N-Nitroso Compounds - ACS Publications - American Chemical Society

10 Formation and Inhibition of N-Nitrosodiethanolamine in an Anionic Oil-Water Emulsion B. L. KABACOFF—Revlon Research Center, Incorporated, 945 Zerega Avenue, Bronx, NY 10473 1

R. J. LECHNIR and S. F. VIELHUBER—Raltech Scientific Services, P.O. Box 7545, Madison, WI 53707 Downloaded by YORK UNIV on June 2, 2018 | https://pubs.acs.org Publication Date: December 9, 1981 | doi: 10.1021/bk-1981-0174.ch010

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M. L. DOUGLASS—Colgate Palmolive Company, 909 River Road, Piscataway, NJ 08854 The effect of various types of inhibitors with res pect to structure and solubility on the formation of N-Nitrosodiethanolamine was studied in a prototype oil in water anionic emulsion. Nitrosation resulted from the action of nitrite on diethanola mine at pH 5.2-5.4. Among the water soluble inhibi

tors incorporated into the aqueous phase, sodium bi

sulfite and ascorbic acid were effective. Potassium sorbate was much less so. The o i l soluble inhibitors were incorporated into the o i l phase of the emulsion. Of these, only ascorbyl palmitate was effective. Butylated hydroxyanisole and α-tocopherol were not. It was found that when α-tocopherol was dispersed in the aqueous phase in absence of the o i l , nitrite was readily destroyed. It was concluded that the reduced inhibition obtained with butylated hydroxy anisole and α-tocopherol was at least in part due to their isolation from the nitrite in water phase. On the other hand, the reducing portion of the ascorbyl palmitate molecule could be in the water phase at the oil/water interface. During the three years since trace levels of N-Nitrosodi ethanolamine (NDE1A) were reported (1) in some cosmetic products, the Cosmetic, Toiletry and Fragrance Association's Nitrosamine Task Force has conducted several research programs to determine its sources. In one, analytical methods were developed for de termination of NDE1A and nitrite in many widely used cosmetic ingredients. No significant NDE1A contamination of the major product ingredients was found (2,3). Such a result suggests that the nitrosamine contamination of some products results from in situ formation during manufacture or storage. 1

The authors represent the Nitrosamine Task Force of the Cosmetic, Toiletry, and Fragrance Association, 1110 Vermont Avenue NW, Washington, DC 20005 0097-6156/81/0174-0149$05.00/0

© 1981 American Chemical Society Scanlan and Tannenbaum; N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

Downloaded by YORK UNIV on June 2, 2018 | https://pubs.acs.org Publication Date: December 9, 1981 | doi: 10.1021/bk-1981-0174.ch010

