Salicylaldehyde

Fragrance raw materiab, monographs

903

SAI,ICYI,AI,DEIIYI)E

Synonyms: Salicylic aldehyde; o-hydroxybcnzaldchyde. Struc'tur~': ItO" C~,Il,t" C1-10. De.~cription told ph.|'sical i,roperties: Merck Index (19761. Oc'c'urretwr Occurs frequently in nature: in the flowers of Spirea uhmtria and olher Spireac. in the roots of Crepi.~'fi~ethhl L., in the fruits of Phur avium, in the rind of Ruuwol.]ia ca.lfra, in the leaves of Ceam~thus z'~'hititms, and in the essential oils o f Cimtwnomum ('as.~iu and of tobacco lea','es (Fcnarol~.~ iluoulh~k of FIm'or Ingredi~'nts, 19751. It also occurs in gral~, tomato, cinnamon, n,ilk and milk products, beer, coffee and tea (CIVO-TNO, 19771. Preparation" Made by heating sodium phenohtte and chlorolorm with sodium hydroxide (Merci, Index, 19761. Uses: In public use since the 1930s. Use in fragrances in the LISA amounts to approximatel) IIX~0Ib/yr. Concentration in final product (%): Usual Maximum

Sottp if01 005

Deter qeot O00l 0.005

Creams, lotions 0095 002

Perfione 0"08 0-2

Status Salicylaldehyde was given GRAS status by FEMA (1965[ is approved by the FDA for food use (21 CFR 172.5151, and was included by the Council of Europe (19741` at a level of 5 ppm, in the list of artificial flavouring substances that may be added to foodstuffs without hazard to public heahh. CAS" Registry No. 90-02-8.

Biological

data

Aeme toxicity. In rats treated se, the LD~o has been reported as 0.9 g/kg (Fas~tt, 1963). and the minimum lethal dose as 1.0g/kg (Merck ludex, 19761. The acute oral LD~o in rats has been reported as 0-52 (0"36-0-76 g/kg) (Moreno, 1977) and tile topical LDso in rats as 0"6 g/kg (Moeser, Bien & Jung, 1968). The acute dermal LD.~o in rabbits was reported as 3.0 (2-0--4.6 g/kg) (Moreno, 19771. Subacute toxicity. Rats fed saficylaldehydc as 2% of the diet for 13 days showed a marked decrease [n cytoplasmic basophilic bodies in the liver cells anti depletion of zymogcn granules from pancreatic acinar cells (Hruban, Swift & Slesers, 19661. Other rats fed I% salicylaldehyde in the same manner were observed to have an increase in the size, number and fibrillar material of hepatic and renal mierobodies, vacuoles eor~taining amorphous dense material, and lipid droplets in the hepatocytes. Irritation. Saliey'laldehyde applied full strength to intact or abraded rabbit skin for 24 hr under occlusion~ was moderately to severely irritating (Moreno, 19771. Tesled at 2% in petrolatum, it produced no irritation after a 48-hr closed-patch test on human subjects (Epstein, 19761. Sensitization. A maximization test (Kligman, 1966; Kligman & Epstein, 1975) was czlrried out on 33 volunteers. The material (RIFM no. 76-249) was tested at a concentration of 2% in petrolatum and produced no sensitization reactions (Epstein, 19761. Absorption and meiabolism. T h e rate of absorption of salicylaldehydc when perfused through the small intestine of the rat from the proximal to the distal region was determined by Nogami, Hanano & Yamada (19681. The metabolic pathway of certain aromatic aldehydes within the animal body comprises oxidation to the corresponding acid, salicylaldehyde being oxidized to .salicylic acid (Williams, 19591. Salicylaldehyde is excreted in the form of its aldehyde conjugates and oxidation products (Will!ares, 1959). Plmrmacology. Salicylaldehyde was found to be primarily a vasodepressor agent when given iv to dogs previously anaesthetized with barbiturates (Wingard, Hitchcock & Teague, 19551. It promoted wound-healing and granulation formation in rats when applied topically in 5-12% concentrations in paraffin oil or injected sc at 10%, but toxicity was also noted (Moescr et al. 1968). It was a less potent analgesic and ,mti-inflamnmtory agent than aspirin or salicylic acid when tested in rodents (Whitehouse, Rainsford, Ardlie, Young & Br'ane, 1977), and in rats salieylaldehyde was shown to be ineffective as ananti-inflammatory agent, as measured by inhibition of mast cell degranulation or anliserum-induced oedema (Yamasaki & Saeki, 1967). The olfactory response of burbots (Lota Iota) to l0 -J M-salicylaldehyde was observed by D~Sving (19661 and the effects of salicylaldehyde vapour ot~ the receptor cells of frog olfactory mucosa by Gesteland (1967). Tumour promotion. A concentration of 20% salicy.!aldehyde applied to the skin of mice previously treated with subcarcinogenic amounts of 9,10-dimethyl-l,2-benzantbracene did not promote the development of papillomas or carcinomas (Boutweil & Bosch, 1959; Wynder & Hoffmann, 19631. Cytotoxicity. The growth of Aseites sarcoma BP8 cells was inhibited by salicylaldehyde in concentrations of 1, 0-1 and 0.01 mM to the extent of I00, 79 and I~ respectively (Pilotti, Ancker, Arrhenius & Enzell, 1975). ~C.i". 17~sorP.21--~.*

