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--NO

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

NITROSAMINE

CHEMISTRY

5 83

Table

Varying CarcinogenicActivity of Nitrosamines

Classification by Rangeof log (l/D5o) a

Highly Potent, >3.0

Structure

D5o a

log (1/Do)
3.2 3.2

(CHaCH2)2NNO
CHaNCH2CHzC1

0.00063
0.00061

I
NO

CHaNCH2C6Hs

0.00080

3.1

I
NO

Potent, 2.1 to 3.0

0.0010

3.0

CHaNCHzCHzNCHa
NO NO

0.0039

2.4

(CHa)2NNO (n-CaH7)zNNO
Intermediate Activity, 1.1 to 2.0
(NCCH2)2NNO

0.0054 0.0088
0.012

2.3
2.1

1.9

NNO
O NNO

0.012

1.9

0.011

1.9
1.8

CHaCHzNCHzCHzOH

0.016

I
NO

(n-CiH9)2NNO

O.O25

1.6

O.O25 NO

1.6

n-C4H9N(CH2)4OH
NO

0.031

1.5

O.O39

1.4

I
Minimal Activity, <1.0
NO

(i-CaHT)zNNO
O

0.11

1.0

II
(CHaCOCHzCHz)zNNO (n-CH)2NNO CHaNCH2COzH
0.18

0.7

0.26 0.24

0.6 0.6

I
NO

(HOCHzCHz)zNNO

0.89

0.05

continuedon p 584

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.50 a

log (1/Ds0)

No DetectableActivity
(C6H.02NNO (C6HCH2)NNO

NO

(HO.,CCH=)=NNO

(12)

aD.50= mean total carcinogenic dose,expressed in mol/kg body wt, for productionof tumors in 50% of the
animals.

carcinogenic activity in animals. Comprehensivereviews of the results have been published(2, 4, 5).
Although there is no direct evidencethat N-nitroso compounds causecancerin man, their carcinogenicity has been demonstrated in many other animal species including mice, rats,hamsters, fish,rabbits,guineapigs,dogsand monkeys(4, 5, 9). About 80% of the N-nitroso compounds testedare carcinogenic to somedegree.Their potency varieswidely, from compounds where a singledoseis sufficientto inducetumors to those where large dosesgiven repeatedlyproduce no malignancy(2, 5). To illustrate the range of activity representativenitrosamines are classified in Table I according to carcinogenic potency(10). The carcinogenic doseis expressed in the way suggestedby Wishnok et al. (11) so that larger numbers indicate higher carcinogenicity.

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. Earlier Wishnok and Archer (13) showed that carcinogenicityis inversely related to the number of carbon atoms of acyclic dialkyl nitrosamines.Lijinsky (14) found that the reverse is true for cyclic nitrosamines,where the larger molecules are more potent, and that there are major changesin target organswith a changein ring
size.

The frequently proposedmechanismof action (2, 3, 15) shownbelow accounts for the enzymaticactivationrequired by nitrosamines, but not nitrosamides, and indicates that only nitrosaminescontaininganq-hydrogen are carcinogenic. The requirement for activation of nitrosaminesis defined as an enzyme-catalysed hydroxylationof an q-carbon. 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).

NITROSAMINE

CHEMISTRY

585

RCH--

N--CHR',,
NO

hydroxylasc
.

RCH--N--CR'
ON OH

RCH--N=N--OH

R.,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. The latter tautomerizes to a diazoniumhydroxide. Alkylation of nucleophilic sites (Nuc) in DNA, RNA and proteins by N-nitroso carcinogens has been demonstrated(5), but the evidence conflictsas to whether a diazoniumion or the diazoalkaneis the alkylating agent (2, 4, 5, 17). In nucleicacids the principle site of alkylationis at N(7) ofguanine. Alkylation of nucleicacid oxygens hasalsobeen demonstrated(18). Nitrosamides do not require metabolicactivationbecausethey can be hydrolysedin vivo to an unstableprimary nitrosamine(2, 3), the proposedprecursorof the alkylating
agent.

II
R'C

N--N:O

H20

R'COzH

RNHNO

IV.
A.

CHEMISTRY
INTRODUCTION

OF N-NITROSO

COMPOUNDS

Much of the chemistry of N-nitroso compoundsin aqueous solution can be summarized by the following scheme.
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)

586

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Nitrosation of secondaryaminesand amidesis describedby eq 1. The effectiveness of

the nitrosating agentY--NO depends on the natureof Y. Catalysis ofnitrosation by Y' species resultsfrom its prior reactionwith Y--NO (eq 3), which produces the more active nitrosating agent Y'--NO. When Y is a secondaryamine function, eq 1
describes transnitrosation asit is definedin this paper.

Inhibition of nitrosationoccurs by reaction of inhibitor Z with nitrosating agent Y--NO in the irreversible eq 4, whichis muchfasterthan 1 andproduces unreactive products.Destruction of N-nitroso compounds by denitrosation is described by eq 2. Addition of Z, in this casecalleda trap or scavenger, is necessary to prevent via 4 the reversalof denitrosation, eq 1. Details of these reactionsand the chemistryof N-nitroso compounds not includedin
this scheme are described below.

B. FORMATION

1. NitrosatingAgents

a. Inorganic Species. Several nitrogen oxide speciesare nitrosatingagents,but nitrous acid (HONO) and the nitrite ion (ONO-) are themselves inactive(19). Known inorganic nitrosatingspeciesare:
Substance Medium

N2Oa

gas(20, 21)
water (19, 22-27) organicsolvent (2)

NO2/N204

water (25-27)
organic solvent (28, 29) gas (21, 30) water ( 19, 22, 23, 31- 37)

YNO

H2ONO +
NO

water(19, 22, 38-40)

plus O2 (25, 27, 36) anaerobic,M n+ (19, 27)

The interrelationshipbetween active nitrosatingagents (underlined) and inactive species is summarized below.For simplicity, the equations are not balanced.
NO +

HONO+

--H +

HNO -

--HO

Mn+

' NOa

NO

NO

YNO

+ H20

NO-

H20

Io_

In moderately acidicaqueous nitrite solutions the nitrosating agentis nitrousanhydride,N2Oa(19, 22-24), formedfrom nitrous acid,pK = 3.138 at 25(41, 42), after protonation of nitrite ion according to eqs5 and6.

NITROSAMINE

CHEMISTRY

587

H+

ONO-

HONO

(5)

2HONO

--'

ONNO2

H20

(6)

At lower pH, more rapid nitrosation by the nitrous acidium ion (19, 22, 38-40) becomesimportant, especiallyfor weakly basicaryl arninesand amides.
HONO + H+ -'-' H2ONO + (7)

Certain anions, Y-, catalyse the reaction in water by forming nitrosating species
Y--NO which are more reactive than NzOa.

HONO

Y-

H+

Y--NO

HO

(8)

Of the anioniccatalysts studiedthiocyanate hasthe greatesteffect (23, 31-37). Halide ions are also catalytic in the order SCN-, 1- > > Br- > Ci- (19, 22, 23, 31, 33, 35).

The equilibriumconcentration of YNO (eq 8) mainlydetermines the order of the

catalyticeffect, rather than the actualreactivitiesof YNO (36). As the pH is lowered below 2, rapid nitrosationby Y--NO dominatesover that by NzOa, lowering the pH at which the nitrosationrate is maximum comparedto the uncatalysed reaction (23, 32-34, 37). Perchlorateand sulfateions are not catalytic(22, 31, 33). Hydrogen phosphate and carboxylate anionsmay catalys e nitros ation (31), but only weakly ( 19, 33).
Substances capableof forming micelies exert a catalytic effect on the nitrosation of aminesin acid solution.The rate of nitrosationof dihexylamineat pH 3.5 increases 800-fold in the presenceof decyltrimethylammonium bromide micelies (43). Other cationicand nonionicsubstances at levels higher than their criticalmicelie concentrations are also catalytic (43, 44). The magnitude of the catalytic effect is smaller for secondaryamineswith alkyl chain lengths shorter than C6. Some nitrosationrate enhancements observedin the presenceof microorganisms havebeen explainedasdue to an analogous hydrophobic interactionbetweenamine and a cellularconstituent(45).