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A r e s e a r c h program i n p r o g r e s s a t R a l t e c h S c i e n t i f i c S e r v i c e s i s designed to f i n d i n h i b i t o r s which w i l l prevent nitrosamine formation i n cosmetic products. A r e v i e w o f t h e l i t e r a t u r e (A) i n d i c a t e d t h a t t h e o i l p h a s e o f e m u l s i o n s may p l a y a n i m p o r t a n t role i n nitrosation chemistry. Thus, r e s u l t s from s t u d i e s i n w a t e r a l o n e c o u l d be m i s l e a d i n g when r e d u c e d t o p r a c t i c e . E v i d e n c e e x i s t s t h a t t h e r e l a t i v e s o l u b i l i t y o f a m i n e s and i n h i b i t o r s i n h e t e r o g e n e o u s o i l - w a t e r s y s t e m s c o u l d be d e c i s i v e in f o r m a t i o n o f n i t r o s a m i n e s and b l o c k i n g t h e s e reactions. Nitrosopyrrolidine formation in bacon predominates in the adipose t i s s u e despite the f a c t that i t s precursor, p r o l i n e , predominates i n the l e a n t i s s u e ( 5 , 6 , 7 ) . M o t t r a m and P a t t e r s o n (8) p a r t l y a t t r i b u t e t h i s phenomenon t o t h e f a c t t h a t the adipose tissue furnishes a medium i n w h i c h n i t r o s a t i o n is favored. Massey, e t a l . (9) found t h a t t h e presence o f decane i n a model heterogeneous system caused a 2 0 - f o l d i n c r e a s e i n r a t e o f n i t r o s a m i n e f o r m a t i o n from l i p o p h i l i c d i h e x y l a m i n e , but had no effect on n i t r o s a t i o n of hydrophilic pyrrolidine. A s c o r b i c a c i d i n t h e p r e s e n c e o f d e c a n e enhanced t h e s y n t h e s i s o f n i t r o s a m i n e s f r o m l i p o p h i l i c a m i n e s , b u t had no e f f e c t o n n i t r o s a t i o n o f p y r r o l i d i n e . The o i l - s o l u b l e i n h i b i t o r a s c o r b y l p a l m i t a t e h a d l i t t l e i n f l u e n c e on t h e f o r m a t i o n o f n i t r o s a m i n e s i n the presence o r absence o f decane. As i n t h e c a s e o f f o o d s and o t h e r consumer p r o d u c t s , n i t r i t e s h a v e been f o u n d i n c o s m e t i c raw m a t e r i a l s ( 3 ) . O t h e r p o t e n t i a l n i t r o s a t i n g s p e c i e s h a v e n o t been r e p o r t e d i n t h e s e s u b s t a n c e s . In view o f these o b s e r v a t i o n s , the r e a c t i o n media chosen f o r the present study are c o s m e t i c - r e l a t e d emulsion systems c o n t a i n i n g b o t h o i l - s o l u b l e and w a t e r - s o l u b l e s e c o n d a r y a m i n e s a n d blocking agents. N i t r i t e was c h o s e n a s t h e n i t r o s a t i n g a g e n t . T h i s p a p e r r e p o r t s i n i t i a l r e s u l t s on t h e n i t r o s a t i o n o f t h e w a t e r - s o l u b l e amine d i e t h a n o l a m i n e ( D E A ) , c h o s e n b e c a u s e o f i t s u b i q u i t o u s presence i n cosmetic products. I n h i b i t i o n o f NDE1A f o r m a t i o n by a s e l e c t g r o u p o f w a t e r - and o i l - s o l u b l e i n h i b i t o r s i n a n o i l - i n - w a t e r e m u l s i o n s t a b i l i z e d by a n a n i o n i c s u r f a c t a n t is described. The n i t r o s a t i o n o f a n o i l - s o l u b l e amine a n d t h e e f f e c t s o f n i t r o s a t i o n b l o c k i n g agents i n emulsion systems w i l l be t h e s u b j e c t o f a f u t u r e p a p e r . Experiment

Procedures

Composition o f Emulsion. The p r o t o t y p e o i l / w a t e r e m u l s i o n described i n Table I contained ingredients t y p i c a l o f a l a r g e number o f c o s m e t i c p r o d u c t s , a l t h o u g h s i m p l i f i e d somewhat t o a v o i d a n a l y t i c a l problems. The aqueous p h a s e c o n t a i n e d s o d i u m l a u r y l s u l f a t e ( S L S ) a s e m u l s i f i e r , 0.2% (19 mM) DEA a s p r e c u r s o r t o NDE1A and 0.1% b e n z o i c a c i d a s p r e s e r v a t i v e . The o i l p h a s e i n c l u d e d a f a t t y a c i d , a f a t t y a l c o h o l a n d hydrocarbons. The e m u l s i o n h a d a pH o f 5.1 t o 5 . 4 , e x h i b i t e d e m u l s i o n and pH s t a b i l i t y a t 3 7 ° f o r a t l e a s t 21 d a y s , and was shown t o be a n o i l - i n - w a t e r t y p e b y b e i n g r e a d i l y d i s p e r s i b l e i n w a t e r and by i t s u p t a k e o f a w a t e r - s o l u b l e d y e . In i n h i b i t i o n

Scanlan and Tannenbaum; N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

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and p o s i t i v e c o n t r o l e x p e r i m e n t s s o d i u m n i t r i t e was added a t a l e v e l o f 10 ppm ( 0 . 2 1 7 mM) N02- T h u s , n i t r i t e was t h e l i m i t i n g r e a g e n t g i v i n g a t h e o r e t i c a l NDE1A y i e l d o f 29 ppm. Table

