa] ‘and a routine shampoo base) The test substance remained in contact with the scalp for 10 to 1S min, and skin ieitation was evaluated immediately ater application and 24 and 48 h later ‘The skin sensitization potential of a mascara containing 8 0% ‘Acacia Senegal was evaluated in the maximization test using 28 healthy adult volunteers It was concluded that, under the con- ditions of this test, the mascara containing 8 0% Acacia Senegal did not possess a detectable contact-sensitizing potential, an, hhence, isnot likely to cause contact sensitivity reactions under ‘normal use conditions ‘The results ofa study involving ten subjects who had ingested various gum-containing foods, indicated that gum arabic could cause allergic disorders in sensitive subjects Analyses of sera from 4 of the 10 subjects indicated that gum arabic was the «dominant gum antigen in two subjects Cross-reactivity between ‘gum alabic and gum tragacanth was reported for a 24-year-old patient who developed sensitization to Quillaja bark (Quillaja, ‘saponaria) dust, which led to rhinitis and asthma ‘Neither significant skin irritation nor allergic reactions 104% ‘Acacia Farnesiana Extract (from flowers) in petrolstum were ‘observed in & maximization test (30 subjects) ‘A mumber of case reports of gum arabic allergenicity have been identified in the published literature DISCUSSION Extensive safety test data are available on gum arabic that demonstrate its safety in a wide variety of applications, includ- ing cosmetic use Based on the available information, the Panel concluded that Acacia Senegal Gum is equivalent to gum arabic and should be considered safe as used in cosmetics Tt also ap- pears that gums from other species are not the same as Acacia ‘Senegal Gum It follows that the safety test data on gum arabic ‘can be used to support the safety of Acacia Senegal Gum and. not gum from other Acacia species Because Acacia Senegal ‘Gum Extract is derived from Acacia Senegal Gum, the Panel considered that Acacia Senegal Gum Extract would present no additional safety issues ‘The Panel recognized the potential for allergic responses to gum arabic However, because of negative results forall 25 sub- jects ina human maximization study (mascara containing 8%ACACIA ‘Acacia Senegal) and the expected slow rate of dermal absorption of gum,arabie duc to its large molecular size and water solubil- ity, the Panel determined that it isnot likely thet normal use of ‘gum arabic in a cosmetic product would result in sensitization ‘The Panel is concerned that the available data suggesting the absence of pesticide residues in Acacia plants harvested wild are limited The Panel advised the industry thatthe total polychlo- tinated biphenyl (PCBY/pesticide contamination of any plant- derived cosmetic ingredient should be limited to not more than 40 ppm, with not mote than 10 ppm for any specific residue The Panel also advised that limits were appropriate for the following impurities arsenic (3 mg/kg maximum), heavy metals (0.002% ‘maximum, and lead (5 mg/kg maximum) ‘The limited safety test data on Acacia Faresiana Extract and con Acacia Concinna Fruit Extract wete ot sufficient to assess the safety of these ingredients in cosmetics ‘The Panel found no information that adequately character- ized the composition of fruit, leaf or other extracts, leaf wax, flower wax, or gum fiom Acacia species other than A. senegal ‘Therefore, the Panel could not extrapolate the available data ‘on gum arabic to support the safety of Acacia Catechu Gum, ‘Acacia Concinna Fruit Extract, Acacia Dealbata Leaf Extract, ‘Acacia Dealbata Leaf Wax, Acacia Decurrens Extract, Acacia Farnesiana Extract, Acacia Farnesiana Flower Wax, Acacia Far- nesiana Gum, and Acacia Senegal Extract The Panel concluded that available data are insufficient to support the safety of these Acacia-derived ingredients ‘The additional data needed for these ingredients include 1 concentration of use in cosmetics; identify the chemical composition, ifthey are sufficiently dif ferent from those of Acacia Senegal Gum, then the following data would be needed: ‘a UVaabsorption spectrum; if there is significant absorbance in the UVA or UVB range, then phototoxicity and photo- sensitization studies may be needed; 'b with the exception of Acacia Farnesiana Extract and Aca- cia Concinna Fruit Extract, sensitization and irritation data are needed, two genotoxicity assays, one in a mammalian system; if positive, then a 2-year dermal carcinogenicity study us- ing National Toxicology Program (NTP) methods may be needed d_ dermal absorption data, i there is any evidence of signif icant dermal absorption, then reproductive and develop- mental toxicity data may be needed CONCLUSION ‘Based on the available animal and clinical data included in this report, the CIR Expert Panel concluded that Acacia Senegal Gum and Acacia Senegal Gum Extact are safe as used in cos- ‘metic products The Panel also concluded that the available data are insufficient to support the safety of the following ingredients in cosmetic products: Acacia Catechu Gum, Acacia Concinna us Fruit Extract, Acacia Dealbata Leaf Extract, Acacia Dealbata Leaf Wax, Acacia Decurrens Extract, Acacia Famesiana Ex- tuact, Acacia Farnesiana Flower Wax, Acacia Famesiana Gum, ‘and Acacia Senegal Extract REFERENCES [Abdalla M H_1988 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Marsh 27-2000 (2 pages)" abvidge, MG andM S Lepator 1969 A hostmedited microbial assay for the detection of mutagenic compounds Proc Soc Exp Biol Med 130831 CGcfand HH 1943 The allergenic properties ofthe vegetable gums J Alergy 1208-219 CGofand H 111949 The vegetable gums by ingestion ‘disorders Allergy 203311321 Gennaro A Red 1990 Remington s Pharmaceutical Scences 18th ed 1304 Easton, PA: Mack Publishing Company GGotwchalck, T'A and GN McEwen Jr eds 2000 Intemational Cosmetic Ingredient Dicuonary and Handbook 10th e8 Washington, DC: CTFA Green, § 1977 Present and fre ses of mutagenicity tse fr asessment of the cafey of fod adives J Ein Pathol Toxicol 19-54 Hagos M_and G Samuelson 1988 Quanitatve determination of quracol A, ' and (+) Sistine! in back and gum of Acacia ors Acta Pham Suse 25:321-324 Hworb, ST Lawlor K Morslmans W Speck, and E Zeiger 1983 ‘Salnonello mutagenicity results for 250 chemicals Environ Mutagen 5 12 Heideberger M_O T Avery and W F Goebel 1929 A soluble specie su stance derived from gum arabic J Exp Med 49347-857 Huynh PNA P'S Hikim C Wang K Stefonovic, Y H Lue A Leung, ‘Atienza §Baravirin, V Reutakol, and RS Swerdoff 2000 Leng ‘exm effects of tiene on spemnatogeness, epididymal sperm functio, an frit in male rats J Androl 21:689-699, lichystyn, A” and @ Smith 1985. 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