In aqueoussolutionat pH > pKa of HNO2 the rate of nitrosationdrops rapidly with increasing pH, because the concentrations of active nitrosatingspecies generatedin situ decrease.No nitrosation by aqueous nitrite has been observed above pH 7.5. When formaldehyde(equimolarwith amine) is added to neutral or basicsolutions,nitrite can nitrosatesecondary amines,but at a slower rate than in acid solutions(46, 47). Nitrosamine yieldsvary with stericaccessibility of the nitrogenatom. Chloral (46, 47), pyridoxal and various benzaldehydes(48) are also catalytic, but less so than formaldehyde.Acetoneand acetaldehyde are inactive.The proposed mechanism (eq 9) involves nucleophilic attack by nitrite on an iminium ion intermediate following by collapse of the adductreleasing the carbonylcatalyst.
--OH+ +

ReNH

O--CHR'

'

RNCHR'

RN--CHR'
..

(9) RzN-CHR'

"
R=N--NO + O---CHR' * N--O

588

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

In organicsolventsNOCI, N2Oa, N204 and NOBF4 have been usedaspreparativenitrosationreagents(23, 25). Use of NOa (2) or NzO4 (28) in carbontetrachlorideor acetic acid gives high yields of nitrosamides. With secondary amines NzO4 in methylene chloride reactscleanly either as a nitrosatingagent at 0 or as a nitrating agent at -80 (29). Since NO2 is in equilibrium with N204 (49), statementsin the literatureon effectsof either substance mustbe criticallyviewed.

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). Nitrosation of aminesdissolved in methylene chloride in contactwith solid sodium nitrite occursby a reaction which involves the solvent (51).

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). Although both nitrogen oxides might be expected to undergo rapid hydrolysis at pH > 5 to yield unreactiveNOz- and NOa-, aminesof widely different reactivitycompeteeffectively with water andOH- for dissolved NzOa andN204. Nitric oxide (NO) alone is inactive but is oxidized by oxygento NOz and thus to the reactive nitrosatingagentsNzOa and N204 (25, 27, 36). Rapid nitrosationby NO under anaerobicconditionsoccursin the presenceof iodine or Ag(I), Cu(I), Cu(II),
Zn(II), Fe(III) or Co(II) salts(19, 27).

b. Organic Species. N-Nitrosamines themselves act as nitrosating agents. Aromatic nitrosamines, such as nitrosodiphenylamine, transnitrosate secondaryaminesunder

neutral conditions in organicsolvents (52, 53) probablyby a free radicalmechanism (53). The process is more rapid in acidicaqueous solutionand occursby a heterolytic mechanism (53, 54). The slowertransnitrosation betweenaliphaticsecondary amines
requires more extreme conditionsor catalysisby nucleophilicagents,such as thiocyanateand halideions(23, 55, 56).

Nitrosation of morpholine by aromatic and aliphaticC-nitro compoundsin tetrahydrofuranat 70Chasrecentlybeenreported(57). 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 and secondarynitroalkanesdecomposeto nitrite in dilute alkaline solutions(58).

2. Nitrogen Compounds
a. Primary Amines. The well-known deamination of primary aliphaticamineswith ni-

trite in cold aqueous acidyieldsa varietyof products (22). The rapidreaction proceeds through unstable primary nitrosamineand diazonium ion intermediates.The latter reactswith nucleophiles presentto form substitution, eliminationand rearrangement products.

RNH2 + NO-,H +

R----N=O
I
H

RI=N--OH
(lO)

alcohols, alkenes (

Nuc

R--N

N+ +

HO

NITROSAMINE

CHEMISTRY

589

Secondary amines andsubsequent nitrosamines formed by reaction of thediazonium

ionwith theprimaryaminestarting material (eq 11)havebeenisolated (22). Thisreaction occurs in low yieldbecause theamine is largely protonated andunreactive under thestrongly acidic andlow temperature conditions commonly used.

R--NN + + RNH2 --N., )

R.,NH

NO%,H +) R.,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).

H2N

NH2

2NO

HCI salt
0.025 M

moist
0.050 M

160C,2 hr
in citrate-phosphate buffer, pH 3.4
100C, 1 hr

22% yield

1.6%
0.39%

22C, 6 days

Under similarconditions n-butylamine, a monoamine, gave much lower yieldsof

N- nitrosodibutylamine.

Higher levels of stableo-alkoxynitrosamines are producedfrom the reactionof primaryamines with aldehydes in the presence of alcohols and nitrite undermildly
acidicconditions(60, 61).

RNH= + CH20 + R'OH + NOj, H +

> R--N--CH=OR'
I NO
(12)

However, mixtures of primary aminesand aldehydes without alcoholdo not reactwith nitrite at pH 3 (62).

b. Secondary Amines. Nitrosaminesformed directly from secondary aminesare stable. In moderatelyacidicaqueousnitrite solutionsN2Oa, formed from two moleculesof HNO2 (eq 6) is the nitrosatingagent. The rate-determining step in the reaction is electrophilic attackby N=Oa on the free electronpair of the unprotonated amine(eq 13). Rate equation 14 describes the kinetics.
R=NH + NzOa --> RzNNO + HNOz (13)

rate =

k[R2NH] [HNO=] z

(14)

Thus, two factorsdeterminethe effectofpH on the rate of nitrosation:

(i) extentof conversion of NO2- to HNO2 andthusto NzOa (favoredby lower

pH)

(ii) concentration of unprotonated amine(favoredby higherpH).

590

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

As predictedby the rate equation(33) for simplebasicamines(pKa > 5), the nitrosation rate in water is maximumat pHmax= 3 to 3.4 (23, 24, 40, 63, 64) nearthe pKa of HNO2. For a given amine as the pH increases abovepHmaxthe rate decreases, because the concentrationof HNO2 decreases. As the pH decreases below pHmaxthe rate decreases, because the concentrationof unprotonatedamine decreases. At a givenpH the rate of nitrosation increasesas the basicityof the amine decreases, becauseof the higher relative concentration of unprotonated amine present. Thus, the following order of reactivityis found at pH 3.0:

Amine /NH
pKa 11.2

OX /NH H=+N/NH
\ /
8.7 5.57

Relative
rate (23, 33)

930

180,000

Nitrosation of secondary amino acids(65, 66) occursat an optimumpHmx = 2.25 to 2.5 (34, 40). The reactionfollowsrate eq 14, but the pH-rate profileis changed by the fact that two amine species react--RNHCHR'CO=and RNHCHR'CO2H. c. Tertiary Aminesand RelatedCompounds. Tertiary amines have generally been regarded as inert to nitrosation, even though their conversion to secondary nitrosamines was reported over 100 yearsago (67). Because dealkylationis required, the reaction occurs to a significantextent only at elevated temperatures in weakly acidic media (68-70). At 25C and pH 3.4 nitrosationof tertiary aminesis about 10,000 times slowerthan that of related secondary amines(23). The followingmechanism hasbeen proposed(23, 68, 69) for nitrosative dealkylation
and nitrosamine formation:

I
RzNCH2R' + N=Oa

' N0+ H0

R=N--CHR'

--HN0

I
ON

I
H

R,N=CHR'
HO

(15)

RNNO

N20a

RNH

R'CHO

With mixed tertiaryalkyl aryl amines ring C-nitrosation alsooccurs (19). Two related compounds--the nitrogen acetalhexamethylenetetramine (71) and the drug antipyrinewhich has an eneaminestructure(23, 72)--undergo N-nitrosation muchmore rapidlyand extensively than normaltertiaryamines. 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).

d. Quaternary Aminesand Amine Oxides. Quaternaryammoniumcompounds apparently react slowlywith nitrite in acidicmedia.The initial dealkylationrequiredaccountsfor their lower activity comparedto tertiary aminesand may not involvethe nitrosatingagent (73). The relative reactivity of secondary,tertiary and quaternary

NITROSAMINE

CHEMISTRY

591

amines is indicated by the following data gathered for reaction of a ratio of 5 mol NaNO2/mol amineat 78CandpH 5.6 for 4 hr (73).
Amine % Yield of (CHa)2NNO

(CHa)2NH
(CHa)aN

9.6
0.9

(CHa)4N + (CHa)2NCH=CH=OH
(CHa)aN + CH= CH=OH

0.6 1.6
0.0002

Severalnaturallyoccurringquaternaryammoniumcompounds were found to be much lessreactivethan the tetramethylammoniurn ion (73). The tribenzylmethylarnmoniurn

ion is reportedto be unreactive undersimilarconditions (68). No nitrosation of 10-a M hexadecyltrimethylammonium bromideby a 20-fold excess of nitrite at 25Cand
pH 3.5 wasobservedafter 40 min (44).