I

0/W E m u l s i o n C o m p o s i t i o n


Aqueous P h a s e

O i l Phase

1

1% S o d i u m L a u r y l S u l f a t e

2% C e t y l

2 3 4

2% DEA 1% B e n z o i c A c i d 94.7% W a t e r

1% P a r a f f i n O i l 1% S t e a r i c A c i d

Alcohol

Preparation of Emulsions. The e n t i r e a q u e o u s p h a s e was s t i r r e d u n t i l a l l s o l i d s were d i s s o l v e d . S u f f i c i e n t w a t e r was w i t h h e l d from the f o r m u l a t i o n so s m a l l volumes o f e x p e r i m e n t a l and c o n t r o l components c o u l d be added t o e m u l s i o n s u b s a m p l e s . S u l f u r i c a c i d (1 N) was added t o t h e a q u e o u s p h a s e t o d e c r e a s e t h e pH t o 5 . 7 . The two p h a s e s i n s e p a r a t e c o n t a i n e r s were b l a n k e t e d w i t h n i t r o g e n , s e a l e d , and h e a t e d t o 7 5 ° i n a n 8 0 ° w a t e r b a t h ( a b o u t 30 m i n u t e s ) . The h o t o i l p h a s e was s t i r r e d s l o w l y and b l a n k e t e d w i t h n i t r o g e n , t h e n t h e h o t a q u e o u s p h a s e was q u i c k l y added w h i l e s t i r r i n g . The e m u l s i o n was b l a n k e t e d with nitrogen and slowly stirred (about 2 hours) in the s t o p p e r e d c o n t a i n e r u n t i l a m b i e n t t e m p e r a t u r e ( ^ 2 5 ° ) was r e a c h e d . S u b s a m p l e s o f t h e m a s t e r b a t c h w e r e removed f o r t h e a d d i t i o n o f e x p e r i m e n t a l components a n d s t o r e d i n 1-oz c o n t a i n e r s . The c o n t a i n e r s h a d b e e n washed w i t h h o t t a p w a t e r , d e i o n i z e d w a t e r , and m e t h a n o l , t h e n d r i e d a t 1 2 0 ° . I n experiments w i t h w a t e r - s o l u b l e i n h i b i t o r s , the subsample was s t i r r e d u n d e r n i t r o g e n d u r i n g p o s t - a d d i t i o n o f a n a q u e o u s s o l u t i o n o f the i n h i b i t o r f o l l o w e d by an aqueous sodium n i t r i t e solution. A l i q u o t s w e r e w e i g h e d i n t o 1-oz o i n t m e n t j a r s , c o v e r e d w i t h n i t r o g e n , s e a l e d , and s t o r e d a t 3 7 ° f o r l a t e r replicate analyses. P r e p a r a t i o n o f t h e p o s i t i v e c o n t r o l s u b s a m p l e was i d e n t i c a l e x c e p t t h a t w a t e r was added i n p l a c e o f i n h i b i t o r . Since p o s t - a d d i t i o n o f o i l - s o l u b l e i n h i b i t o r s would not a s s u r e t h e i r presence i n the o i l phase o f the e m u l s i o n , s e p a r a t e e m u l s i o n s were p r e p a r e d . E a c h i n h i b i t o r was a d d e d t o t h e o i l p h a s e o f e a c h e m u l s i o n b e f o r e h e a t i n g and c o m b i n i n g t h e w a t e r and o i l p h a s e s . Theref o r e , p o s i t i v e c o n t r o l s c o n t a i n i n g no i n h i b i t o r c o u l d n o t be made f r o m t h e same b a s e e m u l s i o n . Instead, a separate emulsion batch r u n s i m u l t a n e o u s l y was u s e d a s a p o s i t i v e c o n t r o l . I n t h e f i r s t s e t o f e x p e r i m e n t s , i t was f o u n d t h a t two o u t o f t h e t h r e e o i l s o l u b l e i n h i b i t o r s had l i t t l e e f f e c t on the amount o f NDE1A f o r m e d . I t was c o n s i d e r e d p o s s i b l e t h a t t h e s e h a d b r o k e n down d u r i n g h e a t i n g a t 7 5 ° . To r u l e o u t t h i s p o s s i b i l i t y , t h e o i l - s o l u b l e i n h i b i t o r s w e r e added t o t h e o i l p h a s e


