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J. Soc. Cosmet. Chem.

,29, 581-606 (September1978)

Thechemistry of nitrosamine formation,
inhibition and destruction

M. L. DOUGLASS Colgate-Palmolive Company, 909 RiverRd., Piscataway, NJ 08854; B. L. KABACOFF Revlon Research Center, 945 ZeragaAve., Bronx, NY 10473; G. A. ANDERSON The Dow Chemical Company, 1710 Building,Midland, M148640, and M. C. CHENG, The Procter and Gamble Company, Ivorydale Technical Center,5299 Spring GroveAve., Cincinnati, OH 45217.

Received June29, 1978. Authors represent theNitrosamine Task Force oftheCosmetic, Toiletryand Fragrance Association, 1133 15th St., N.W., Washington, D.C. 20005.

Synopsis

N-Nitroso compounds are formed from the interactionof many types of organo-nitrogen compounds and nitrosatingagents.Ease of nitrosationis determined by compoundstructure, nature of the medium and the presence of catalysts. The two categories, nitrosamines and nitrosamides, differ mainlyin their CHEMICAL stabilityandmechanism of biological activity.NITROSAMINES are more stableand difficultto DESTROY, but their FORMATION can be INHIBITED by substances which react preferentiallywith the nitrosating agent.The carcinogenic activityof thesecompounds in laboratoryanimalsvarieswidely from highly potent
to innocuous.

I.

INTRODUCTION

Advances in analytical techniquesallow modern industrial society to detect trace amountsof undesirablesubstances in its physicalenvironment.There hasbeen legitimate concern that we are creating conditions that have serious adverse effects on human health. Recently, minute levels of nitrosamines have been found in some consumerproducts,including cosmetics (1). While not attempting to judge whether thesesubstances at parts-per-billion levelshave a significant physiological effect, we are presentinga review of nitrosaminechemistryto aid workers in the cosmetic and allied industries in their research on the subject.
581

582
II. TYPES

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
OF N-NITROSO COMPOUNDS

N-Nitroso compoundsare formed by the interactionof a nitrogen-containing organic compound--suchas an amine, amide, urea, guanidine,urethaneor cyanamide--and a nitrosatingagent, suchasa nitrogen oxide.
These compounds can be divided into two categories--nitrosamines and nitrosamides--which differ in their chemicalstability, the mechanism of their carcinogenicityand their mutagenicity (2-4).
N-Nitrosamines
R

N--N=O

R,R'

=

alkyloraryl

/
R'

N-Nitrosamides
R

N--N•O

=

alkyloraryl
O

/
z

nitrosamide
O

R',2NC-NH

nitrosourea

II
R',.,NC-0 R'OC-NC l

nitrosoguanidine

nitrosourethane

nitrosocyanamide
nitrososulfonamide

R'SO2--

The nitrosaminesare very stable once they are formed. They require chemical modification in an enzyme-catalysed reactionbefore they exhibit carcinogenic and mutagenicactivity(2, 3, 5). By comparison the nitrosamides can be hydrolysed, especially in neutral and alkaline solution. They exhibit carcinogenicand mutagenic activitieswithout modificationand malignanttumors are produced at the site of their
application (2-5).

III.

CARCINOGENICITY

OF N-NITROSO

COMPOUNDS

The first report that nitrosaminescausecancer in laboratory animalswas that rats fed low levels (50 ppm) of dimethylnitrosamine in their diet developedliver cancer(6, 7).
Since then more than 120 nitrosamines and nitrosamides have been examined for

00063 0.1 to 3.11 1.2 (CHaCH2)2NNO CHaNCH2CHzC1 0.00080 3.9 NNO O NNO 0.O25 1.1 to 2.NITROSAMINE CHEMISTRY 5 83 Table I Varying CarcinogenicActivity of Nitrosamines Classification by Rangeof log (l/D5o) a Highly Potent.05 continuedon p 584 .89 0.012 1.0039 2.9 1.011 1.1 1.6 I NO (HOCHzCHz)zNNO 0.6 0.012 2.0088 0.0 NO (i-CaHT)zNNO O 0.4 I Minimal Activity.5 O.0 (NCCH2)2NNO 0.031 1.6 n-C4H9N(CH2)4OH NO 0.3 2.00061 I NO CHaNCH2C6Hs 0.O39 1.0 Structure D5o a log (1/D•o) 3.0010 3.0 0.26 0.4 (CHa)2NNO (n-CaH7)zNNO Intermediate Activity.6 O.O25 NO 1.0054 0. •<1.24 0. 1.0 CHaNCHzCHzNCHa NO NO 0.016 I NO (n-CiH9)2NNO O. >3.0 II (CHaCOCHzCHz)zNNO (n-C•H•)2NNO CHaNCH2COzH 0.2 3.8 CHaCHzNCHzCHzOH 0.18 0.9 0. 2.7 0.1 I NO Potent.

The frequently proposedmechanismof action (2. 5). To illustrate the range of activity representativenitrosamines are classified in Table I according to carcinogenic potency(10).hamsters.Their potency varieswidely.expressed in mol/kg body wt.where the larger molecules are more potent. 4.50= mean total carcinogenic dose. fish. This step is supportedby correlations of the degreeof carcinogenicitywith q-carbon substituents(11) and by recent work showing that preformed q-acetoxy nitrosaminesare direct acting carcinogens not requiring enzymaticmodificationfor activity(16). Earlier Wishnok and Archer (13) showed that carcinogenicityis inversely related to the number of carbon atoms of acyclic dialkyl nitrosamines. 3. for productionof tumors in 50% of the animals.CCH=)=NNO (12) aD.Lijinsky (14) found that the reverse is true for cyclic nitrosamines. Although there is no direct evidencethat N-nitroso compounds causecancerin man. 5). and indicates that only nitrosaminescontaininganq-hydrogen are carcinogenic. The carcinogenic doseis expressed in the way suggestedby Wishnok et al. their carcinogenicity has been demonstrated in many other animal species including mice. .. Comprehensivereviews of the results have been published(2. from compounds where a singledoseis sufficientto inducetumors to those where large dosesgiven repeatedlyproduce no malignancy(2.dogsand monkeys(4.rabbits. 5. rats. (11) so that larger numbers indicate higher carcinogenicity. 9).02NNO (C6H•CH2)•NNO NO (HO. The requirement for activation of nitrosaminesis defined as an enzyme-catalysed hydroxylationof an q-carbon. and that there are major changesin target organswith a changein ring size.584 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table I (continued) Varying Carcinogenic Activity of Nitrosamines Classification by Rangeof log (i/D50) a Structure D.guineapigs.50 a log (1/Ds0) No DetectableActivity (C6H. About 80% of the N-nitroso compounds testedare carcinogenic to somedegree. but not nitrosamides. Wishnok and coworkers (11) recently demonstratedthat the carcinogenic potency of many nitrosamines correlatesquantitativelywith a combinationof their hexane-water partition coefficientsand the electronic inductive effects of substituentson the qcarbon. 15) shownbelow accounts for the enzymaticactivationrequired by nitrosamines. carcinogenic activity in animals.

CH- NHNO + O:CR'2 -H + R2CHN• + diazonium ' R2CN2 diazoalkane ion N'---•3 R2CH-Nuc + N2 The hydroxyalkylgroup is eliminated as an aidehyde or ketone leaving an unstable primarynitrosamine. Alkylation of nucleicacid oxygens hasalsobeen demonstrated(18).. CHEMISTRY INTRODUCTION OF N-NITROSO COMPOUNDS Much of the chemistry of N-nitroso compoundsin aqueous solution can be summarized by the following scheme. R•CH--N--CR'• ON OH R•CH--N=N--OH ( R.. A. but the evidence conflictsas to whether a diazoniumion or the diazoalkaneis the alkylating agent (2. the proposedprecursorof the alkylating agent. H R N N[+_NO + Y/N--H+ Y--NO ( (l) ' R-R' (2) I R' (1) (2) (3) Y--NO + Y'- (3) • Y'--NO + Y- Y--NO + Z (4)) unreactiveproducts (4) . The latter tautomerizes to a diazoniumhydroxide. Nitrosamides do not require metabolicactivationbecausethey can be hydrolysedin vivo to an unstableprimary nitrosamine(2. O II R'C N--N:O + H20 ) R'COzH + RNHNO IV. 3). In nucleicacids the principle site of alkylationis at N(7) ofguanine. Alkylation of nucleophilic sites (Nuc) in DNA. 5. NO hydroxylasc • . RNA and proteins by N-nitroso carcinogens has been demonstrated(5). 4.NITROSAMINE CHEMISTRY 585 R•CH-- N--CHR'. 17).