Tertiaryamineoxides in thepresence of excess nitriteatpH 1 to 3 andtemperature 25

to 75C are converted to secondarynitrosaminesto a greater extent than are tertiary

amines (74). However, at 90 to 100C and pH 4 to 5 both classes show similar reactivity (68, 70, 74). Two mechanisms that accountfor the changein relative reactivity with conditions havebeenproposed (70, 74). e.Secondary and TertiaryAmides. For secondary amides,aswith amines, the nitrosation condition mostwidelyinvestigated hasbeennitrite in aqueous acid.

N-Alkyl ureas andcarbamates are rapidlynitrosated at pH 1 to 2. The nitrousacidium ion is the main nitrosating agentfor theseand other amides(eq 16) and the reaction
rate follows eq 17 (23, 39, 40).

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 pH > 2.5 nitrosation by NzOa contributes (39).
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,N-acylureas,N-alkylguanidines and tertiary amines(23).

High yieldsof nitrosamides are obtainedfrom reactions of amideswith N=Oa (2) or SgO4 (28) in organicsolvents. However, N-methylacetamide in aqueous solutionat pH 13 doesnot reactwith addedSzO4, conditions underwhichsecondary amines are rapidly nitrosated(27). Apparently the weakly basic amide is too unreactive to competewith hydrolysis of the nitrosating agent.
Nitrosation of tertiary amidesin acidicaqueoussolutionsof nitrite at high concentrations and temperatures produceeither nitrosamides or nitrosamines (23, 70, 75). Nitrosationof trialkylureas givesthe corresponding nitrosoureas. Dialkylnitrosamines are the major productfrom dialkyl-or trialkylthioureas, 1,1-dialkylureas, 1,1-dialkyl3-phenylureas and tetraalkylureas.

592
C. 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. The reductionpotentials of various nitrogenoxides(76) listedbelowcanaid in selecting appropriate oxidizing andreducingagents for destruction of nitrite.
In acid solution:

E(volts)

HNO2 + H20 NOa- + 3H + + 2eNO + H20 ,- HNOz + H + + eNzO + 3HzO 2HNOz + 4H + + 4eIn basic solution:

-0.94 -0.99 -1.29

NO2-

2OH-

NOa-

HzO

2e-

-0.01

NO
NzO

+
+

2OH6OH-

NOz2NO2-

+
+

HzO

e+ 4e-

+0.46
-0.15

3HzO

i. InhibitionbyAscorbic Acid Ascorbic acid inhibits nitrosamineformation by rapid reduction of the nitrosating agent(77). Sincetheproduct NO canbe air-oxidized to
CH2OH CH2OH

HO C_O_xO HOCH /O O __ +N2Oa -O +2NO +HO (18)

HO OH

Ascorbic acid

Dehydroascorbic acid

the nitrosatingagent $204, excess ascorbic acidmust be addedto inhibit nitrosationin systems exposedto air. Literature reports describing ascorbic acid inhibition of nitrosamine formation in amine-nitritesystems are summarized in Table II. Under in vitro conditions ascorbic acid inhibited nitrosamineformation. It inhibited the toxic and carcinogenic effectsattributable to in vivo nitrosamine formationwith two exceptions. In one caseadenoma inductionby N-nitrosomorpholine and mononitrosopiperazine increased with added ascorbicacid (78). In anotherit inhibited in vivo synthesis of N-nitrosomorpholinein rats and consequent liver tumors,but enhanced forestomach papillomas and carcinoma
(79).
Table II

Inhibition of In Vitro andIn Vivo NitrosamineFormationby AscorbicAcid in the Presence of Nitrite

(or Amide) Aminopyrine

System Investigated Hepaticnecrosis, Mice

Effectof Ascorbic Acid 2 M excess of ascotbate prevented necrosis. Equimolarascotbate

gave incompleteprotection.

Reference 80

continued on p 593

NITROSAMINE

CHEMISTRY

93

Table II (continued)
Amine

(or Amide)
Aminopyrine

System Investigated
Hepatotoxicity, Rats

Effect of Ascorbic Acid

Reference

Inhibits elevation of GPT, Ala. aminotransferase,nitrosodimethylamine serumlevels.

Greater incidence of cancer in rats in absence of ascorbic acid.

81, 82

Aminopyrine

Carcinogenesis, Rats
In vitro

83 84
85

Chlordiazepoxide
Chlordiazepoxide

Inhibits nitrosamine

formation.

Toxicity, Rats

Ascorbate protected against increases in liver and spleen

wt.; decreasein adrenal wt., increasesin GPT, LDH.

Dimethylamine Dimethylamine

Acute tox., Rats

In vitro

Hepatic necrosis inhibited. GOT, GPT elevationinhibited.

Low conc. of ascorbate enhanced

86

87

nitrosamineformation. High
concentrations inhibited such
formation. Formation and

inhibition are a function ofpH.

Ethylurea Morpholine
Pregnant rats
In vitro

Preventscarcinoma in offspring. Amount ofascorbaterequired dependson the presenceor

absence of 02.
Inhibits nitrosamine formation.

88

Morpholine Morpholine

In vitro

90

Nitrosomorpholine
formation and tumor-

Inhibits nitrosomorpholine formation and liver tumors. Enhanced forestomach

genesisin rats

papillomas and carcinoma.

Piperazine
Proline

In vitro, human gastric juice Fried, nitrite-cured bacon

Inhibits nitrosamine formation.

91 92 93

Formationof nitrosopyrrolidine from prolineis inhibited.

Inhibits nitrosamine formation.

Dimethylamine Pyrrolidine
Proline

Model food systems

Dimethylamine, Pyrrolidine, Piperidine

Meat-curing mixtures

Inhibits nitrosamine formation.

94

Morpholine Piperazine Methylurea

Adenoma, lung, in mice

Ascorbate decreased adenoma

78

frequency in some cases. Increases adenoma frequency when given with the
nitrosamines.
In vitro

Morpholine, Oxytetracycline, Piperazine,NMethylaniline, Methylurea, Dimethylamine Piperazine, Aminophenazone

Inhibits nitrosamine and nitrosamide formation.

In vitro, human gastric juice

Inhibits nitrosarnine formation.

Review

96
97

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.

Morpholine
Diethylamine

Adenomainduction, Adenomastronglyinhibited.
Mice

78 99

Gallic Acid

In vitro

Inhibited or catalysed dependingon pH andrel.

conc. of reactants.

Gallic Acid

Diethylamine

In vitro

Catalyses nitrosamineformation
(see text). Inhibited nitrosamine formation.
Inhibited nitrosamine formation.

100
96
93

Gallic Acid

Piperazine Aminophenazone Proline

Proline Dimethylamine

In vitro, human gastricjuice Oil/water system

Propyl
Gallate

Propyl
Gallate

Fried, nitrite-treated Inhibited nitrosopyrrolidine

bacon formation.

92
101

Propyl
Gallate

Hepatotoxicity, Rats Inhibited liver pathol. GOT, GPT and ornithine carbamoyl
transf erase.

Tannic Acid

Dimethylamine

In vitro

Inhibited nitrosamine formation.

93

Tannin
o-Tocopherol o-Tocopherol

Piperazine, Aminopherazone
Dimethylamine Dimethylamine
Proline

In vitro, human gastricjuice

In vitro Cigarettes
Bacon

Inhibited nitrosamine formation.

Inhibited nitrosamine formation.

96
93

Inhibited dimethylnitrosamine
formation.

102,103

Inhibited nitrosopyrrolidine
formation.

Aminopyrine
t-ButylPyrrolidine hydroquinone

Hepatotoxicity, Rats Inhibited hepatotoxicity.

In vitro, Oil/Water
Hepatotox., Rats

Inhibited

nitrosamine formation.

93

Dimethylamine t-Butylhydroquinone

Inhibited hepatox. GOT, GPT, ornithine carbamoyltransferase.

101

2,6-Di-t-butylp-cresol
(BHT)

Dimethylamine

Hepatotox., Rats

Relativelyineffective.

101

Butylated Hydroxyanisole (BHA)

Dimethylamine

Hepatotox., Rats

Relatively ineffective.

101

4-Methylcatechol

Piperidine
Piperidine
Dimethylamine

In vitro

Catalysed nitrosamine formation.

Catalysednitrosamineformation.
Inhibited Inhibited nitrosamine formation. nitrosamine formation.

104
104
93 93

Chlorogenic
Acid
Vanillin

In vitro

In vitro In vitro In vitro

Hydroquinone
Thymol

Dimethylamine
Dimethylamine

Inhibited nitrosamine formation.

93

NITROSAMINE

CHEMISTRY

595

2. Efjct ofPhenols onNitrosamine Formation In Table TTT are summarized literature reportsof the cc. of phenolson the c __ .. of nitrosamines in amine--nitrite systems. In most cases phenolsinhibited nitrosamine formation,but sometimes their presence intensifiednitrosamineproduction.