152

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when the temperature had been lowered to about 52°. The two phases were then mixed as described above. No appreciable d i f ference was observed i n the degree of i n h i b i t i o n and the results are pooled i n Table I I I . Analytical Method. Three grams of emulsion were weighed into a tared test tube containing 300 \xL of 10% ammonium s u l f a mate, and the sample was immediately mixed with a vortex-type shaker. Ten percent calcium chloride (300 \xh) was added and the sample was mixed, heated to 50° f o r 5 minutes, and mixed again. After being cooled to room temperature, the sample was f i l t e r e d through glass wool to remove calcium sulfate and calcium stéarate. Anion exchange was used to remove benzoic acid from the extracts. A 1.5-cm Pasteur pipette column to Biorad X-1 (hydroxide form, 100 - 200 mesh) was slurry packed. One m i l l i l i t e r of extract was passed through the column followed by two 0.5-mL washed with M i l l i - Q water. The NDE1A content of these extracts was determined by HPLC using a Zorbax (DuPont) octadecyl silane column and a UV detector at 237 nm and using M i l l i - Q water as c a r r i e r solvent at 1.0 mL/min. Validation assays f o r the extraction and quantitation of added NDE1A from the emulsion were conducted. The range of r e coveries at NDE1A levels of 0.3, 1.0, 3.0, 10.0, and 30.0 ppm (4-6 replicates at each level) was 94%-102% with a mean of 98%. The coefficient of variation at each l e v e l f e l l between 2% and 7% with a mean of 4%. Experimental Results. The i n h i b i t i o n of NDE1A formation after 16 days at 37° f o r three water-soluble and three o i l - s o l u b l e i n h i b i t o r s i s displayed i n Tables I I and I I I , respectively. So that r e l a t i v e effectiveness could be compared, the concentration of each i n h i b i t o r was chosen to provide an i n h i b i t o r / n i t r i t e mole r a t i o = 10. Each i n h i b i t o r was tested i n two separate emulsion batches with two or more aliquots analyzed. The data shown f o r positive controls are from similar replicate experiments. Table I I Water Soluble Inhibitors (10 Molar Excess*) Inhibitor

Ascorbic Acid

NDE1A Produced i n 16 days at 37°C Without Inhibitor With Inhibitor ppm SD Ν ppm SD Ν

3.00 .04 3.42 .14 K. Sorbate .10 3.91 3.00 .04 Na B i s u l f i t e .01 3.91 3.00 .04 * Based on n i t r i t e present

2 2 3 2 3 2

0.57 0.81 2.23 2.39 0 0.01

.30 .04 .10 .03 0 .01

2 4 3 3 3 3

Inhibition ΊΕ SD 79

3

32

16

100

—


10.

KABACOFF E T AL.

N~Nitrosodiethanolamine Table

O i l Soluble Inhibitors Inhibitor

3.27 2.89 Alpha Tocopherol 3.37


3.00·· 2.74 3.00»

.12 .13 .19 .04 .17 .04

5 5 5 2 5 2

153

Emulsion

III (10 M o l a r E x c e s s * )

NDE1A P r o d u c e d i n 16 Days a t 3 7 ° C Without I n h i b i t o r With I n h i b i t o r ppm SD Ν ppm SD Ν

BHA

Ascorbyl Palmitate

in Oil-Water

.28 .14 .11 .79 .16 .02

3.00 2.19 3.17 2.74 0.47 0.09

Inhibition % SET

5 5 5 4 5 3

* Emulsion without i n h i b i t o r run just p r e v i o u s l y . * * C a l c u l a t e d v a l u e i s 8% i n h i b i t i o n b u t v a l u e o b t a i n e d statistically significant.

16

11

0**

—

90

10

is

not

I n h i b i t i o n o f NDE1A f o r m a t i o n a f t e r 16 d a y s a t 3 7 ° b y a s c o r b i c a c i d was e x a m i n e d more e x t e n s i v e l y a t a s c o r b i c a c i d / n i t r i t e m o l e r a t i o s = 0 . 1 , 0 . 2 5 , 0 . 5 , 1 . 0 , 5 . 0 , and 1 0 . 0 . F i g u r e 1 shows t h a t a l i n e a r r e l a t i o n s h i p e x i s t s b e t w e e n l o g NDE1A f o r m e d and a s c o r b i c a c i d / n i t r i t e mole r a t i o s o v e r the range 0 - 5 . However, the t r e n d was reversed at mole ratio = 10, where inhibition was s i g n i f i c a n t l y l e s s than at r a t i o = 5. T h i s i s shown b y t h e f o l l o w i n g d a t a o b t a i n e d f r o m e x p e r i m e n t s where e a c h ascorbic acid level was t e s t e d i n two e m u l s i o n b a t c h e s : Ascorbic Acid/ N i t r i t e Mole Ratio Batch 5 5 10 10