~/~

D . L . J . Ot.t)vgt

Rcferenee,~ Boutv.ell. R. K & Bosch. D. K. {1959). The tumor-promoting action of phenol and rclatcd compounds for mouse skin. ('am'or Rex. 19, 413. CIVO T N O (1977} I'olarih. Compounds in i~,od. 4th I-d. Edited by S Van Stratcn. Ccntraal instituul Voor Vocdingsondermek TNO, Zeist, The Netherlands. Council of Europe |1974). Natural Fhsvounng Substances. Their Sources and Added Artificial Flavouring Substam:es. Partial Agreement in thc Soci:d and Public }lcalth Field. List I, no. 605. p. 252. Strasbourg. Diiving. K. FI. ( I q ~ ) The iuflucncc of olhctory stimuli on the activity of secondary neurons in the burbnt (Loin h~ta). ..Iota ph.vsi,'pl. .wand. 66, 290. l:.pstcit~. W. U (19761. Report to RIFM. 27 May. I:a~,~tt. O. W. (19631. Aldch)dcs and acttals, in I,tdustri~ll lt.v!jlene , m l "ib~icolo~.ty. 2nd E d Edited by F A. Patty. Vof il. p 1987. lnterscicnee Publishcr~ New York. Fenarah's I h m d h m ~ q[ FI, n~r hu./re,lWnls(1975). Edited by T. E. Furia and N. Bell;inca. 2nd Ed. Vol. II. p. 516. CRC Press. Cleveland. Oil. Flamring Extract Manufacturerr As~ciation (19651. Survey of flavoring ingredient usage levels. No. 3004. Fd "l'edm,q.. Ch~lnlpdi!ln 39 (2k part 2. 155. Gcstcland. R ('. 119fl71 l))ffcrential hnpcdancc Changes or the Olfactory Mucosa with Odorous Stimulation. Pr~:ccdmgs'of the 2nd Intcrnalional Symposium on Olfaction and Taste (IlL Tokyo. 1965. 821. Ilruban. Z . Swift. II. & S)cscrs. A. (1~t661 Ultrastruclura[ altcr:ttions of hcpatic microbodics. Lab. Ira,est. 15, 181q4. Klign~.m.A.M. 119661 The identification of contact allergens by human assay. IlL The maximiz.'ltiou tcsts. A pr(~.'cdure for screening and rating contact scnsiti~,crs. J. inn.st. Dcrm 47. 393. Khgman. A. M. & Fpstcin. W. (19751. Updating the maximitation Its! for identifying calif.'let allcrgens. Cunl,ct L)~'r.'natuts I, 731. Merck Imh'v (19761. A,I E,c.vch~pedio of Chemicals and Drnqs 9th Ed. No. ~0~7. Merck & Co.. Inc.. Railway, NJ. M tx'.,.cr. E.. Bicn. l!. & Jung. F. (19681. Detection of the promotion of gratmlation by Peru balsam, salic~[aldch.~dr mclh.vlanfino.p-h)droxyacttophcnonc, p.tolylmclhy}carbinol, and phth:dic acid mono-p--tolylmethylcarb=nol ester v, ith the Rutl:v, test...leta biol. reed. g,.rm. 21,693. Moreno. O. M. (19771. Report to RIFM. 27 January. Nogami. it.. llanano. M. & Y;,mada. II. (19681. Studies on absorption and cxcretion of drugs. IX. Relation bet's, ten chcnfical .'qruchlre and absorption rate. I. Effects of the number and the position of Oi|-groups on the intcstin:d absorption r.'ttc or ben,~o)l dcrivafi'.cs. Chem. ph,rm, lhdl.. "l'okyo 16. 