Several nitrogen oxide speciesare nitrosatingagents. 31.Destruction of N-nitroso compounds by denitrosation is described by eq 2. in this casecalleda trap or scavenger. 21) water (19. whichis muchfasterthan 1 andproduces unreactive products. eq 1. NO + H•ONO+ --H + • HNO• - --H•O Mn+ ' N•Oa ß NO + NO• YNO + H20 NO•- + H20 Io_ In moderately acidicaqueous nitrite solutions the nitrosating agentis nitrousanhydride. eq 1 describes transnitrosation asit is definedin this paper. the equations are not balanced. 22. 38-40) plus O2 (25.M n+ (19. Catalysis ofnitrosation by Y' species resultsfrom its prior reactionwith Y--NO (eq 3). Details of these reactionsand the chemistryof N-nitroso compounds not includedin this scheme are described below.138 at 25ø(41.For simplicity. 22-27) organicsolvent (2) NO2/N204 water (25-27) organic solvent (28. . 27) The interrelationshipbetween active nitrosatingagents (underlined) and inactive species is summarized below. Inhibition of nitrosationoccurs by reaction of inhibitor Z with nitrosating agent Y--NO in the irreversible eq 4. FORMATION 1.but nitrous acid (HONO) and the nitrite ion (ONO-) are themselves inactive(19). 30) water ( 19. after protonation of nitrite ion according to eqs5 and6. B.pK• = 3. 22. 29) gas (21.586 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Nitrosation of secondaryaminesand amidesis describedby eq 1. NitrosatingAgents a. When Y is a secondaryamine function.37) YNO H2ONO + NO water(19. 42). 23. Inorganic Species. which produces the more active nitrosating agent Y'--NO. Known inorganic nitrosatingspeciesare: Substance Medium N2Oa gas(20. 22-24). Addition of Z.N2Oa(19. 27. is necessary to prevent via 4 the reversalof denitrosation. The effectiveness of the nitrosating agentY--NO depends on the natureof Y. formedfrom nitrous acid. 36) anaerobic.

(19. especiallyfor weakly basicaryl arninesand amides.but at a slower rate than in acid solutions(46. --OH+ + ReNH + O-•-CHR' - ' R•N•CHR' ( ) R•N--CHR' .The rate of nitrosationof dihexylamineat pH 3.Acetoneand acetaldehyde are inactive. 22. 22. Some nitrosationrate enhancements observedin the presenceof microorganisms havebeen explainedasdue to an analogous hydrophobic interactionbetweenamine and a cellularconstituent(45). rather than the actualreactivitiesof YNO (36). Y-. The magnitude of the catalytic effect is smaller for secondaryamineswith alkyl chain lengths shorter than C6. rapid nitrosationby Y--NO dominatesover that by NzOa. pyridoxal and various benzaldehydes(48) are also catalytic. but less so than formaldehyde. HONO + Y- + H+ •- Y--NO + H•O (8) Of the anioniccatalysts studiedthiocyanate hasthe greatesteffect (23. catalyse the reaction in water by forming nitrosating species Y--NO which are more reactive than NzOa.> > Br.5.nitrite can nitrosatesecondary amines. Hydrogen phosphate and carboxylate anionsmay catalys e nitros ation (31). When formaldehyde(equimolarwith amine) is added to neutral or basicsolutions. As the pH is lowered below 2. Substances capableof forming micelies exert a catalytic effect on the nitrosation of aminesin acid solution. 31. because the concentrations of active nitrosatingspecies generatedin situ decrease. 32-34. 44). 31-37). 47). 37). lowering the pH at which the nitrosationrate is maximum comparedto the uncatalysed reaction (23. Chloral (46. Other cationicand nonionicsubstances at levels higher than their criticalmicelie concentrations are also catalytic (43.5 increases 800-fold in the presenceof decyltrimethylammonium bromide micelies (43). 1.NITROSAMINE CHEMISTRY 587 H+ + ONO- • HONO (5) 2HONO --' ONNO2 + H20 (6) At lower pH. (9) RzN-CHR' " R=N--NO + O•---CHR' * N--O I . 23. 35).No nitrosation by aqueous nitrite has been observed above pH 7. 31.The proposed mechanism (eq 9) involves nucleophilic attack by nitrite on an iminium ion intermediate following by collapse of the adductreleasing the carbonylcatalyst. Perchlorateand sulfateions are not catalytic(22. The equilibriumconcentration of YNO (eq 8) mainlydetermines the order of the catalyticeffect. Nitrosamine yieldsvary with stericaccessibility of the nitrogenatom. Halide ions are also catalytic in the order SCN-. but only weakly ( 19. In aqueoussolutionat pH > pKa of HNO2 the rate of nitrosationdrops rapidly with increasing pH.> Ci. more rapid nitrosation by the nitrous acidium ion (19. 47). 33. 38-40) becomesimportant. 33).. 33). HONO + H+ -'-' H2ONO + (7) Certain anions.

Although both nitrogen oxides might be expected to undergo rapid hydrolysis at pH > 5 to yield unreactiveNOz. Nitrosation of amides occurs faster in two-phase systemscomposedof an organic solventand aqueousHNOz solutionat pHi or in methylenechloride extractsof 2 M aqueous HNO2 than in water alone at pHi (50). 27. The slowertransnitrosation betweenaliphaticsecondary amines requires more extreme conditionsor catalysisby nucleophilicagents. eliminationand rearrangement products. 54). Cu(I). The process is more rapid in acidicaqueous solutionand occursby a heterolytic mechanism (53. b.588 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS In organicsolventsNOCI. Rapid nitrosationby NO under anaerobicconditionsoccursin the presenceof iodine or Ag(I). 53) probablyby a free radicalmechanism (53). Fe(III) or Co(II) salts(19. The well-known deamination of primary aliphaticamineswith ni- trite in cold aqueous acidyieldsa varietyof products (22). Nitrogen Compounds a. Primary and secondarynitroalkanesdecomposeto nitrite in dilute alkaline solutions(58). The rapidreaction proceeds through unstable primary nitrosamineand diazonium ion intermediates. 25). Furtherwork is required to ascertain whether nitrosationoccursby direct reactionof aminewith the C-nitro functionor is causedby agentsderived from inorganicnitrite present asa syntheticcontaminantor decomposition product. Primary Amines. Aromatic nitrosamines. With secondary amines NzO4 in methylene chloride reactscleanly either as a nitrosatingagent at 0ø or as a nitrating agent at -80 ø (29). transnitrosate secondaryaminesunder neutral conditions in organicsolvents (52. Zn(II). 36). N204 and NOBF4 have been usedaspreparativenitrosationreagents(23. RNH2 + NO•-. N2Oa. Nitrosation of morpholine by aromatic and aliphaticC-nitro compoundsin tetrahydrofuranat 70øChasrecentlybeenreported(57).for dissolved NzOa andN204. Organic Species. 55. alkenes ( Nuc R--N• N+ + H•O . Since NO2 is in equilibrium with N204 (49). Nitrosation of aminesdissolved in methylene chloride in contactwith solid sodium nitrite occursby a reaction which involves the solvent (51). Use of N•Oa (2) or NzO4 (28) in carbontetrachlorideor acetic acid gives high yields of nitrosamides. 56). statementsin the literatureon effectsof either substance mustbe criticallyviewed.such as thiocyanateand halideions(23.and NOa-. aminesof widely different reactivitycompeteeffectively with water andOH. Recent studieshave shown that secondaryamines react with NzOa and NzO4 gases dissolved in aqueous alkalinesolutions (pH 6-14) at a rate greaterthanin acidifiednitrite (25-27). 27). Nitric oxide (NO) alone is inactive but is oxidized by oxygento NOz and thus to the reactive nitrosatingagentsNzOa and N204 (25. Cu(II).H + • R--•--N=O I H R•I=N--OH (lO) alcohols. such as nitrosodiphenylamine.The latter reactswith nucleophiles presentto form substitution. N-Nitrosamines themselves act as nitrosating agents. 2.