1 2 1 2

Mean % Inhibition 90.5 92.4 76.3 81.2

Ν 4 2 3 2

SEM 0.61 1.55 0.57 8.05

Discussion The c r i t e r i a f o r c h o o s i n g i n h i b i t o r s i n t h i s s t u d y w e r e t h e a b i l i t y t o compete w i t h d i e t h a n o l a m i n e f o r t h e n i t r i t e and l a c k of t o x i c i t y . An a t t e m p t was made t o c o v e r a s b r o a d a g r o u p a s p o s s i b l e w i t h i n the l i m i t s o f f e a s i b i l i t y . A s c o r b i c a c i d i n i t s w a t e r s o l u b l e f o r m and i t s o i l s o l u b l e f o r m , t h e p a l m i t a t e , r e p r e s e n t the e n e d i o l s . Sorbate i s a diene f a t t y a c i d which has b e e n shown t o i n h i b i t n i t r o s a t i o n ( 1 0 ) . S i n c e t h e pK o f s o r b i c a c i d i s 4 . 7 6 , a t t h e pH o f t h e s e e x p e r i m e n t s , b o t h w a t e r s o l u b l e s o r b a t e i o n and o i l s o l u b l e s o r b i c a c i d a r e p r e s e n t i n s i g n i f i c a n t amounts. Sodium b i s u l f i t e i s a s t r o n g i n o r g a n i c r e d u c i n g agent w h i c h has an a c c e p t a b l e l a c k o f t o x i c i t y a t the c o n c e n t r a t i o n


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N-NITROSO COMPOUNDS

Figure 1.

Effect of ascorbic acid on N DELA

formation.



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used h e r e . Two p h e n o l s w h i c h a r e f r e q u e n t l y u s e d a s a n t i o x i d a n t s a r e i n c l u d e d , BHA a n d α - t o c o p h e r o l . N e i t h e r o f t h e s e have open para p o s i t i o n s , the presence o f which can l e a d to c a t a l y s i s ( 4 ) . S t u d i e s h a v e shown t h a t one o f t h e i n h i b i t o r s , a s c r o b i c a c i d , may c a t a l y z e n i t r o s a t i o n ( 1 1 , 1 2 ) e s p e c i a l l y a t h i g h c o n c e n t r a tions (13). In the present study, the i n h i b i t o r y e f f e c t o f a r a n g e o f c o n c e n t r a t i o n s was i n v e s t i g a t e d . Between a mole r a t i o o f a s c o r b a t e t o n i t r i t e o f z e r o t o 5 : 1 , t h e r e was a n inverse l i n e a r r e l a t i o n s h i p between t h e a s c r o b a t e c o n c e n t r a t i o n and t h e l o g o f NDE1A f o r m e d ( F i g u r e 1 ) . A t a mole r a t i o o f 1 0 : 1 , t h e degree o f i n h i b i t i o n decreased s i g n i f i c a n t l y . Conceivably at s t i l l h i g h e r c o n c e n t r a t i o n s , c a t a l y s i s may o c c u r . The a s c o r b a t e e f f e c t on n i t r o s a t i o n i s s t i l l q u i t e u n c l e a r and s h o u l d be i n vestigated further, because o f the frequency o f i t s use in blocking this reaction. Sodium b i s u l f i t e gave e s s e n t i a l l y complete p r o t e c t i o n a g a i n s t NDE1A f o r m a t i o n and t h u s was s u p e r i o r t o t h e o t h e r i n h i b i t o r s i n this regard. However, i t s s t r o n g r e d u c i n g p r o p e r t i e s as w e l l as i t s r e a c t i v i t y w i t h c a r b o n y l compounds f o u n d i n f r a g r a n c e s may m i l i t a t e a g a i n s t i t s u s e i n some c o s m e t i c p r o d u c t s . Three o f t h e b l o c k i n g a g e n t s showed p o o r i n h i b i t i o n , p o t a s s i u m s o r b a t e a n d t h e l i p o p h i l i c i n h i b i t o r s , BHA a n d α - t o c o p h e r o l . The p o o r r e s u l t s w i t h t h e two p h e n o l s w e r e u n e x p e c t e d i n view o f t h e i r e f f e c t i v e n e s s as a n t i o x i d a n t s i n e m u l s i o n s . R. S t a d n i c k and A . G o v i l i n v e s t i g a t e d t h e e f f e c t o f α - t o c o p h e r o l i n a system i d e n t i c a l t o t h a t used i n the present study except f o r t h e absence o f t h e o i l phase ( 1 4 ) . They f o u n d t h a t a f t e r i n c u b a t i o n f o r 90 h o u r s , t h e r e c o v e r y o f n i t r i t e i n t h e p r e s e n c e o f α - t o c o p h e r o l was h a l f t h a t o b s e r v e d i n i t s a b s e n c e . Since α-tocopherol destroys nitrite in the system in absence of the oil phase, we may postulate that the i n e f f e c t i v e n e s s o f t h e s e two o i l s o l u b l e i n h i b i t o r s r e s u l t e d from t h e i r absence from t h e aqueous p h a s e . Diethanolamine i s m i s c i b l e w i t h w a t e r and p r e s u m a b l y i t s n i t r o s a t i o n o c c u r s i n t h e aqueous phase. There i s a s i g n i f i c a n t d i f f e r e n c e in the s o l u b i l i t y characteristics of ascorbyl palmitate. The r e d u c i n g p o r t i o n o f the molecule i s water s o l u b l e . Thus t h e ascorbate m o i e t y may be i n t h e a q u e o u s p h a s e w h i l e t h e f a t t y a c i d t a i l s may l i e w i t h i n t h e o i l g l o b u l e s . The α - t o c o p h e r o l a n d t h e BHA may w e l l be e f f e c t i v e i f t h e y a r e d i s p e r s e d i n t h e aqueous p h a s e a f t e r p r e p a r a t i o n o f t h e e m u l s i o n . T h i s w i l l be i n v e s t i g a t e d i n future experiments. Acknowledgements. The a u t h o r s e x p r e s s t h e i r g r a t i t u d e t h e t e c h n i c a l c o n t r i b u t i o n s o f D r s . M . Goodman, A . C o o p e r , I . E . Rosenberg. Literature