3'99. PilottJ. A.. Anckcr. K.. Arrhcnius. E. & Fn,,cll, C. (1975). FIh'cls of tobacco and tobacco smoke constitl,cnts on cell mu(tiplication in ritro. Toxirohal)" 5. 49. Whttchousc. M. W., Rainsford, K. !).. Ardlic. N G.. Yot,ng I. G. & Bruno. K. (1977]. Alternatives to aspirin, dcri~.cd from biological source~.. Agents & Actio*ts Suppl. [. p. 43. Wdliams. R. T. |lqSq). Detoxiralion Meclumisms. The Metabolism and Deto.xirutio~l o.f Dr,,gs, Toxi~" Substances and Otlwr Ore,talc ('mnl~nmds. 2nd Ed. p. 333. f.'hapm.'m & l lall Lid. London. Wingard. C.. ltitchcock, P. & Tcague. R. S. (19551. A survey of aldehydes with respect to their action on the brood pres,,ure. Archs int. Phartmwody~t. Th(;r. i02, 65. Wyndcr, E. L. & Hoffmann, O. 1.19631. Experimental contribution to tobacco-smoke carcinogenesis. Dr. reed. B'whr. leg, 623. Yamasaki, !!. & Saeki. K. (19671 Inhibition of mast.cell degranulation by antiinllammztory agents Archs int. I~lu~rm,'h'od)n. Th,:r. 168. 166. Additicmal references I.~dated tis.m.'s and tells Jobln. F. ,r Trembl,ty. F. (Iq691. Plalelet reactions and immune processes. !1. Inhibition or platelet aggregation by complement inhibitors. Thromb. Dhtth. haemorrh. 22., 466; cited from Chem. Abstr. 1970, 73, 23561. Pulkkineo. P., Stnervirta2 R. & l a n n ~ J. (19771. Mcchatfism of action of oxidized polyamines on the metabolism or human spermatoma. J. Reprod. Ft'rL 51, 399. Reunancn, M_ }lanninen. O. & l't.'trliala, K. (19671. Inhibitory effect of salicylales and cinchophenderivatives in amino acid incorporation. Nature, Load. 213, 918. Whitehousc, M. W. (1962L Structure-activity relations among drugs acting on connective tissues (antirheumatic agents). Nature, Land. 194, 964. F..n'..~~w.~ and proteins Elorchardt, R. T. (1973). Catechol O-meth)ltr:msferase. 3. Mechanism of pyridoxal 5'-phosphate inhibition. J. medal Chem. 16, 387. Borchardt. R. T. & tlabcr, J. A. (19751 C;ttcchol O-mcthyltransferase. 5. Structure.activity relations for inhibitiou hy fla',onoids ,I. mvdnl Chem. 18, 120. Fan. ('. C. & Plaut. G. W. E. (19741. Funclion-'d groups of diphosphopyridine nucleotide linked isocitrate dehydrogenase from I~ovinc heart. 11. Studies of an active amino group by reaction with aldehydes. Biot'hemi~tr); N. )7 13. 52. Feldman. K., Zeisel. I!. J. & Iielmreieh, E. J. M. (1976). Complementation of sttbunits from glycogen phosphoryl~ses of frog and rabbit skeletal muscle and rabbit li~,'er. Eur. 2. llh~chem. 65, 285. Okulov. V.. !. 11963}. Effect of aldehydes on the ek'clrophoretic properties of serum proteins. Ukr. Biold~im. Zh. 35, 327. Okulm. V. 1. (1965I. ,Mutual influence of albumin and ~'-globulin of male bovine blood serum in the presence of denaturation by aldehydes and heat. Ukr. Biol, him. Zh. 37, 324.