.050 M 160øC. H + > R--N--CH=OR' I NO (12) However. ) R. .2 hr in citrate-phosphate buffer. R=NH + NzOa --> RzNNO + HNOz (13) rate = k[R2NH] [HNO=] z (14) Thus.NH NO%. H2N NH2 + 2NO• ) HCI salt 0. b. pH 3. a monoamine. Higher levels of stableo•-alkoxynitrosamines are producedfrom the reactionof primaryamines with aldehydes in the presence of alcohols and nitrite undermildly acidicconditions(60.4 100øC. mixtures of primary aminesand aldehydes without alcoholdo not reactwith nitrite at pH 3 (62). RNH= + CH20 + R'OH + NOj.NITROSAMINE CHEMISTRY 589 Secondary amines andsubsequent nitrosamines formed by reaction of thediazonium ionwith theprimaryaminestarting material (eq 11)havebeenisolated (22). In moderatelyacidicaqueousnitrite solutionsN2Oa..H +) R.. 6 days Under similarconditions n-butylamine. formed from two moleculesof HNO2 (eq 6) is the nitrosatingagent. two factorsdeterminethe effectofpH on the rate of nitrosation: (i) extentof conversion of NO2. Secondary Amines. Nitrosaminesformed directly from secondary aminesare stable.6% 0.NNO (11) Diamines with a second primary amine function appropriately located for intramolecularreaction with the diazonium ion form secondarynitrosaminesat high temperatures or longreaction timesasillustrated by the followingexamples (59).39% 22øC. Thisreaction occurs in low yieldbecause theamine is largely protonated andunreactive under thestrongly acidic andlow temperature conditions commonly used. R--N•N + + RNH2 --N. Rate equation 14 describes the kinetics.nitrosodibutylamine. gave much lower yieldsof N. 1 hr 22% yield 1.025 M moist 0.to HNO2 andthusto NzOa (favoredby lower pH) (ii) concentration of unprotonated amine(favoredby higherpH). 61). The rate-determining step in the reaction is electrophilic attackby N=Oa on the free electronpair of the unprotonated amine(eq 13).

the reaction occurs to a significantextent only at elevated temperatures in weakly acidic media (68-70). because the concentrationof unprotonatedamine decreases. At 25øC and pH 3. the following order of reactivityis found at pH 3. As the pH decreases below pHmaxthe rate decreases.2 OX /NH H=+N/•NH \ / 8.0: Amine •/NH pKa 11. At a givenpH the rate of nitrosation increasesas the basicityof the amine decreases.4 nitrosationof tertiary aminesis about 10. Quaternary Aminesand Amine Oxides. Tertiary Aminesand RelatedCompounds. The reactionfollowsrate eq 14. Thus. 66) occursat an optimumpHm•x = 2.4 (23.5 (34. Two related compounds--the nitrogen acetalhexamethylenetetramine (71) and the drug antipyrinewhich has an eneaminestructure(23.tertiary and quaternary . c. Quaternaryammoniumcompounds apparently react slowlywith nitrite in acidicmedia. In bothcompounds at least one of the three N-substituents is in a higher oxidationstatethan in typical tertiaryamines andnitrosation undoubtedly occurs by a differentmechanism (70). The relative reactivity of secondary. 64) nearthe pKa of HNO2.N=CHR' H•O (15) R•NNO ( N20a R•NH + R'CHO With mixed tertiaryalkyl aryl amines ring C-nitrosation alsooccurs (19). 40. 69) for nitrosative dealkylation and nitrosamine formation: I RzN•CH2R' + N=Oa ' N•0+ H•0 R=N--CHR' --HN0 I ON I H R. d. the nitrosation rate in water is maximumat pHmax= 3 to 3.000 times slowerthan that of related secondary amines(23). 72)--undergo N-nitrosation muchmore rapidlyand extensively than normaltertiaryamines. The followingmechanism hasbeen proposed(23. becauseof the higher relative concentration of unprotonated amine present.The initial dealkylationrequiredaccountsfor their lower activity comparedto tertiary aminesand may not involvethe nitrosatingagent (73). even though their conversion to secondary nitrosamines was reported over 100 yearsago (67). 24. 40). because the concentrationof HNO2 decreases. 63.7 5. For a given amine as the pH increases abovepHmaxthe rate decreases. Tertiary amines have generally been regarded as inert to nitrosation.000 Nitrosation of secondary amino acids(65.57 Relative rate (23. Because dealkylationis required. 68. 33) 1 930 180. but the pH-rate profileis changed by the fact that two amine species react--RNHCHR'CO=and RNHCHR'CO2H.590 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS As predictedby the rate equation(33) for simplebasicamines(pKa > 5).25 to 2.

Nitrosation of tertiary amidesin acidicaqueoussolutionsof nitrite at high concentrations and temperatures produceeither nitrosamides or nitrosamines (23. .NITROSAMINE CHEMISTRY 591 amines is indicated by the following data gathered for reaction of a ratio of 5 mol NaNO2/mol amineat 78øCandpH 5. At pH > 2. N-methylacetamide in aqueous solutionat pH 13 doesnot reactwith addedSzO4.Secondary and TertiaryAmides.5 nitrosation by NzOa contributes (39).1-dialkyl3-phenylureas and tetraalkylureas.aswith amines. the nitrosation condition mostwidelyinvestigated hasbeennitrite in aqueous acid. ZNHR + H2ONO + --> ZN(NO)R rate = k[ZNHR] [HNO=] + H=O + H+ (16) (17) [H +] The reactionrate increases aboutten timesfor each 1-unit drop in pH from 3 to 1 and doesnot show a pH maximum. at 90 to 100øC and pH 4 to 5 both classes show similar reactivity (68. 75).0002 Severalnaturallyoccurringquaternaryammoniumcompounds were found to be much lessreactivethan the tetramethylammoniurn ion (73). However. Tertiaryamineoxides in thepresence of excess nitriteatpH 1 to 3 andtemperature 25 to 75øC are converted to secondarynitrosaminesto a greater extent than are tertiary amines (74). 1. N-Alkyl ureas andcarbamates are rapidlynitrosated at pH 1 to 2. 1. Apparently the weakly basic amide is too unreactive to competewith hydrolysis of the nitrosating agent. 74). Nitrosationof trialkylureas givesthe corresponding nitrosoureas. 70.6 0. The tribenzylmethylarnmoniurn ion is reportedto be unreactive undersimilarconditions (68). Two mechanisms that accountfor the changein relative reactivity with conditions havebeenproposed (70. 70.6 0. Dialkylnitrosamines are the major productfrom dialkyl-or trialkylthioureas. No nitrosation of 10-a M hexadecyltrimethylammonium bromideby a 20-fold excess of nitrite at 25øCand pH 3.6 1. However. 74). For secondary amides. conditions underwhichsecondary amines are rapidly nitrosated(27). Amine % Yield of (CHa)2NNO (CHa)2NH (CHa)aN 9.N-acylureas.5 wasobservedafter 40 min (44). In acidicaqueous media nitrogensubstrates decrease in propensitytoward nitrosation in the order 2-imidazolidone> acyclicN-alkylurea > N-arylurea > N-alkylcarbamate > less basic dialkyl and secondaryaromatic amines (pK• < 9) and tertiary eneamines> more basicdialkyl amines> N-alkylamides.6 for 4 hr (73). 39. e.9 (CHa)4N + (CHa)2NCH=CH=OH (CHa)aN + CH= CH=OH 0.N-alkylguanidines and tertiary amines(23).1-dialkylureas. 40). High yieldsof nitrosamides are obtainedfrom reactions of amideswith N=Oa (2) or SgO4 (28) in organicsolvents. The nitrousacidium ion is the main nitrosating agentfor theseand other amides(eq 16) and the reaction rate follows eq 17 (23.