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Fan, T.Y.; Goff, U.; Song, L.; Fine, D.H.; Arsenault, G.P.; Biemann, K. Food Cosmet. Toxicol. 1977,15.,423-430.


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CTFA F i n a l Report on Midwest Research I n s t i t u t e Program f o r Development of Analytical Methods f o r NDE1A Using HPLC-TEA, Determination of " N i t r i t e s " , Determination of NDE1A by a non-TEA Method. July 10, 1980. Cosmetic, Toiletry and Fragrance Association, Inc., 1110 Vermont Avenue, N.W., Washington, D.C. 20005. 3. "Analysis of Cosmetic Ingredients f o r N i t r i t e s , " by Raltech S c i e n t i f i c Services. Available from the Cosmetic, T o i l e t r y and Fragrance Association, Inc. 4. Douglass, M.L.; Kabacoff, B.L.; Anderson, G.A.; Cheng, M.C. J . Soc. Cosmet. Chem. 1978, 29, 581-606. 5. Gough, T.A.; Goodhard, K.; Walter, C.L. S c i . Fd. Agric. 1976, 27, 181. 6. Fiddler, W.; Pensabene, J.W.; Fagan, J.C.; Thorne, E.J.; Protrowski, E.G.; Wasserman, A.E. J . Food S c i . 1974, 39, 1070-1071. 7. Coleman, M.H. J . Food Technology, 1978, J 3 , 55-69. 8. Mottram. D.S.; Patterson, R.L.S. J . S c i . Food Agric., 1977, 28, 352-354. 9. Massey, R.C.; Dennis, M.J.; Crows, C.; McWeeny, D.J.; "NNitroso Compounds; Analysis, Formation and Occurance," IARC S c i e n t i f i c Publication No. 31, International Agency for Research on Cancer, Lyon, France, 1980; p. 291. 10. Tanaka, K.; Chung, K.C.; Hayatsu, H.; Kada, T. Fd. Cosmet. Toxicol., 1978, 16, 209-215. 11. Chang, S.K.; Harrington, G.W.; Rothstein, M.; Shergalis, W.A.; Swern, D.; Vohra, S.K. Cancer Res., 1979, 39, 38713874. 12. Kawabata, T.; Shazuk, H.; Ishibashi, T. Nippon Suisan Gakkaishi, 1974, 40, 1251. 13. Kim, Y.K.; Tannenbaum, S.R.; Wishnok, J.S. "N-Nitroso Compounds: Analysis, Formation and Occurance", IARC Scien t i f i c Publication No. 31, International Agency f o r Research on Cancer, Lyon, France, 1980, 207-214. 14. Stadnick, R.; Govil, A. personal communication, 1981, March 27. RECEIVED

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1981.


N-Nitroso Compounds - ACS Publications - American Chemical Society

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