Fragrance raw materials monographs

905

Rahcja, M, C.. Dylewski, I. & Crawhall, J_ C. 0973). Estimation of.p-hydroxyphenylpyruvic acid hydrox)lase activity based on carbon-14-labeled carbon dioxide evolution from the 1-carbon-14-labeled substrate. CmL J. Biochem. 51. 172. Shimomura. S. & Fukui, T. (19771. The mode of binding of pyridoxal Y-phosphate in rabbit muscle glycogen phosphorylase b: circular diehroism and absorption studies. J. Biochem., Toky, 81, 1781. Wermuth, B. & Bodbech, U, (1973). Inhibition of acetyleholinestera~ activity by aromatic chelating agents. Eur. J. Buwhem. 35, 499. Inrertt'hrates Barker. J. L. & Levitan, II. (1976). Mitochondrial uncoupling agents. Effects on membrane-permeability of molluscan neurons. J. Membrtme Biol. 25, 361. Bringmann, G. & Kuehn, R. (1977). Results of the damaging effect of water pollutants on Daphnia nm'..Ina. Z, iVasser Abwasser Forsch. I0, 161. Clarke, A. J. & Shepherd, A. M. 119641. Synthetic hatching agents for Heterodera schachtii and their mode of action. Nenmtoloyica 10, 431. Frayha, G. J., Saheb, S. E. & Dajani, R. (197l). Systematic search for a systemic hydatid scolicide, I. In ritro screening of chemicals against the scolices of hydatid cysts (Schinococcus tlranulosus}. Chemotheraphy 16. 37 I. Kikuchi, T. (1973). Specificity and molecular features of an insect attractant in a Drosophihl mutant. Nature. l.ond. 243, 36. Weide W. (; 961). Prolongation of the diapause between flights of the honey-bee. Z. Biene~Jrsch. 5, I13. M icrorortlanisms AxI, G. (1973), Continuous toxicity measurements with bacteria. Vom Wass. 41, 409. Barnslcy, E. A. (1975). Induction of the enzymes of naphthalene metabolism in Pseudomonads by salicylate and 2-aminobenzoate. J. yen. Microbiol. 88, 193. Bringmann, G . & Kuehn. R, (1975). Comparative results of the damaging effects of water pollutants against bacteria (Psuedomonas putida) and blue algae (Microcystis aerugit, osa). Gas- u. IVassFat'h 117, 410, Bringmann. G. (1975). Determination of the biologically harmful effect of water I)ollutants by means of the retardation of cell proliferation of the blue algae Micrm'ysds. GesmldheitsimJe,ieur 96, 238. Bringmann, G. & Kuehn, R. (1977). Limiting values for the damaging action of water pollutants to baclcria (Pseudomonas putida) and greetl algae (Scenedesn;us quadricuuda) in the cell multiplication inhibition test. Z. |Vasser Abw~zsser Forsch. 10, 87. Burton, K~ C., Clarke, K, & Gray, G. W. (1965), The mechanism of the antibacterial action of phenols and ~licylaldehydes. IV. Subslituled salieylaldehydcs. J. chem. Soc. p. 438. Clarke, I. K.. Cowen. R. A., Gr;~y. G. W. & Osborne. E. H. (1963). Mechanism of the antibacterial action of phenols and ~dicylaldchydes. J. ('hem. Sac. p. 168, Cronenberger, L., Dolfin. B.. Paeheco, H., Decoret. C., Laforgue, A., Chaise, A. M.. Lalue-Destcrme. S. & Hinault, B. 11970). Correlations between antifungal properties of substituted salicylic aldehydes and physical and physicochcmieal parameters. Chim. ther. 5. 99. DeFusco, R., Diurno, M. V., Mazzacca. F., Parrella, A. & Piscopo, E. (1971). Alkoxyazomethine derivatives. I11. Rchttions between structure and antimycotic and antibacterial activity. Amihiotica 9, 159. DcGrecf, J. A. & VanSumcre. C. F. (19661. Effect of phenolic aldehydes, phenolic acids, coumarins, and related compounds on the growth of Saccharomyces ct.ret'isiae. Arehs int. Physiol, Biochim, 74, 512, Fiedler, H. & Kaben, U. (1966). Antimycotic and antibacterial action of 1.3-benzoxathiols and hydroxybcnzaldehydes. Pharma:ie 21, 178. Gupta, S. R.. Pras;mna. H. R., Viswanathan, L. & Venkitasubramanian, T. A. (1975). Synthesis of aflatoxins by the non-growing mycelia of Asperyillu.~ parasiticus and the effect of inhibitors. J. gen. MicrobioL 91.417. Kennedy, S. I, T. & Fewson, C. A. (1968), Metabolism of mandelate and related compot.nds by bacterium NCIB 8250. J. yen. Microbiol. 53, 259. Leifcrtova, I,, Hejtmankova, N., Hlava, H., Kndrnacova, J. & Santavy, F. (1975)..Antifungal .and antibacterial effects of phenolic substances. A study of the relation between the biological activity and the constitution of the investigated compounds. Sh, Praci pBr. Fak. palack. Unlit. OIomouci 74. 83. ToP,enaere, J. P. (1970). Analysis of the structure-activity relation (SAR) of salicyialdehyde and some of its derivatives. Chhn. ther. 6. 88. Weuffen. W, & Richter, L. (19711. Relation between chemical constitution and antimicrobial activity. 24. Microbiostatic properties of phenols and related compounds against pathogenic bacteria and fungi as well as against microbes in x-ray film.production materials. Pharma:ie 25, 480.