Reference 80 continued on p 593 . Sincetheproduct NO canbe air-oxidized to CH2OH CH2OH I HO C•_O_x•O HOCH /O O __ +N2Oa •-•O +2NO +H•O (18) HO OH Ascorbic acid Dehydroascorbic acid the nitrosatingagent $204. INHIBITION JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS OF NITROSATION Studies of nitrosamine inhibition have consisted of the use of substances which competewith the amine for nitrosating species. Mice Effectof Ascorbic Acid 2 M excess of ascotbate prevented necrosis.29 NO2- + 2OH- • NOa- + HzO + 2e- -0.46 -0.592 C.but enhanced forestomach papillomas and carcinoma (79). In anotherit inhibited in vivo synthesis of N-nitrosomorpholinein rats and consequent liver tumors.01 NO NzO + + 2OH6OH- • • NOz2NO2- + + HzO + e+ 4e- +0.99 -1. The reductionpotentials of various nitrogenoxides(76) listedbelowcanaid in selecting appropriate oxidizing andreducingagents for destruction of nitrite. Literature reports describing ascorbic acid inhibition of nitrosamine formation in amine-nitritesystems are summarized in Table II. Equimolarascotbate gave incompleteprotection.15 3HzO i. It inhibited the toxic and carcinogenic effectsattributable to in vivo nitrosamine formationwith two exceptions. In acid solution: Eø(volts) HNO2 + H20 • NOa.+ 3H + + 2eNO + H20 .94 -0. excess ascorbic acidmust be addedto inhibit nitrosationin systems exposedto air. Under in vitro conditions ascorbic acid inhibited nitrosamineformation. Table II Inhibition of In Vitro andIn Vivo NitrosamineFormationby AscorbicAcid in the Presence of Nitrite (or Amide) Aminopyrine System Investigated Hepaticnecrosis. InhibitionbyAscorbic Acid Ascorbic acid inhibits nitrosamineformation by rapid reduction of the nitrosating agent(77). In one caseadenoma inductionby N-nitrosomorpholine and mononitrosopiperazine increased with added ascorbicacid (78).-• HNOz + H + + eNzO + 3HzO • 2HNOz + 4H + + 4eIn basic solution: -0.

Ala. human gastric juice Fried. Oxytetracycline. Enhanced forestomach genesisin rats papillomas and carcinoma.. Low conc. In vitro Morpholine. nitrite-cured bacon Inhibits nitrosamine formation. 88 Morpholine Morpholine In vitro 90 Nitrosomorpholine formation and tumor- Inhibits nitrosomorpholine formation and liver tumors. Rats In vitro Hepatic necrosis inhibited. Piperidine Meat-curing mixtures Inhibits nitrosamine formation. GPT elevationinhibited. Dimethylamine Pyrrolidine Proline Model food systems Dimethylamine.NITROSAMINE CHEMISTRY •93 Table II (continued) Amine (or Amide) Aminopyrine System Investigated Hepatotoxicity. 81. Ethylurea Morpholine Pregnant rats In vitro Preventscarcinoma in offspring. In vitro. of ascorbate enhanced 86 87 nitrosamineformation. Amount ofascorbaterequired dependson the presenceor absence of 02. Greater incidence of cancer in rats in absence of ascorbic acid. LDH.. Dimethylamine Dimethylamine Acute tox. Toxicity. 91 92 93 Formationof nitrosopyrrolidine from prolineis inhibited. GOT.nitrosodimethylamine serumlevels. Piperazine Proline In vitro. Piperazine. High concentrations inhibited such formation. Methylurea. aminotransferase. 94 Morpholine Piperazine Methylurea Adenoma. Increases adenoma frequency when given with the nitrosamines. Aminophenazone Inhibits nitrosamine and nitrosamide formation. human gastric juice Inhibits nitrosarnine formation. Rats Ascorbate protected against increases in liver and spleen wt. Pyrrolidine. Rats In vitro 83 84 85 Chlordiazepoxide Chlordiazepoxide Inhibits nitrosamine formation. increasesin GPT. 82 Aminopyrine Carcinogenesis. decreasein adrenal wt.NMethylaniline.. Inhibits nitrosamine formation. Formation and inhibition are a function ofpH. Review 96 97 . Inhibits nitrosamine formation. lung. Dimethylamine Piperazine. in mice Ascorbate decreased adenoma 78 frequency in some cases. Rats Effect of Ascorbic Acid Reference Inhibits elevation of GPT.

100 96 93 Gallic Acid Piperazine Aminophenazone Proline Proline Dimethylamine In vitro.. Rats Relativelyineffective. Rats Inhibited liver pathol. Inhibited nitrosamine formation. Aminopherazone Dimethylamine Dimethylamine Proline In vitro. Morpholine Diethylamine Adenomainduction. Rats Relatively ineffective. 93 . Rats Inhibited hepatotoxicity. Oil/Water Hepatotox. 101 4-Methylcatechol Piperidine Piperidine Dimethylamine In vitro Catalysed nitrosamine formation. 93 Tannin o•-Tocopherol o•-Tocopherol Piperazine. In vitro. Gallic Acid Diethylamine In vitro Catalyses nitrosamineformation (see text). Inhibited nitrosamine formation. 96 93 Inhibited dimethylnitrosamine formation. GOT. of reactants.103 Inhibited nitrosopyrrolidine formation.. human gastricjuice Oil/water system Propyl Gallate Propyl Gallate Fried. 93 Dimethylamine t-Butylhydroquinone Inhibited hepatox. Mice 78 99 Gallic Acid In vitro Inhibited or catalysed dependingon pH andrel. Adenomastronglyinhibited. Inhibited nitrosamine formation. GPT and ornithine carbamoyl transf erase. 104 104 93 93 Chlorogenic Acid Vanillin In vitro In vitro In vitro In vitro Hydroquinone Thymol Dimethylamine Dimethylamine Inhibited nitrosamine formation. human gastricjuice In vitro Cigarettes Bacon Inhibited nitrosamine formation. Inhibited Inhibited nitrosamine formation. 101 2. 102. Rats Inhibited nitrosamine formation. conc. nitrosamine formation. 101 Butylated Hydroxyanisole (BHA) Dimethylamine Hepatotox. Tannic Acid Dimethylamine In vitro Inhibited nitrosamine formation. ornithine carbamoyltransferase.6-Di-t-butylp-cresol (BHT) Dimethylamine Hepatotox. 92 101 Propyl Gallate Hepatotoxicity. Aminopyrine t-ButylPyrrolidine hydroquinone Hepatotoxicity. GPT. Catalysednitrosamineformation.594 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table III Effect of Phenols on Nitrosamine Formation In Vitro and In Vivo Phenol Phenol Gallic Acid Amine -- System In vitro Effectsof the Phenol Phenol reacts with nitrite 104 X Reference 98 asrapidly asdimethylamine. nitrite-treated Inhibited nitrosopyrrolidine bacon formation.. GOT.

of phenolson the c __ .but sometimes their presence intensifiednitrosamineproduction..39 mM nitrosamine was formed. However. of nitrosamines in amine--nitrite systems. In most cases phenolsinhibited nitrosamine formation.Figure 1 and Table IV are adaptedfrom their data obtainedat pH 4.5 mM.2 where maximumnitrosamine formationoccured. nitrosamine formation increasednine-fold.In the absence of gallicacid 0. 12. Walker. In systems containing nitrite. This result is consistent with that obtainedby Davies and coworkers(105) who found that the rate of nitrosation of pyrrolidine by nitrite increased linearly with the concentrationof p-nitroso-0-cresol.A similar mechanism probably operateswith gallic acid where a large excessof nitrite would lead to catalysis by C-nitrosogallicacid. phenols andsecondary amines several reactions compete: --formation ofquinones(eq 19) --formation ofC-nitrosophenols(eq 20) --direct formation of N-nitrosamines --phenol-catalysed formationof N-nitrosamines --aerobic oxidationof C-nitrosophenols to noncatalytic nitrophenols(105). Extrapolationof the linear relationship(Figure 1) indicatesthat addition of 144 mM gallic acid would result in complete inhibition of nitrosamineformation. further increasesin gallic acid concentration decreased nitrosamineformation linearly.NITROSAMINE CHEMISTRY 595 2. At the lowest level of gallic acid added.This is equivalentto approximately2 mol of gallicacidper mol of nitrite. In the presenceof excess nitrite 4-methylcatechol catalyses the nitrosation of dimethylamine and piperidine (104) and both p-cresol and p-nitroso-0-cresolcatalysethe nitrosation of pyrrolidine (105). Efj•ct ofPhenols onNitrosamine Formation In Table TTT are summarized literature reportsof the •cc•. Inhibition of nitrosamineformation by phenols occursby reduction of nitrite to unreactivenitric oxide (104) OH O + 2HNO2 > + 2NO + 2H20 (19) or by removalof nitrite via C-nitrosation(98): OH OH •+ HNO2 )• + H20 NO (20) Under someconditions phenolscancatalyse nitrosamineformation. They demonstratedthat the nitrosating species responsible for catalysis is an adductof nitrite and a tautomer of the nitrosophenol. . Pignatelliand Castegnaro (100) investigatedthe effects of 0-65 mM_gallic acid on the formation of nitrosodiethylamine from 75 mM nitrite and 500 mM diethylamine.