In systems containing nitrite, 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).

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. 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).

Walker, Pignatelliand Castegnaro (100) investigatedthe effects of 0-65 mM_gallic acid on the formation of nitrosodiethylamine from 75 mM nitrite and 500 mM diethylamine.Figure 1 and Table IV are adaptedfrom their data obtainedat pH 4.2 where maximumnitrosamine formationoccured.In the absence of gallicacid 0.39 mM nitrosamine was formed. At the lowest level of gallic acid added, 12.5 mM, nitrosamine formation increasednine-fold. However, further increasesin gallic acid concentration decreased nitrosamineformation linearly. Extrapolationof the linear relationship(Figure 1) indicatesthat addition of 144 mM gallic acid would result in complete inhibition of nitrosamineformation.This is equivalentto approximately2 mol of gallicacidper mol of 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. They demonstratedthat the nitrosating species responsible for catalysis is an adductof nitrite and a tautomer of the nitrosophenol.A similar mechanism probably operateswith gallic acid where a large excessof nitrite would lead to catalysis by C-nitrosogallicacid.

596

JOURNAL

OF THE SOCIETY OF COSMETIC CHEMISTS

20

qO

60

80

100

120

lqO

6ALLICAClD mM

Figure 1. Effect of gallicacidon N-nitrosodiethylaminesynthesis

Thus, whether a phenol inhibitsor catalyses nitrosamineformationlargelydependson the relative concentration of nitrite and phenol. Excess nitrite C-nitrosatesthe phenol and subsequently forms the catalyticspecies. A large excess of phenol removesnitrite so that it is unavailable for reaction with amine, either directly or catalytically.No catalysis shouldoccur with phenolssuchasc-tocopherol,which are not C-nitrosated because the ring is fully substituted.
Table IV

Effect of Gallic Acid Concentration on Nitrosodiethylamine (NDEA) Synthesis from 75 mM Nitrite and 500 mM Diethylamine at pH 4.2
mM NDEA

mM Gallic Acid (g)

62.5
37.5 25.0

Found (N)
2.15
2.81 3.10

Calc. (N a)
2.15
2.80 3.13

12.5
0.0

3.48
0.39

3.46
--

N ' = -0.0263 g + 3.79, the leastsquares line of bestfit.

3. Inhibition bySulfur Compounds

Bisulfite reducesnitrite in two steps(106)--first to nitric oxide (eq 21) and then to nitrous oxide (eq 22). Sulfamate reduces nitrite to molecular nitrogen (107) (eq 23). These substances inhibit nitrosamineformation (Table V).
SO2 + 2HNO2 --> 2NO +

H=SO4 qqHzSO4 + H=O

(21) (22) (23)

SOz

2NO

HzO

-->

N=O

NaNO=

H2NSOaH

-->

NaHSO4

N=

NITROSAMINE

CHEMISTRY

597

Table

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.

Ammonium
Sulfamate

Sulfamic Acid

Inhibits nitrosamine formation. Dimethylamine,mor- Invitro pholine, piperazine Piperazine Human gastricjuice, Inhibits nitrosamineformation.

Aminophenazone

in vitro

Cysteine
Cysteine
Glutathione
Glutathione

Dimethylamine
Piperazine

In vitro
in vitro

Inhibits nitrosamine formation.

93

Human gastricjuice, Inhibits nitrosamineformation.

In vitro
in vivo

108
93

Aminophenazone

Dimethylamine
Piperazine

Inhibits nitrosamine formation.

Human gastricjuice, Inhibits nitrosamineformation.

In vitro Inhibits nitrosamine formation.

91
93

Methionine

Dimethylamine

The thioIs cysteine and glutathione also inhibit nitrosamine formation. The thioether methionine is less effective. It is postulated that nitrite oxidizes methionine to the sulfoxideor sulfoneand is in turn reducedto nitric oxide (93).

ThioIs reactwith nitrite to form S-nitrosocompounds (109). In the absence of nitrite preformednitrosocysteine reacts withN-methylaniline, morpholine andpyrrolidineto form N-nitrosamines (105). In contrastcatalysis of nitrosation by p-nitroso-0-cresol does not occur in the absence of nitrite. One would suggest transnitrosation of secondary aminesby nitrosothiols, exceptthat molecularoxygenappearsto be necessary
(105).
4. 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).

NH2OH + HNO2 --> N20 + 2H20 (25)

Vitamin A reacts with nitrite in acid solution but not under neutral conditions (108).

Presumably oxidationof the vitamin involvesits double bonds.

Table VI summarizes literature indicatingthat urea, caffeine and ethanol are relatively ineffectiveinhibitors, but reducednicotinamideadeninedinucleotide(NAD) is effective.

In alkalinesolutioneven weak oxidantssuchasO2 convert nitrite to nitrate (110).

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. Inhibitory effect decreases with time.
Inhibits nitrosamine formation.

Reference 93
95
93

In vitro

Caffeine
Ethanol

Lungadenoma, Moderatelyinhibited.
Mice

78 99

Chlordiazepoxide In vitro

Slightinhibitoryeffect.

D.

DESTRUCTION

OF N-NITROSO

COMPOUNDS

N-Nitrosamines are stable compounds and are difficult to destroy once they are formed.They are stablein neutraland strongalkalinesolutions in the absence of light (2, 5). Denitrosation (eq 2) occurs slowlyin acidsolution(1 to 5 M) andiscatalysed by nucleophiles in the order of effectiveness Y = I- > SC(NH2)2> SCN- > Br- > C1(36, 111). To preventreversalof the reaction a substance, whichreacts irreversibly with YNO (eq 4) andmore rapidlythanamine,mustbe added.Relativeefficiency of

variousnitrite traps in 5 M H2SO4was found to be hydrazoicacid and hydrazine > sulfamicacid> aniline > hydroxylamine > urea (112). Ease of denitrosation variesin the order R,R' = aryl > R = aryl,R' = alkyl > R,R' = alkyl (53,113).
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. Analysis of thenitrite released provides a measure of theoriginal nitrosamine concentration (114). When exposed to ultravioletlight nitrosamines decompose either to aldehydes, nitrogenand nitrousoxideor quantitatively to amineand nitrousaciddepending on thewavelength used. Thereaction isfastest in acid andfaster in neutral than basic solutions.Apparatus andconditions for the photochemical destruction of nitrosamines in solution in thepresence ofa HNO scavenger have beendescribed (115, 116). Nitrosamines can be reducedby zinc in aceticacid,sodiumamalgam, tin in hydrochloricacid,lithiumaluminum hydrideandcatalytic hydrogenation (4, 117). A reduction procedure for destruction of nitrosamines in alkalinesolution with aluminum has beenpublished (118). The corresponding hydrazines are usually formed(eq 26), but other products can be produceddepending on the reducing agentandexperimental
conditions (119). Many hydrazines are carcinogenic, but about 100 timeslesssothan the corresponding nitrosamines (2).

NITROSAMINE

CHEMISTRY

599

reduction

R2NNO

> R2NHNHz

(26)

N-Nitrosamides are hydrolytically unstable. In aqueousacid they decomposeby both denitrosationand deamination pathways(120, 121). Hydrogen bromide in carbon tetrachloridehasbeen usedfor syntheticconversionof nitrosamideto amide (28).

At alkalinepH nitrosamides decompose to diazoalkanes (eq 27) (2, 4, 17, 23, 122).
OH

RCH2N--Z

+ H20

) RCH2NHNO

ZOH

(27)

l
RCHN=N + H20 < RCH2N=NOH

The rate of decomposition increases with increasing pH and varieswith amidestructure (2). At pH 9 the order of stabilitywasfound to be nitrosourea < nitrosamide <
nitrosourethane< nitrososulfonamide < nitrosoguanidine (2). In the solid stateN-nitrosamides sometimesdecomposeexplosively (2). Nitrosourea

samples should be frozen,not merelyrefrigerated (123). Nitrososulfonamides are stable only if kept coolanddry (124).
V. PRACTICAL CONSIDERATIONS

The basicproblem in minimizing nitrosamineformation is prevention of the reaction between nitrosatingspecies and amines.The nitrosatingspecies are ubiquitousin the environment.Roughly 50 ppb of nitrousoxide and nitrogendioxide are presentin the atmosphereof our cities (125). In soils, streamsand rivers, organismsof the genus nitrosomonasoxidize ammonia to nitrite (126). Some foods have a high nitrate content. These can be reduced in vivo after ingestionof the food. Nitrites are added to somefoodsto preventgrowth of botulinusorganisms. Nitrites are alsowidely usedas
metal corrosion inhibitors.