either directly or catalytically. Excess nitrite C-nitrosatesthe phenol and subsequently forms the catalyticspecies.0263 g + 3. the leastsquares line of bestfit. Sulfamate reduces nitrite to molecular nitrogen (107) (eq 23).48 0.80 3.5 25.0 Found (N) 2. SO2 + 2HNO2 --> 2NO + H=SO4 qqHzSO4 + H=O (21) (22) (23) SOz + 2NO + HzO --> N=O NaNO= + H2NSOaH --> NaHSO4 N= . These substances inhibit nitrosamineformation (Table V).15 2. 3.81 3.46 -- N •' = -0.39 3.2 mM NDEA mM Gallic Acid (g) 62. A large excess of phenol removesnitrite so that it is unavailable for reaction with amine.15 2.which are not C-nitrosated because the ring is fully substituted.5 37.5 0. (N a) 2. Effect of gallicacidon N-nitrosodiethylaminesynthesis Thus.0 3.10 Calc. Inhibition bySulfur Compounds Bisulfite reducesnitrite in two steps(106)--first to nitric oxide (eq 21) and then to nitrous oxide (eq 22).79.No catalysis shouldoccur with phenolssuchasc•-tocopherol. Table IV Effect of Gallic Acid Concentration on Nitrosodiethylamine (NDEA) Synthesis from 75 mM Nitrite and 500 mM Diethylamine at pH 4. whether a phenol inhibitsor catalyses nitrosamineformationlargelydependson the relative concentration of nitrite and phenol.596 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS 20 qO 60 80 100 120 lqO 6ALLICAClD• mM Figure 1.13 12.

. Table VI summarizes literature indicatingthat urea. In vitro in vivo 108 93 Aminophenazone Dimethylamine Piperazine Inhibits nitrosamine formation. 4. Dimethylamine. caffeine and ethanol are relatively ineffectiveinhibitors. Inhibits nitrosamineformation. The thioether methionine is less effective. 91 93 Methionine Dimethylamine The thioIs cysteine and glutathione also inhibit nitrosamine formation. In vitro Inhibits nitrosamine formation.Invitro pholine. Inhibits nitrosamineformation. One would suggest transnitrosation of secondary aminesby nitrosothiols. Human gastricjuice. NH2OH + HNO2 --> N20 + 2H20 (25) Vitamin A reacts with nitrite in acid solution but not under neutral conditions (108). It is postulated that nitrite oxidizes methionine to the sulfoxideor sulfoneand is in turn reducedto nitric oxide (93). Presumably oxidationof the vitamin involvesits double bonds. In contrastcatalysis of nitrosation by p-nitroso-0-cresol does not occur in the absence of nitrite.mor. but reducednicotinamideadeninedinucleotide(NAD) is effective. In alkalinesolutioneven weak oxidantssuchasO2 convert nitrite to nitrate (110). 93 Human gastricjuice.NITROSAMINE CHEMISTRY 597 Table V In Vitro Inhibitionof NitrosamineSynthesis by SulfurCompounds Sunur Compound Sodium Bisulfite Amine Dimethylamine System Effectof SulfurCompound Reference 93 93 108 Model food systems Inhibits nitrosamine formation. Inhibits nitrosamineformation. Aminophenazone in vitro Cysteine Cysteine Glutathione Glutathione Dimethylamine Piperazine In vitro in vitro Inhibits nitrosamine formation. Miscellaneous Inhibitors The ammonium ion reactswith nitrite to form molecular nitrogen (107) by the following sequence: NH4 + 2H + + • NHa NO2+ + • H+ H2ONO + ---> H20 (24) + NHaNO + • N= + H+ + H20 H2ONO + NHa Hydroxylamine reducesnitrite to nitrous oxide (107). morpholine andpyrrolidineto form N-nitrosamines (105). In the absence of nitrite preformednitrosocysteine reacts withN-methylaniline. exceptthat molecularoxygenappearsto be necessary (105). ThioIs reactwith nitrite to form S-nitrosocompounds (109). piperazine Piperazine Human gastricjuice. Ammonium Sulfamate Sulfamic Acid Inhibits nitrosamine formation.

but other products can be produceddepending on the reducing agentandexperimental conditions (119). 5). Denitrosation (eq 2) occurs slowlyin acidsolution(1 to 5 M) andiscatalysed by nucleophiles in the order of effectiveness Y = I.Apparatus andconditions for the photochemical destruction of nitrosamines in solution in thepresence ofa HNO• scavenger have beendescribed (115.R' = alkyl > R. nitrogenand nitrousoxideor quantitatively to amineand nitrousaciddepending on thewavelength used. Analysis of thenitrite released provides a measure of theoriginal nitrosamine concentration (114). Thereaction isfastest in acid andfaster in neutral than basic solutions.113).lithiumaluminum hydrideandcatalytic hydrogenation (4. . To preventreversalof the reaction a substance. Many hydrazines are carcinogenic. Reference 93 95 93 In vitro Caffeine Ethanol Lungadenoma. Inhibitory effect decreases with time. Moderatelyinhibited. Inhibits nitrosamine formation. Ease of denitrosation variesin the order R. The corresponding hydrazines are usually formed(eq 26).They are stablein neutraland strongalkalinesolutions in the absence of light (2.sodiumamalgam.> C1(36. D. When exposed to ultravioletlight nitrosamines decompose either to aldehydes.Relativeefficiency of variousnitrite traps in 5 M H2SO4was found to be hydrazoicacid and hydrazine > sulfamicacid> aniline > hydroxylamine > urea (112).> SC(NH2)2> SCN. but about 100 timeslesssothan the corresponding nitrosamines (2). H R R--N[ +--NO + YI R' • / R' N--H + Y--NO (2) Y--NO + Z --> unreactiveproducts (4) Quantitativedenitrosation of nitrosamines canalsobe achievedat room temperature using a solution of HBr (5 to 10%) in glacial acetic acidif waterisexcluded. 116). whichreacts irreversibly with YNO (eq 4) andmore rapidlythanamine. DESTRUCTION OF N-NITROSO COMPOUNDS N-Nitrosamines are stable compounds and are difficult to destroy once they are formed. tin in hydrochloricacid. 111). Nitrosamines can be reducedby zinc in aceticacid. Mice 78 99 Chlordiazepoxide In vitro Slightinhibitoryeffect.598 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table VI Miscellaneous Nitrosamine Inhibitors Inhibitor Urea Urea Reduced NAD Amine Dimethylamine Piperazine Morpholine Dimethylamine Pyrrolidine Piperidine Morpholine System In vitro In vitro Effectof Inhibitor Relatively ineffectivein inhibiting.> Br.R' = aryl > R = aryl. 117).mustbe added.R' = alkyl (53. A reduction procedure for destruction of nitrosamines in alkalinesolution with aluminum has beenpublished (118).

OH RCH2N--Z + H20 ) RCH2NHNO + ZOH (27) l RCH•N=N + H20 < RCH2N=NOH The rate of decomposition increases with increasing pH and varieswith amidestructure (2). In soils.canbe incorporatedinto the raw materialor finishedproduct.in the productionof organicraw materials.Thus. Removalof nitrosating species from our environmentis a sociological tasknot amenable to immediate solution.NITROSAMINE CHEMISTRY 599 reduction R2NNO > R2NHNHz (26) N-Nitrosamides are hydrolytically unstable. 4. Nitrites are added to somefoodsto preventgrowth of botulinusorganisms. V. Sulfamatesand sulfitesreduce the nitrites to . 121). 122). PRACTICAL CONSIDERATIONS The basicproblem in minimizing nitrosamineformation is prevention of the reaction between nitrosatingspecies and amines. a sufficientexcess of theseinhibitorsshouldbe incorporated to scavenge oxidized NO. The excessSO2 would be eliminated by the drying process. These can be reduced in vivo after ingestionof the food. Some foods have a high nitrate content. In certain cases. Scavengers which reducenitrosating species can be classified into thosewhich convert nitrite to NO and those which reduce it further.where a nitration step occursin the synthesis.Already industry is moving to replace nitrite as a corrosioninhibitor in someapplications and reduceits useasan additivein meat. Hydrogen bromide in carbon tetrachloridehasbeen usedfor syntheticconversionof nitrosamideto amide (28).The nitrosatingspecies are ubiquitousin the environment. Nitrites are alsowidely usedas metal corrosion inhibitors. At pH 9 the order of stabilitywasfound to be nitrosourea < nitrosamide < nitrosourethane< nitrososulfonamide < nitrosoguanidine (2). organismsof the genus nitrosomonasoxidize ammonia to nitrite (126). In the presenceof molecular oxygen NO is readily oxidized to N204 which is a good nitrosating agent.Alternatively. suchas ascorbic acid. A more likely generalapproachto preventingthe reactionof nitrosatingspecies and amines is the inclusionof appropriatescavengers into raw materialsand finished products. Nitrososulfonamides are stable only if kept coolanddry (124). a smallamount of SO2 can be added before solventremoval in the final step to destroy any traces of nitrite. streamsand rivers. In the solid stateN-nitrosamides sometimesdecomposeexplosively (2). a nontoxic nitrite scavenger. 17. In aqueousacid they decomposeby both denitrosationand deamination pathways(120.Roughly 50 ppb of nitrousoxide and nitrogendioxide are presentin the atmosphereof our cities (125). Nitrosourea samples should be frozen.not merelyrefrigerated (123). At alkalinepH nitrosamides decompose to diazoalkanes (eq 27) (2.For example.steps can be taken to minimize such contamination. 23. Most inhibitors described here reduce nitrite to NO.

J. 1123 (1974). Preussmann. Ivankovic. Chapter 4. 216 (1977). Challisand A. J. Cancer. Neurath. MageeandJ.These inhibitorsare not asinnocuous assomeof the weakerreducingagents. Patai.Z. Rand. Baldwin. Pein.Mirvish has shown that lipids readily extract nitrosating speciesfrom water.. NewSci.. (13) J. Arsenault and K. (9) C. Singer. Mfiller. Chem.M.Lyon. U. Mennel. B.. (10) Another analysis of nitrosamine carcinogenicity is presented by Druckrey et al. VenuletandR. Cosmeticsare frequently in the form of emulsions. Barnes.423 (1977)."The Chemistry of theNitro and Nitroso Groups. Br.. 264. Carcinogenesis and chronictoxicityof nitrilotriacetic acid in Swiss mice. "Environmental N-Nitroso Compounds: Analysis and Formation.Nitrosamines--environmental carcinogens?. R. EngL.307 (1976). S.R. France.. M. . Sinskey andS. P. Walker. (15) D. Y. International Agencyfor Researchon Cancer. 107 (1975).14. (2) H. pp 227-236. 333 (1976). Griciute. REFERENCES (1) T. Substitution at an Amino Nitrogen in S. Van Etten. Food Cosmet.1976. (16) J. N-Nitroso Compounds andRelated Carcinogens. pp 201-287. J. H.33.. G. Bogovskiand L. (18) B. 114 (1956).R. New York. lotionsandshampoos."The Chemistryof the Amino Group. 1968. (17) J.559 (1967). Adv. L. 15. respectively. Archer. 103 (1967). Under these conditions. pp 491-625. Ed. 14. E. S. Int. New York. WishnokandM. (14) W. J. R. Chapter6. M. 52. P. Angew. Fan.Nitrosamine carcinogenicity: a quantitative Hansch-Taftstructure-activity relationship. Gomez. Terracini. S. N. New York.Interact. (11) J.20. MageeandJ. Krebsforsch. however. Schneider. Greenblattand W. 43 (1978). GANN Monogr.Biol. 333 (1976)." IARC Scientific Publicationsno. Cancer Res. (12) M. 69. Umpolung of aminereactivity. Blum. Dfinger and F.A. The production of malignant primary hepatic tumors in the rat by feeding dimethylnitrosamine. D. Chem." Part 2.Biochemistry andPharmacology of the Nitro andNitrosoGroups in H.. pp 277-345. P. 1976. Druckrey. 21. N. (2). (7) Laterstudies showed thataslittleas2 to 5 ppmfedovera lifetimeproduced livertumors (8).D. into suchproductsfor maximum inhibition of nitrosamineformation. G..Organotropecarcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. 163 (1967). Nitrosation of Nornicotine and Nicotine in GaseousMixtures and AqueousSolutions. L Song. Tannenbaum. Kraft. Nature. Afkham. (4) P. New York.10. Walters. Sinceaminesare alsomore solublein the oil phaseof emulsions.P. Druckrey.Hepatic pathologyin rats on low dietary levels of dimethylnitrosamine. C. 10. S. Preussman. Butler. 1970. Goff. Cancer. G. N. J.C. (3) H.in E. Archer.Edelmann andW. Wiley Interscience. which are not reoxidizedby molecularoxygen. in C.n. They conclude thatihe carcinogenic effectis dueto a summation of irreversibleprimary effects. Branz. Lijinsky. Schmlihl. S. Barnes. 15 (1975). Tetrahedron Lett.Structure-activity relationships in nitrosamine carcinogenesis.. (6) P. J.All oxygens in nucleicacidsreact with carcinogenic alkylatingagents. Seebach andD. Chemical activationof nitrosamines into mutagenic agents."Chemical Carcinogens" (ACS Monograph173). They showthat the total doserequiredfor carcinogenesis in rats becomes smaller with decreasing dailydoses and longerinduction times. How nitrosamines cause cancer. Biemann. Cancer. Br. (20) G.it is appropriateto incorporateoil solubleinhibitors.27. A.Chemical carcinogenesis on N-nitrosoderivatives. Toxicol.600 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS N2 and N20. Chem. Petropoulos and H. N. Nucleophilic a-(secondary amino)-alkylation via metalated nitrosamines. Fine. Lijinsky. P.M. E. L. (5) P. M. D. Montessano andR. Nat. Br. Searle.140 (1977).Cancer Res. Magee and J. L.N-Nitrosodiethanolamine in cosmetics.The log of the induction time is directlyproportional to the log of the daily dose. H.suchas ascorbylpalmitate and g-tocopherol. nitrosation reactionsare very fast. R. Barnes. (8) B. Br. M." Wiley Interscience. rulingout a recovery process. (19) B. H. A. F. 17. Magee.E. Enders. Carcinogenic N-nitrosocompounds. C.. Feuer. Wishnok. 13. CancerInst. The American Chemical Society.