Removalof nitrosating species from our environmentis a sociological tasknot amenable to immediate solution. In certain cases,steps can be taken to minimize such contamination.Already industry is moving to replace nitrite as a corrosioninhibitor in someapplications and reduceits useasan additivein meat. A more likely generalapproachto preventingthe reactionof nitrosatingspecies and amines is the inclusionof appropriatescavengers into raw materialsand finished products.For example,in the productionof organicraw materials,where a nitration step occursin the synthesis, a smallamount of SO2 can be added before solventremoval in the final step to destroy any traces of nitrite. The excessSO2 would be eliminated by the drying process.Alternatively, a nontoxic nitrite scavenger, suchas ascorbic acid,canbe incorporatedinto the raw materialor finishedproduct. Scavengers which reducenitrosating species can be classified into thosewhich convert
nitrite to NO and those which reduce it further. Most inhibitors described here reduce

nitrite to NO. In the presenceof molecular oxygen NO is readily oxidized to N204 which is a good nitrosating agent.Thus, a sufficientexcess of theseinhibitorsshouldbe incorporated to scavenge oxidized NO. Sulfamatesand sulfitesreduce the nitrites to

600

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

N2 and N20, respectively, which are not reoxidizedby molecularoxygen.These inhibitorsare not asinnocuous assomeof the weakerreducingagents, however. Cosmeticsare frequently in the form of emulsions.Mirvish has shown that lipids readily extract nitrosating speciesfrom water. Under these conditions, nitrosation reactionsare very fast. Sinceaminesare alsomore solublein the oil phaseof emulsions,it is appropriateto incorporateoil solubleinhibitors,suchas ascorbylpalmitate and g-tocopherol, into suchproductsfor maximum inhibition of nitrosamineformation.

REFERENCES

(1) T. Y. Fan, U. Goff, L Song,D. H. Fine, G. P. Arsenault and K. Biemann,N-Nitrosodiethanolamine in cosmetics, lotionsandshampoos, Food Cosmet. Toxicol., 15,423 (1977). (2) H. Druckrey, R. Preussmann, S. Ivankovic, D. Schmlihl, J. Afkham, G. Blum, H. D. Mennel,

H. Mfiller, P. Petropoulos and H. Schneider,Organotropecarcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten,Z. Krebsforsch., 69, 103 (1967). (3) H. Druckrey,Chemical carcinogenesis on N-nitrosoderivatives, GANN Monogr. Cancer Res.,n. 17,
107 (1975).

(4) P. N. Magee,R. Montessano andR. Preussman, N-Nitroso Compounds andRelated Carcinogens, in C. E. Searle,"Chemical Carcinogens" (ACS Monograph173), The American Chemical Society,1976,
pp 491-625.

(5) P. N. MageeandJ.M. Barnes, Carcinogenic N-nitrosocompounds, Adv.Cancer Res.,10, 163 (1967). (6) P. N. MageeandJ.M. Barnes, The production of malignant primary hepatic tumors in the rat by feeding dimethylnitrosamine, Br. J. Cancer, 10, 114 (1956). (7) Laterstudies showed thataslittleas2 to 5 ppmfedovera lifetimeproduced livertumors (8). (8) B. Terracini, P. N. Magee and J. M. Barnes,Hepatic pathologyin rats on low dietary levels of dimethylnitrosamine, Br. J. Cancer, 21,559 (1967). (9) C. L. Walters,Nitrosamines--environmental carcinogens?, Chem. Br., 13,140 (1977). (10) Another analysis of nitrosamine carcinogenicity is presented by Druckrey et al. (2). They showthat the total doserequiredfor carcinogenesis in rats becomes smaller with decreasing dailydoses and longerinduction times.The log of the induction time is directlyproportional to the log of the daily dose, rulingout a recovery process. They conclude thatihe carcinogenic effectis dueto a summation
of irreversibleprimary effects.

(11) J. S. Wishnok, M. C. Archer,A. S.Edelmann andW. M. Rand,Nitrosamine carcinogenicity: a quantitative Hansch-Taftstructure-activity relationship, Chem.Biol.Interact.,20, 43 (1978). (12) M. Greenblattand W. Lijinsky, Carcinogenesis and chronictoxicityof nitrilotriacetic acid in Swiss
mice, J. Nat. CancerInst., 52, 1123 (1974).

(13) J. S. WishnokandM. C. Archer,Structure-activity relationships in nitrosamine carcinogenesis, Br. J.

Cancer,33,307 (1976).

(14) W. Lijinsky, How nitrosamines cause cancer, NewSci.,27, 216 (1977). (15) D. Seebach andD. Enders, Umpolung of aminereactivity. Nucleophilic a-(secondary amino)-alkylation via metalated nitrosamines, Angew. Chem. Int. Ed. EngL,14, 15 (1975). (16) J. E. Baldwin, S.E. Branz, R. F. Gomez,P. L. Kraft, A. J. Sinskey andS.R. Tannenbaum, Chemical activationof nitrosamines into mutagenic agents, Tetrahedron Lett., 333 (1976). (17) J. VenuletandR. L. Van Etten,Biochemistry andPharmacology of the Nitro andNitrosoGroups in H. Feuer,"The Chemistry of theNitro and Nitroso Groups," Part 2, Wiley Interscience, New York,
New York., 1970, Chapter 4, pp 201-287. (18) B. Singer,All oxygens in nucleicacidsreact with carcinogenic alkylatingagents, Nature, 264, 333
(1976). (19) B.C. Challisand A. R. Butler, Substitution at an Amino Nitrogen in S. Patai,"The Chemistryof the Amino Group," Wiley Interscience, New York, New York, 1968, Chapter6, pp 277-345. (20) G. B. Neurath, M. Dfinger and F. G. Pein, Nitrosation of Nornicotine and Nicotine in GaseousMixtures and AqueousSolutions,in E. A. Walker, P. Bogovskiand L. Griciute, "Environmental N-Nitroso Compounds: Analysis and Formation," IARC Scientific Publicationsno. 14, International Agencyfor Researchon Cancer,Lyon, France, 1976, pp 227-236.

NITROSAMINE

CHEMISTRY

601

(21) W. Rolle, P. Gehlert and E. Renner, Kinetische Untersuchungen fiber die Bilding von Diethylnitrosamin ausStickstoffoxiden undDiethylaminin der Gasphase, Z. Chem.,18, 99 (1978). (22) J. H. Ridd, Nitrosation,diazotization anddeamination, Q. Rev.Chem. Soc., 15,418 (1961). (23) S.S. Mirvish,Formation of N-nitrosocompounds. Chemistry, kinetics andin vivooccurrence, Toxicol. Appl. Pharmacol., 31,325 (1975). (24) S.S. Mirvish, Kinetics of dimethylaminenitrosationin relation to nitrosaminecarcinogenesis, J. Nat. CancerInst., 44, 633 (1970). (25) B.C. Challisand S. A. Kyrtopoulos,Nitrosationunder alkalineconditions, J. Chem. Sac., Chem.Cammun.,877 (1976). (26) B.C. Challisand S. A. Kyrtopoulos, Rapidformationof carcinogenic N-nitrosamines in aqueous alkaline solutions, Br. J. Cancer,35,693 (1977). (27) B.C. Challis,A. Edwards, R. R. Hunma,S. A. Kyrtopoulos andJ. R. Outram,RapidFormation of NNitrosaminesfrom Nitrogen Oxides Under Neutral and Alkaline Conditions,in E. A. Walker, M. Castegnaro, L. Griciute and R. E. Lyle, "Environmental Aspects of N-Nitroso Compounds," IARC ScientificPublications no. 19, InternationalAgency for Research on Cancer,Lyon, France, 1978, pp
127-142.

(28) E. H. White, The chemistry of theN-alkyl-N-nitrosamides. I. Methodsof preparation, J. Amer.Chem. Sac., 77, 6008 (1955). (29) E. H. White and W. R. Feldman,The nitrosationand nitration of aminesand alcohols with nitrogen tetroxide,J. Amer.Chem. Sac.,79, 5832 (1957). (30) P. Gehlert and W. Rolle, Formationof diethylnitrosamine by reactionof diethylamine with nitrogen dioxidein the gasphase, Experientia, 33,579 (1977). (31) E. Boyland, The Effect of Some Ions of PhysiologicalInterest on Nitrosamine Synthesis,in P. Bogovski, R. Preussman andE. A. Walker, "N-Nitroso Compounds: Analysis andFormation," IARC ScientificPublicationsno. 3, International Agency for Researchon Cancer, Lyon, France, 1972, pp
124-126.