Challisand S.Lyon.NITROSAMINE CHEMISTRY 601 (21) W.237 (1973). Soc. Br. 77.Lyon.. Agr. Edwards. Kinetics of nitrosamide formation from alkylureas. (44) J. Mirvish. Walker. (34) S. 1833 ( 1973). (22) J.J. Lyon. Chem.. (33) T. (26) B. Cancer Inst.Formation of N-nitrosocompounds. H. C. 639 (1971). Experientia. Ridd. (31) E.. France.S. Okun and M. J. ActaChem. 1972. Sac.418 (1961). A. (36) D. "Environmental Aspects of N-Nitroso Compounds. Scand. D. 2. 44. PerkinTrans.877 (1976).T. CancerInst. Griciute. Catalysis of NitrosamineSynthesis. Kineticsof N-Nitrosation Reactions in Relation to Tumorigenesis Experiments with Nitrite Plus Amines or Ureas.E.diazotization anddeamination. Chem.. 1978.in E. 5832 (1957).The catalysis of nitrosationby thiocyanate from saliva. Preussmann and E. International Agency for Researchon Cancer.S..J. 9. Outram. Walker. P. E.Lyon. Weast.The nitrosationand nitration of aminesand alcohols with nitrogen tetroxide. Schweinsberg.18. A.S. "Environmental N-Nitroso Compounds: Analysis and Formation.. J. Archer.S..1972. A. France. Nitrosyl thiocyanateand the S-nitroso-adduct of thioureaasnitrosating agents. Nitrosation. A.in P. N-alkylurethans. Ridd. Fan and S.. A. ¾. R. A. Q. 31.79. Walker. (24) S. InternationalAgency for Research on Cancer.S. Walker. Selected Data for MolecularBiology. J. Methodsof preparation. Feldman. Toxicol. (30) P. 9.Chem. The kinetics of N-nitrosation ofN-methylaniline.128 (1977).1974. pp 127-142. France. France.A. 3. Walker. Micellar Catalysis of NitrosamineFormation. H.. (32) E.409 (1977). Lyle. Kyrtopoulos andJ. R. Sac. Amer.Chem. Mirvish.. Challis. H. International Agency for Researchon Cancer. I. J. (25) B. Pharmacol.693 (1977).Nitrosationunder alkalineconditions. L. Sac.Chem. A. Griciute and R. Cancer Inst.hydroxyproline andsarcosine. Nat. Food Chem. Kinetische Untersuchungen fiber die Bilding von Diethylnitrosamin ausStickstoffoxiden undDiethylaminin der Gasphase." IARC ScientificPublicationsno."IARC Scientific Publications no. Mirvish. pp 132-136. Chem. R. 1974. Okun and M.. France. Boyland. Tannenbaum.J. 529 (1966). The chemistry of theN-alkyl-N-nitrosamides. Renner. Nat. Sams. KalatzisandJ. InternationalAgency for Research on Cancer. Bogovskiand E. Rolle. Lumme. ¾. P. R. PartXII. pp 80-85. (43) J. Kinetics of nitrosationof the amino acids proline. J."Handbookof Biochemistry. (38) E.579 (1977).RapidFormation of NNitrosaminesfrom Nitrogen Oxides Under Neutral and Alkaline Conditions. Rapidformationof carcinogenic N-nitrosamines in aqueous alkaline solutions. Kinetics of dimethylaminenitrosationin relation to nitrosaminecarcinogenesis. Boylandand S.35. Z.Food Cosmet. Possible implications for the etiologyof humangastric cancer. "N-Nitroso Compounds in the Environment. Sac. Nitrosation. Cancer. 99 (1978). H. Amer. (40) S. (23) S. ThiocyanateCatalysis of NitrosamineFormationand SomeDietary Implications. Williams. J.Cammun. kinetics andin vivooccurrence. Kyrtopoulos. Kineticsof nitrosamine formationin the presence of micelie-forming surfactants. 15."IARC ScientificPublications no. 51. Rolle. Formationof diethylnitrosamine by reactionof diethylamine with nitrogen dioxidein the gasphase. TaxicoL. Archer. S-Nitrosation of thiourea and thiocyanateion. (41) R. (39) S. in P. Fan and S. 2003 (1968).and alkylguanidines. (28) E.Factorsinfluencingthe rate of formation of nitrosomorpholine from morpholineand nitrite: acceleration by thiocyanate and other anions. Boyland. Chem. 22. pp 124-126. Chem. Cleveland. C. B. Lyon. R.C. pp 104-108. 46. Walker. Chemistry. 3. Bogovski. C.. p J131."IARC ScientificPublicationsno. Tummavuoriand P. Nice and K.in P. Walker. D.R."The Chemical Rubber Co. White and W.. Mirvish. Bogovski and L. The Effect of Some Ions of PhysiologicalInterest on Nitrosamine Synthesis. A. 58. Nat. A..325 (1975). Gehlert and E."IARC .21. R.J. (29) E. InternationalAgencyfor Research on Cancer. (35) F. 33. Tannenbaum. "N-Nitroso Compoundsin the Environment. R. "N-Nitroso Compounds: Analysis and Formation. Castegnaro. Bogovski. L. 9. (42) J. Challisand S. Cancer Inst. Appl. Soc. Rev. in P.C. J. 633 (1970). Hunma. Preussman andE. 1183 (1971). Williams.." IARC ScientificPublications no. A.in E. White. Bogovskiand E.diazotization anddeamination. J. Gehlert and W. 1968.S. Mirvish. 6008 (1955). Nat. Kyrtopoulos. H. 19. (27) B. M. "N-Nitroso Compounds: Analysis andFormation. Ohio. (37) E.C.Protolysis of nitrousacidin aqueous sodium nitrateandsodium nitrite solutions at different temperatures.

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(95) S.Food Chem... P. Davies. Challisand C.Sci. (89) M.124 (1974). "Environmental N-Nitroso Compounds:Analysisand Formation. Sen.R. International Agency for Research on Cancer.France. 24. P. pp 279-290. Griciute and R. (99) B.Chem."IARC ScientificPublications no.Lyon. 9. 254. B. 177.Y. Blocking the formation of N-nitroso compounds with ascorbic acidin vitro and in vivo. P. in E. InternationalAgencyfor Research on Cancer. Toxicol. Zeller. Wallcave. 258.S. T. France. Shubik. Nature. Mirvish. Griciute.Natural inhibitorsof nitrosationreactions. France. (86) A.Lyon. "N-Nitroso Compoundsin the Environment. (92) N.15. "Environmental N-Nitroso Compounds: Analysisand Formation.in E. Inhibition of nitrosamineformation in fried bacon by propylgallateandL-ascorbyl palmirate. J.S. P. 175 (1975). in P."IARC ScientificPublications no. Proc. Hisatune. R. R. T. Pensabene. A. France.Lyon. Mirvish. Walker. F. Miles.. R. Ann. VIII. Preussmann. (103) W. Donaldson.. International Agencyfor Research on Cancer. E. Eagen and P. J. (98) B. Scheunig. L.1974. A. M. Nature. FoodSci. Nat. M. Nature. L. Phys. Med. Possible carcinogenic effectsof coffee constituents. Acad. 14. Newmark and W.C. Griciute. Kawabata. Exp. L.Rapid nitrosationof phenolsandits implications for healthhazards from dietarynitrite. 2249 (1961). Astill and L. J. Mirvish. Fan and M. Inhibitionof N-nitrosamineformationin modelfoodsystems. Griciute. Bogovskiand E. C. 167 (1977). W. BogovskiandL. A. 40. Walker. M. Y. Walker.Lyon. (87) T.in E. Seaman. Phenolic autoxidantsand the inhibition of hepatotoxicity from N-dimethylnitrosamine formedin situin the rat stomach. 532 (1975). N-Nitroso compounds in food. Griciute and R. R.Biol..H. (106) I. (94) N.S. Effectsof gallicacidon nitrosamine formation. S. (100) E. Bartlett. Fiddler andJ. Weisman.. C. Castegnaro. 981 (1975). T.Inhibitory effect of ascorbic acidon the acute toxicityof dimethylamine plusnitrite in the rat. Kamm. A. "EnvironmentalAspectsof N-Nitroso Compounds. J. Alpha-Tocopherol:Usesin Preventing Nitrosamine Formation. Charbonneau and W. Appl. pp 183-197. 19. Walker. Tannenbaum. pp 101-102.C. (105) R. C. Kamm. Lyon. A. Ascotbate-nitrite reaction: Possiblemeans of blockingthe formationof carcinogenic N-nitroso compounds.. Cancer Inst. A. 1251 (1974). Effect of Some Inhibitors on the Nitrosation of Drugs in Human GastricJuice. Some Effects of Phenol. Vitam. 9. D. 397 (1976).Lyon. effectofascorbic acid on the formationof N-nitrosodimethylamine in vitro.J. pp 103-106. (97) S. 41."IARC ScientificPublications no. 466 (1973). BogovskiandL. pp 301-304. (88) S. Cardesa. I. The Effect of AscorbicAcid and Glutathione on the Formationof Nitrosopiperazines from PiperazineAdipate and Nitrite. Dashman. McWeeny." IARC ScientificPublicationsno. F. Dennis. Mulligan. (102) J.1978. Effects of Gallic Acid and of Ethanol on Formation of Nitrosodiethylamine. H. J. Walker. Castegnaro. conceptof available nitrite. A. Castegnaro. B."IARC ScientificPublications no.S. Donaldson.604 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Bogovskiand L.H.. Walker. Agric. A. Food Cosmet. C. 1067 (1974).T.1976. (91) N. Y.65. Challis. International Agency for Researchon Cancer. pp 199-212. 1125 (1974). Food Sci. Inhibition of amine-nitritehepatotoxicity byo•-tocopherol. "EnvironmentalAspectsof N-Nitroso Compounds.S. W. Ivankovic.1978. .' (90) T. Schm•ihl andJ.575 (1977). J. Sen and B. Castegnaroand E. J.J. Shubik.40. Pharmacol. J. Haven and P. 244. Walker. France. pp 173-178. D. 2nd).Jr. "Environmental N-Nitroso Compounds: Analysisand Formation.22. 19. Mergens.1976. Ziebarth and G. M.L. Sen. D. Lyle. Pignatelli andM. M. Shazukiand T. France. Preventionby AscorbicAcid of In Vivo Formation of N-Nitroso Compounds. N. C. Toxicol. Ishibashi. Mergens. Tannenbaum.in P. InternationalAgencyfor Research on Cancer. Lyle. 145. P."IARC ScientificPublications no. 258 (Conf. 176 (1975). (104) B.. (101) B. InternationalAgencyfor Research on Cancer. Newmark. E.. 54.1974. Miles. 14. J. Bogovski and E. Agric. R. France. Masseyand D. 38. (96) D. "N-Nitroso Compounds in the Environment.. Soc.and Thiol- nitrosationReactionson N-Nitrosamine Formation. Archer. Pignatelli.Food Chem. Fan and S. 1203 ( 1975)•. InternationalAgencyfor Research on Cancer. in E. J. Dugan. 14. (93) J. Donaldson.NipponSuisan Gakkaishi. 65 (1972). Effect of additives on the formation of nitrosamines in meat curingmixturescontaining spices and nitrites. Science. Gray andL. G.1976. J. Walker. B.Lyon."IARC ScientificPublications no. J. Reaction of nitrite with ascotbate and its relation to nitrosamineformation. Iyengar and W. Thermodynamicpropertiesof some oxides of nitrogen.

.C. PerkinTrans.an exampleof amidehydrolysis via SN2displacement on the N-conjugate acid.J. P. L. Bassow. 22. 1976. Challis and S. SharmaandR. Williams..Direct nitrosationof anilinederivatives andother nucleophilic species by N-nitrosodiphenylamine. Nyholm and A. 1932 (1977). Efficient Degradation of Nitrosamines by Photolysis. The chemistry of nitrosamides. A.. 126) B. p 60. 730 (1972). 2. "N-Nitroso Compounds: Analysis and Formation. F. L. Griciute. Bailar. CancerInst."Wiley. Griciute. T. (116) (117) (118) (119) Bogovski and L. 34 ( 1971). Chem. pp 372-374. Chem. 107 (1975). A. Walker. Johnston.Investigationof a Colorimetric Procedurefor Determina- tion of Nitrosamidesand Comparison with Other Methods. Org.The chemistryof nitroso-compounds.Lyon. New Jersey." IARC Scientific Publications no. 1513 (1970). Gangolli. R.(Incomplete)Ind. 183. 56. L. S. Perkin Trans. (121) B. JohnJ.J. Jones.12. (120) R. L. Russ. FoodCosmet.N-Nitrosamines: A Review of Chemical and Biological Properties and Their Estimation in Foodstuffs. Chem. D. pp 1-56. Nitrification and nitrogenremoval. Ailment. Synthesis of potentialanticancer agents.897 (1977). "Environmental N-Nitroso Compounds: Analysis and Formation. pp 81-86. C.part V. Novikov. C.1976. in P. "EnvironmentalN-Nitroso Compounds:Analysisand Formation. Perkin Trans. Sawyer. 14. (124) T. J. Biggsand D.153 (1975).. T. The Journal intends to continue publication of review articles of this nature." Hayden Book Company. 40. A. Ph. Efficient photolyricdegradationof nitrosamines. Advances in the chemistry of aliphatic Nnitrosamines. Polo and Y. F. 1976. D. Sciarra. J. New York. M." Vol.New York. Toxicity and Carcinogenicity of Nitroso-N-methylbenzylamine. 3.Soc. An Experimenter's Sourcebook. F. N. Arzneim. Kineticsand mechanism of the Fischer-Hepprearrangement and denitrosation. France. BianchiandG. Schott-Kollaf.Eng. C hem..399 (1960). H. Bogovski and L. New York. XXI. C. O. Chow. 2. L. Chow. 13.Instabilityof N-nitrosamides.Soc. 11.49. General acid catalysed decomposition of N-nitroso-2-pyrrolidone. T. "InorganicChemistry. p 615.J. the mechanism ofdenitrosation. PergamonPress. Lobl.Chem. A method for the destructionof nitrosamines in solution. Williams.NITROSAMINE CHEMISTRY 605 (107) K." IARC Scientific Publicationsno.25. International Agency for Researchon Cancer.the JournaloftheSociety ofCosmetic Chemists inaugurates the review sectionof the Journal. Preussmann and F. Nitrosated sulfonamides relatedto myleran. 118 (1974). Shillingand A. Review articlesare solicitedby special invitation from the Editor and Editorial Committee and are not subject to reviewby the EditorialCommittee.in E. Preussmann andE. Williams. Jr. P. Effect of Vitamin A on Formation. I. Preussman. 20. 1952.. D. The Chemistry of Nitrogen. A. (108) (109) (110) (111) (112) (113) (114) Trotman-Dickenson. Catoni. Walker.Transl.S.WaterResearch. Part IX.J.1972. G. "Advances in Food Research. Chichester. Toiletry and Fragrance Association for granting the authors permission to publishthis articlein ourJournal.1976. L. (122) T. InternationalAgencyfor Research on Cancer. Thompsonand D.M. Chapter 19. Jones."Volume 2.-Forsch. Crosby and R. A. Mukhametshin and S.R.Soc. H. Bogovski. G. part VI. Toxico/. Rev. H. Kussner andLB. 14. (115) J. 368 (1974). 997 (1976).New York."Comprehensive InorganicChemistry. L. in C. J. (123) W.Educ. Schweinsbergand P. 1973. J. Lijinsky. Beretta. Emel•us.Lyon. J. W. New York.655 (1975). J.in E. Chem..Science. Perkin Trans. Moeller.. J. InternationalAgencyfor Researchon Cancer. Fridman. C. Lyon. pp 453-459." IARC Scientific Publications no. Academic Press. 168 (1974). P.. the relative reactivity of a number of nitrogen containing speciestoward nitrosation and further evidenceagainstan intermolecularmechanismfor the rearrangement. Polo and Y. Editor . Schaper-Druckrey. (125) H.D. Walker. Chem. Rochelle Park. France. in J. Eisenbrand and R. Ahler. Kinetics and mechanism of the Fischer-Hepprearrangement and denitrosation. P. pp 473-486.We are especially appreciative andindebtedto the Cosmetic. Eine neue methode zur kolorimetrische bestimmung yon nitrosaminennach spaltungder N-nitrosogruppe mit bromwasserstoff in eisessig. Soc. Editor's Note: With the acceptance of thisreviewarticle."Air Pollution Chemistry. Nat. Holum. France. Lloyd. 2. 2. H. New York. H.

m. Holidays: Closed .606 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS VISIT THE LIB RARY of the Society of Cosmetic Chemists Room 96 50 East 41st Street New York. to 4 p.m. New York 10017 Library hours are: Monday through Friday 9 a.