(32) E. Boyland,E. Nice and K. Williams,The catalysis of nitrosationby thiocyanate from saliva,Food Cosmet. TaxicoL, 9, 639 (1971). (33) T. . Fan and S. R. Tannenbaum,Factorsinfluencingthe rate of formation of nitrosomorpholine from morpholineand nitrite: acceleration by thiocyanate and other anions,J. Agr. Food Chem.,21,237
(1973).

(34) S.S. Mirvish, J. Sams,T. . Fan and S. R. Tannenbaum, Kinetics of nitrosationof the amino acids proline,hydroxyproline andsarcosine, J. Nat. Cancer Inst., 51, 1833 ( 1973). (35) F. Schweinsberg, Catalysis of NitrosamineSynthesis, in P. Bogovskiand E. A. Walker, "N-Nitroso Compounds in the Environment,"IARC ScientificPublications no. 9, InternationalAgency for Research on Cancer,Lyon, France,1974, pp 80-85. (36) D. L. H. Williams, S-Nitrosation of thiourea and thiocyanateion. Nitrosyl thiocyanateand the S-nitroso-adduct of thioureaasnitrosating agents, J. Chem. Sac. PerkinTrans. 2,128 (1977). (37) E. Boylandand S. A. Walker, ThiocyanateCatalysis of NitrosamineFormationand SomeDietary Implications,in P. Bogovskiand E. A. Walker, "N-Nitroso Compoundsin the Environment,"IARC ScientificPublicationsno. 9, International Agency for Researchon Cancer, Lyon, France, 1974, pp
132-136.

(38) E. KalatzisandJ. H. Ridd, Nitrosation,diazotization anddeamination. PartXII. The kinetics of N-nitrosation ofN-methylaniline,J. Chem. Soc., B, 529 (1966). (39) S.S. Mirvish, Kinetics of nitrosamide formation from alkylureas, N-alkylurethans,and alkylguanidines. Possible implications for the etiologyof humangastric cancer,J. Nat. Cancer Inst., 46, 1183
(1971).

(40) S.S. Mirvish, Kineticsof N-Nitrosation Reactions in Relation to Tumorigenesis Experiments with Nitrite Plus Amines or Ureas, in P. Bogovski,R. Preussmann and E. A. Walker, "N-Nitroso Compounds: Analysis and Formation,"IARC Scientific Publications no. 3, InternationalAgencyfor Research on Cancer,Lyon, France,1972, pp 104-108. (41) R. C. Weast,"Handbookof Biochemistry, Selected Data for MolecularBiology,"The Chemical Rubber Co., Cleveland, Ohio, 1968, p J131. (42) J. Tummavuoriand P. Lumme,Protolysis of nitrousacidin aqueous sodium nitrateandsodium nitrite solutions at different temperatures, ActaChem. Scand., 22, 2003 (1968). (43) J. D. Okun and M. C. Archer, Kineticsof nitrosamine formationin the presence of micelie-forming surfactants, J. Nat. Cancer Inst., 58,409 (1977). (44) J. D. Okun and M. C. Archer, Micellar Catalysis of NitrosamineFormation,in E. A. Walker, P. Bogovski and L. Griciute, "Environmental N-Nitroso Compounds: Analysis and Formation,"IARC

602

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Scientific Publications no. 14, International Agencyfor Research on Cancer,Lyon, France,1976, pp
147-152.

(45) M. C. Archer, H. S. Yang and J. D. Okun, Accelerationof Nitrosamine Formationat pH 3.5 by Microorganisms, in E. A. Walker, M. Castegnaro, L. Griciute and R. E. Lyle, "Environmental Aspects of N-Nitroso Compounds,"IARC ScientificPublicationsno. 19, International Agencyfor Research on Cancer,Lyon, France, 1978, pp 239-246. (46) L. K. Keefer andP. P. Roller, N-Nitrosation by nitrite ion in neutraland basic medium,Science, 181, 1245 (1973). (47) P. P. Roller and L. K. Keefer, Catalysisof Nitrosation Reactionsby ElectrophilicSpecies,in P. Bogovski and E. A. Walker, "N-Nitroso Compounds in the Environment," IARC Scientific Publicationsno. 9, InternationalAgencyfor Research on Cancer,Lyon, France, 1974, pp 86-89. (48) M. C. Archer, S. R. TannenbaumandJ. S. Wishnok, Nitrosamine Formationin the Presence of Carbonyl Compounds, in E. A. Walker, P. Bogovski and L. Griciute, "Environmental N-Nitroso Compounds: Analysis andFormation," IARC Scientific Publications no. 14, InternationalAgencyfor Research on Cancer,Lyon, France,1976, pp 141-146. (49) P. Gray andP. Rathbone,Dissociation of liquid dinitrogentetroxide;Henry'sLaw coefficients, heats and entropiesof solution,and the thermodynamics of homolyticdissociation in the pure liquid, J. Chem. Soc., 3550 (1958) show the following influence of solvent on equilibrium constant K (moles/L)= [NO212/[N204] at 20C.
Solvent
Gas Phase

K x 10 5
382

CC14 CHCIa C6H6

8.05 5.53 2.23

(50) S.S. Mirvish, K. Karlowski, J.P. Samsand S. D. Arnold, StudiesRelated to Nitrosamide Formation: Nitrosationin Solvent:Water andSolventSystems, NitrosomethylureaFormationin the Rat Stomach and Analysis of a Fish Productfor Ureas,in E. A. Walker, M. Castegnaro, L. Griciute and R. E. Lyle, "EnvironmentalAspectsof N-Nitroso Compounds,"IARC Scientific Publicationsno. 19, Interna-

tionalAgencyfor Research on Cancer, Lyon,France,1978, pp 161-174. (51) R. M. Angeles,L. K. Keefer, P. P. Roller and S. J. Uhm, Chemical Models for Possible Artifactual NitrosamineFormationin EnvironmentalAnalysis,in E. A. Walker, M. Castegnaro, L. Griciute and R. E. Lyle, "Environmental Aspectsof N-Nitroso Compounds," IARC ScientificPublicationsno. 19, InternationalAgencyfor Research on Cancer,Lyon, France,1978, pp 109-115. (52) C.L. Bumgardner, K. S. McCallum andJ.P. Freeman,Smallring heterocyclic nitrosamines, J. Amer. Chem. Soc., 83, 4417 (1961). (53) A.J. Buglass, B.C. Challisand M. R. Osborne,Transnitrosation and Decompositionof Nitrosamines, in P. Bogovskiand E. A. Walker, "N-Nitroso Compoundsin the Environment,"IARC Scientific Publications no. 9, International Agencyfor Research on Cancer,Lyon,France,1974, pp 94-100. (54) B.C. Challisand M. R. Osborne,The chemistry of nitrosocompounds. Part VI. Direct andindirect transnitrosation reactions ofN-nitrosodiphenylamine, J. Chem.Soc. PerkinTrans. 2, 1526 (1973). (55) S, S. Singer,W. Lijinsky and G. M. Singer,Transnitrosation by aliphaticnitrosamines, Tetrahedron Lett., 1613 (1977). (56) S.S. Singer,W. Lijinsky and G. M. Singer,Transnitrosation: An Important Aspectof the Chemistry of Aliphatic Nitrosamines, in E. A. Walker, M. Castegnaro,L. Griciute and R. E. Lyle, "Environmental Aspectsof N-Nitroso Compounds,"IARC ScientificPublicationsno. 19, International Agency for Researchon Cancer, Lyon, France, 1978, pp 175-181. (57) T. Y. Fan, R. Vita and D. H. Fine, C-Nitro compounds: a new class of nitrosatingagents, Toxicol, Lett., 2, 5(1978). (58) A.M. Unrau, Reactionof 2-methyl-2-nitro-l,3-propanediol, Can. J. Chem.,42, 1741 (1964). (59) J. J. Warthesen, R. A. Scanlan, D. D. Bills and L. M. Libbey, Formation of heterocyclic N-nitrosaminesfrom the reactionof nitrite and selected primary diaminesand aminoacids,J. Agric. FoodChem., 23,898 (1975). (60) S. Yanagida, D. J. Barsotti, G. W. Harrington and D. Swern, 2-Methyl-4-methoxy-l,2,3-oxadiazetidine. a correction, Tetrahedron Lett., 2671 (1973). (61) K. Eiter, K. F. Hebenbrok and H. J. Kabbe, Neue offenkettige und cyclische o-Nitrosaminoalkylither,Justus Liebigs Ann. Chem.,765, 55 (1972).

NITROSAMINE

CHEMISTRY

603

(62) J. T. Marshall,Jr. and L. R. Dugan,Jr., Carbonyl-aminereactionproductsasa possiblesourceof nitrosatable nitrogen,J. Agr. FoodChem., 23,975 (1975). (63) "Scientific and Technical AssessmentReport on Nitrosamines," U.S. Environmental Protection Agency,EPA-600/6-77-001, November, 1976. (64) D. Ziebarth, N-Nitrosation of Secondary Amines, and Particularlyof Drugs, in Buffer Solutionsand Human GastricJuice, in P. Bogovskiand E. A. Walker, "N-Nitroso Compoundsin the Environment," IARC Scientific Publications no. 9, InternationalAgencyfor Research on Cancer,Lyon, France,1974, pp 137-141. (65) W. Lijinsky, L. Keefer andJ. Loo, The preparationand propertiesof somenitrosaminoacids,Tetrahedron,26, 5137 (1970). (66) R. Bonnett and P. Nicolaidou,Nitrite and the environment--the nitrosationofc-aminoacid derivatives,Heterocycles, 7,637 (1977). (67) G.E. Hein, The reactionof tertiary amineswith nitrousacid,J. Chem.Educ.,40, 181 (1963). (68) P. A. S. Smith and H. G. Pars,Nitrosative cleavage of N',N'-dialkylhydrazides and tertiary amines,J. Org.Chem.,24, 1325 (1959). (69) P. A. S. Smith and R. N. Loeppky, Nitrosative cleavageof tertiary amines, J. Amer. Chem.Soc.,89, 1147 (1967). (70) W. Lijinsky, L. Keefer, E. Conrad and R. Van De Bogart, Nitrosation of tertiary aminesand somebiologicimplications, J. Nat. CancerInst., 49, 1239 (1972). (71) W. E. Bachmann and N. C. Deno, The nitrosation of hexamethylenetetramineand related compounds,J. Amer. Chem.Soc.,73, 2777 (1951). (72) W. Lijinsky, E. Conrad and R. Van De Bogart, Carcinogenic nitrosamines formed by drug/nitrite interactions,Nature, 239, 165 (1972). (73) W. Fiddler, J. W. Pensabene, R. C. Doerr and A. E. Wasserman, Formation of N-nitrosodimethylaminefrom naturally occurringquaternary ammonium compoundsand tertiary amines, Nature, 236, 307 (1972). (74) H. Ohshima and T. Kawabata,Mechanismof the N-Nitrosodimethylamine Formation from Trimethylamine and Trimethylaminoxide, in E. A. Walker, M. Castegnaro,L. Griciute and R. E. Lyle, "Environmental Aspectsof N-Nitroso Compounds," IARC Scientific Publicationsno. 19, International Agencyfor Researchon Cancer,Lyon, France, 1978, pp 143-153. (75) R. K. Elespuruand W. Lijinsky, The formation of carcinogenic nitroso compounds from nitrite and sometypesof agricultural chemicals, Food Cosmet. Toxicol., 11,807 (1973). (76) P. Gray and A.D. Yoffe, The reactivity and structure of nitrogen dioxide, Chem. Rev., 55, 1069
(1955).

(77) H. Dahn,L. Loewe andC. A. Bunton, Oberdieoxydation vonascorbinsiiure dutch salpetrige siiure.
Teil VI: ibersicht unddiskussion der ergebnisse, Helv.Chim.Acta, 43, 320 (1960). (78) S.S. Mirvish, A. Cardesa, L. Wallcaveand P. Shubik, Induction of mouselung adenomas by aminesor ureasplus nitrite and by N-nitroso compounds:effect of ascorbate, gallic acid, thiocyanateand caffeine, J. Nat. Cancer Inst., 55,633 (1975). (79) S.S. Mirvish, A. F. Pelfrene, H. Garcia and P. Shubik, Effect of sodiumascorbate on tumor induction in ratstreatedwith morpholineand sodiumnitrite, and with nitrosomorpholine, Cancer Letters, 2, 101 (1976). (80) M. Greenblatt, Ascorbicacid blocking of aminopyrine nitrosationin MZO/B1 mice, J. Nat. Cancer
Inst., 50, 1055 (1973). (81) J.J. Kamm, T. Dashman, A. H. Commey and A. J. Burns, The Effect of Ascorbateon Amine-Nitrite Hepatoxicity, in P. Bogovski and E. A. Walker, "N-Nitroso Compounds in the Environment," IARC ScientificPublicationsno. 9, International Agency for Researchon Cancer, Lyon, France, 1974, pp
200-204.

(82) J. J. Kamm, T. Dashman, A. H. Commey and A. J. Burns, Protective effect of ascorbicacid on hepatoxicity caused by nitrite plusaminopyrine, Proc. Nat. Acad.Sci.USA, 70, 747 (1973). (83) Y. Y. Fongand W. C. Chan, Effect of Ascorbateon Amine-Nitrite Carcinogenicity, in E. A. Walker, P. BogovskiandL. Griciute, "Environmental N-Nitroso Compounds: Analysis and Formation,"IARC

Scientific Publications no. 14, International Agencyfor Research on Cancer, Lyon,France,1976, pp

461-464.

(84) V. A. Kinawi, D. Doting and I. Witte, Reaktionkinetischeuntersuchungen zur entstehungvon 7-chlor-2-N-nitrosomethylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxid, Arzneim.-Forsch., 27, 747
(1977).

(85) N. Preda, L. Popa, V. Galea and G. Simu, N-Nitroso-compound Formation byChlordiazepoxide and
Nitrite InteractionIn Vitro and In Vivo: ProtectiveAction of AscorbicAcid, in E. A. Walker, P.

604

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Bogovskiand L. Griciute, "Environmental N-Nitroso Compounds: Analysisand Formation,"IARC ScientificPublications no. 14, InternationalAgencyfor Research on Cancer,Lyon, France,1976, pp
301-304.

(86) A. Cardesa,S.S. Mirvish, G. T. Haven and P. Shubik,Inhibitory effect of ascorbic acidon the acute toxicityof dimethylamine plusnitrite in the rat, Proc. Soc. Exp.Biol. Med., 145,124 (1974). (87) T. Kawabata,H. Shazukiand T, Ishibashi, N-Nitroso compounds in food. VIII. effectofascorbic acid on the formationof N-nitrosodimethylamine in vitro,NipponSuisan Gakkaishi,40, 1251 (1974). (88) S. Ivankovic,R. Preussmann, D. Schmihl andJ. W. Zeller, Preventionby AscorbicAcid of In Vivo Formation of N-Nitroso Compounds,in P. Bogovski and E. A. Walker, "N-Nitroso Compoundsin the Environment,"IARC ScientificPublications no. 9, International Agency for Research on Cancer, Lyon,France,1974, pp 101-102. (89) M. C. Archer, S. R. Tannenbaum,T. Y. Fan and M. Weisman, Reaction of nitrite with ascotbate and its relation to nitrosamineformation,J. Nat. Cancer Inst., 54, 1203 ( 1975),' (90) T. Y. Fan and S. R. Tannenbaum,Natural inhibitorsof nitrosationreactions. conceptof available nitrite, J. FoodSci., 38, 1067 (1974). (91) N. P. Sen and B. Donaldson, The Effect of AscorbicAcid and Glutathione on the Formationof Nitrosopiperazines from PiperazineAdipate and Nitrite, in P. Bogovskiand E. A. Walker, "N-Nitroso Compounds in the Environment,"IARC ScientificPublications no. 9, InternationalAgencyfor Research on Cancer,Lyon, France,1974, pp 103-106. (92) N. P. Sen, B. Donaldson,S. Seaman, J. R. Iyengar and W. F. Miles, Inhibition of nitrosamineformation in fried bacon by propylgallateandL-ascorbyl palmirate, J. Agric.Food Chem., 24, 397 (1976). (93) J. I. Gray andL. R. Dugan,Jr., Inhibitionof N-nitrosamineformationin modelfoodsystems, J. Food Sci., 40, 981 (1975). (94) N. P. Sen, B. Donaldson, C. Charbonneau and W. F. Miles, Effect of additives on the formation of nitrosamines in meat curingmixturescontaining spices and nitrites, J. Agric.Food Chem.,22, 1125 (1974). (95) S.S. Mirvish, L. Wallcave, M. Eagen and P. Shubik, Ascotbate-nitrite reaction: Possiblemeans of blockingthe formationof carcinogenic N-nitroso compounds, Science, 177, 65 (1972). (96) D. Ziebarth and G. Scheunig, Effect of Some Inhibitors on the Nitrosation of Drugs in Human GastricJuice,in E. A. Walker, P. BogovskiandL. Griciute, "Environmental N-Nitroso Compounds: Analysisand Formation,"IARC ScientificPublications no. 14, International Agency for Researchon Cancer,Lyon, France,1976, pp 279-290. (97) S.S. Mirvish, Blocking the formation of N-nitroso compounds with ascorbic acidin vitro and in vivo, Ann. N.Y. Acad.Sci., 258 (Conf. Vitam. C. 2nd), 175 (1975). (98) B.C. Challis,Rapid nitrosationof phenolsandits implications for healthhazards from dietarynitrite, Nature, 244, 466 (1973). (99) B. Pignatelli, M. Castegnaroand E. A. Walker, Effects of Gallic Acid and of Ethanol on Formation of Nitrosodiethylamine, in E. A. Walker, P. BogovskiandL. Griciute, "Environmental N-Nitroso Compounds:Analysisand Formation," IARC ScientificPublicationsno. 14, InternationalAgencyfor Research on Cancer,Lyon, France,1976, pp 173-178. (100) E. A. Walker, B. Pignatelli andM. Castegnaro, Effectsof gallicacidon nitrosamine formation, Nature, 258, 176 (1975). (101) B. D. Astill and L. T. Mulligan, Phenolic autoxidantsand the inhibition of hepatotoxicity from N-dimethylnitrosamine formedin situin the rat stomach, Food Cosmet. Toxicol.,15, 167 (1977). (102) J. J. Kamm, T. Dashman,H. Newmark and W. J. Mergens, Inhibition of amine-nitritehepatotoxicity byo-tocopherol, Toxicol. Appl. Pharmacol., 41,575 (1977). (103) W. J. Mergens,J. J. Kamm, H. L. Newmark, W. Fiddler andJ. Pensabene, Alpha-Tocopherol:Usesin Preventing Nitrosamine Formation, in E. A. Walker, M. Castegnaro,L. Griciute and R. E. Lyle, "EnvironmentalAspectsof N-Nitroso Compounds,"IARC ScientificPublications no. 19, International Agencyfor Research on Cancer,Lyon, France,1978, pp 199-212. (104) B.C. Challisand C. D. Bartlett, Possible carcinogenic effectsof coffee constituents, Nature, 254, 532
(1975). (105) R. Davies, M. J. Dennis, R. C. Masseyand D. J. McWeeny, Some Effects of Phenol- and Thiol-

nitrosationReactionson N-Nitrosamine Formation,in E. A. Walker, M. Castegnaro, L. Griciute and R. E. Lyle, "EnvironmentalAspectsof N-Nitroso Compounds,"IARC ScientificPublications no. 19, InternationalAgencyfor Research on Cancer,Lyon, France,1978, pp 183-197. (106) I. C. Hisatune, Thermodynamicpropertiesof some oxides of nitrogen, J. Phys.Chem.,65, 2249 (1961).

NITROSAMINE

CHEMISTRY

605

(107) K. Jones, The Chemistry of Nitrogen, in J. C. Bailar, Jr., H. J. Emelus, R. Nyholm and A. F.

(108)

(109)

(110)
(111) (112)

(113)

(114)

Trotman-Dickenson,"Comprehensive InorganicChemistry,"Volume 2, PergamonPress,New York, New York, 1973, Chapter 19, pp 372-374. F. Schweinsbergand P. Schott-Kollaf, Effect of Vitamin A on Formation, Toxicity and Carcinogenicity of Nitroso-N-methylbenzylamine,in E. A. Walker, P. Bogovski and L. Griciute, "Environmental N-Nitroso Compounds: Analysis and Formation," IARC Scientific Publications no. 14, InternationalAgencyfor Researchon Cancer,Lyon, France,1976, pp 453-459. C. Catoni,M. A. BianchiandG. Beretta,(Incomplete)Ind. Ailment., 13, 118 (1974). T. Moeller, "InorganicChemistry,"Wiley, New York, New York, 1952, p 615. I. D. Biggsand D. L. H. Williams, Kineticsand mechanism of the Fischer-Hepprearrangement and denitrosation.part V. the mechanism ofdenitrosation,J. Chem.Soc. Perkin Trans., 2, 107 (1975). D. L. H. Williams, Kinetics and mechanism of the Fischer-Hepprearrangement and denitrosation. part VI. the relative reactivity of a number of nitrogen containing speciestoward nitrosation and further evidenceagainstan intermolecularmechanismfor the rearrangement,J. Chem.Soc. Perkin Trans. 2,655 (1975). J. T. Thompsonand D. L. H. Williams,Direct nitrosationof anilinederivatives andother nucleophilic species by N-nitrosodiphenylamine. J. Chem. Soc. PerkinTrans. 2, 1932 (1977). G. Eisenbrand and R. Preussman, Eine neue methode zur kolorimetrische bestimmung yon nitrosaminennach spaltungder N-nitrosogruppe mit bromwasserstoff in eisessig, Arzneim.-Forsch.,
20, 1513 (1970).

(115) J. Polo and Y. L. Chow, Efficient Degradation of Nitrosamines by Photolysis,in E. A. Walker, P.

(116)
(117)

(118) (119)

Bogovski and L. Griciute, "EnvironmentalN-Nitroso Compounds:Analysisand Formation," IARC Scientific Publicationsno. 14, International Agency for Researchon Cancer, Lyon, France, 1976, pp 473-486. J. Polo and Y. L. Chow, Efficient photolyricdegradationof nitrosamines, J. Nat. CancerInst., 56, 997 (1976). A. L. Fridman, F. M. Mukhametshin and S.S. Novikov, Advances in the chemistry of aliphatic Nnitrosamines, Russ. Chem. Rev.Eng.Transl., 40, 34 ( 1971). S. D. Gangolli, W. H. Shillingand A. G. Lloyd, A method for the destructionof nitrosamines in solution, FoodCosmet. Toxico/.,12, 168 (1974). N. T. Crosby and R. Sawyer,N-Nitrosamines: A Review of Chemical and Biological Properties and
Their Estimation in Foodstuffs, in C. O. Chichester, "Advances in Food Research," Vol. 22, Academic

Press,New York, New York, 1976, pp 1-56.

(120) R. Preussmann and F. Schaper-Druckrey,Investigationof a Colorimetric Procedurefor Determina-

tion of Nitrosamidesand Comparison with Other Methods, in P. Bogovski,R. Preussmann andE. A. Walker, "N-Nitroso Compounds: Analysis and Formation," IARC Scientific Publications no. 3, InternationalAgencyfor Research on Cancer,Lyon, France,1972, pp 81-86. (121) B.C. Challis and S. P. Jones,The chemistryof nitroso-compounds. Part IX. General acid catalysed decomposition of N-nitroso-2-pyrrolidone,an exampleof amidehydrolysis via SN2displacement on the N-conjugate acid,J. C hem.Soc. Perkin Trans. 2,153 (1975). (122) T.J. Lobl, The chemistry of nitrosamides, J. Chem.Educ.,49, 730 (1972). (123) W. Lijinsky,Instabilityof N-nitrosamides,Science, 183, 368 (1974). (124) T. P. Johnston, C. L. Kussner andLB. Holum, Synthesis of potentialanticancer agents. XXI. Nitrosated sulfonamides relatedto myleran, J. Org.Chem.,25,399 (1960). (125) H. Bassow,"Air Pollution Chemistry. An Experimenter's Sourcebook," Hayden Book Company, Rochelle Park, New Jersey,1976, p 60. 126) B. SharmaandR. C. Ahler, Nitrification and nitrogenremoval,WaterResearch, 11,897 (1977).
Editor's Note:

With the acceptance of thisreviewarticle,the JournaloftheSociety ofCosmetic Chemists inaugurates the review sectionof the Journal.We are especially appreciative andindebtedto the Cosmetic, Toiletry and Fragrance Association for granting the authors permission to publishthis articlein ourJournal. Review articlesare solicitedby special invitation from the Editor and Editorial Committee and are not subject to reviewby the EditorialCommittee. The Journal intends to continue publication of review
articles of this nature.

JohnJ. Sciarra, Ph.D.

Editor

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,

New

York

10017

Library hours are:

Monday through Friday 9 a.m. to 4 p.m.

Holidays: Closed