Migration and Formation of - American Chemical Society

Chapter 12

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Migration and Formation of N-Nitrosamines from Food Contact Materials Nrisinha P. Sen Food Research Division, Bureau of Chemical Safety, Food Directorate, Health Protection Branch, Ottawa, Ontario K1A 0L2, Canada Recent research has focused our attention on the occurrence of N-nitrosamines, many of which are potent carcinogens, and secondary amines, in food contact materials. In addition to the possibility of migration of these chemicals to foods, there is also the possibility that the migrated amines, after ingestion, may form additional amounts of nitrosamines, either in vivo in the human stomach, or during processing or cooking of foods containing nitrite as an additive (e.g., cured meats). This paper reviews the topic with particular emphasis on paper-, wax-, and rubber-based food contact materials. The available evidence indicates that certain nitrosamines may migrate to or form in foods which come in contact with rubber based products such as baby bottle rubber nipples and elastic rubber nettings. N-Nitrosamines are a group of environmental carcinogens that have been detected i n a wide variety of consumer products such as pesticide formulations; cigarette and other tobacco products; cosmetics; rubber products; and i n various foods and beverages, especially f r i e d bacon, cured meats and beer. In foods, these compounds are formed mainly as a result of the interaction of naturally occurring amines i n the foods, and n i t r i t e additives (e.g., in bacon) or nitrogen oxide gases (e.g., i n hot f l u e gases used f o r drying malt) used i n the processing of the products. Since most of the nitrosamines detected i n foods are potent carcinogens, these findings have aroused a great deal of concern among health o f f i c i a l s and consumers throughout the world. Details of these findings have been published i n several recent reviews (1-3). Recent research has shown that some of the nitrosamines detected in foods may originate or form from various food contact materials such as packaging papers, waxed containers, and e l a s t i c rubber nettings. In these cases, the food contact materials, not the foods, 0097-6156/88/0365-0146$06.00/0 Published 1988 American Chemical Society

Hotchkiss; Food and Packaging Interactions ACS Symposium Series; American Chemical Society: Washington, DC, 1988.


12.

SEN

Migration & Formation of

Ν-Nitrosamines

147

are the source of the nitrosatable amines or amine derivatives. The concern, here, appears to be three-fold. F i r s t , the nitrosamines from these products can migrate to foods that come i n contact with them for a prolonged period. Secondly, the amines, which are usually present in much higher concentrations than the corresponding n i t r o s amines, can also migrate to foods and form additional amounts of nitrosamines during processing or cooking. And t h i r d l y , the migrated amines, after ingestion, can also form nitrosamines i n vivo i n the acidic environment of the human stomach due to interaction with salivary or ingested (e.g., through cured meats) n i t r i t e . Table I summarizes the type of food contact materials that have been implicated i n the contamination of foods with nitrosamines and nitrosatable amines. The available evidence suggests that N-nitrosomorpholine (NMOR) and morpholine (MOR) are present as contaminants i n paper-based packaging materials and l i q u i d waxes, whereas rubber-

Table I.

Food Contact Materials Reported to Contain N-Nitrosamines

Type

Use pattern

Nitrosamines detected

Paper-based products including waxed papers

Used for packaging dry as well as moist foods

NMOR

Liquid waxes

As a coating on f r u i t s and vegetables

NMOR

Rubber-based products

Baby bottle rubber nipples

N-Nitrosodimethylamine (NDMA) N-Nitrosodiethylamine (NDEA) N-Nitrosodi-n-butylamine (NDBA) N-Nitro sop iper id ine (NPIP) NMOR N-Nitrosomethylphenylamine (NMPhA) N-Nitrosoethylphenylamine (NEPhA) N-Nitrosodiphenylamine (NDPhA)

E l a s t i c rubber nettings used for packaging cured meats

NDEA NPIP NDBA N-Nitro sod ibenzy lamine (NDBzA)

American Chemical Society Library 5 5 and 15th St., N.W. Hotchkiss;"Food Packaging Interactions ACS Symposium Series;Washington, American Chemical D.C.Society: 2003fiWashington, DC, 1988. u

148

FOOD AND PACKAGING INTERACTIONS

based products contain a variety of nitrosamines and the correspon ding amine d e r i v a t i v e s . Although only limited information is a v a i l able, some interesting observations have been made. An attempt w i l l be made, i n this review, to summarize these findings and discuss their significance with regard to the possible health hazard to man.


N-Nitrosamines and Precursor Amines in Paper-Based Food Contact Materials The f i r s t evidence of the presence of NMOR i n paper-based packaging materials was reported independently by Hoffmann e_t a l . (4J and Hotchkiss and Vecchio ( 5 K While investigating the o r i g i n of NMOR i n snuff, Hoffmann e_t a l . (4·) observed that the wax coating used on the snuff containers was the source of the NMOR contamination. Since MOR is widely used as a solvent in most wax formulations and since most commercial MOR i s contaminated with NMOR ( 6^), the finding of NMOR in the wax-coated snuff containers was not e n t i r e l y unexpected. The above researchers (4_) also analyzed a variety of waxed containers commonly used for packaging dairy products for the presence of both NMOR and MOR (Table I I ) . F a i r l y high levels of MOR and traces of NMOR were detected i n such containers. The respective dairy products, packaged i n these containers, also contained s i g n i f i c a n t levels of MOR and traces of NMOR (Table I I ) . On careful examination of the data (Table II) i t appears that the concentration of NMOR i n six of the dairy foods was higher than that present in the corresponding containers. If NMOR i n these foods had solely originated from the containers the reverse should have been true as i n the case for MOR, which was present in much higher concentrations i n the containers than i n the respective foods. The Table I I .

NMOR and MOR in Food and Food Containers (ppb)

Sample

Food

Butter Cream cheese Yogurt Cottage cheese Frozen peas and carrots Cheese (semi-soft)b Cheese (semi-soft) Cheese (semi-soft)b Cheese (semi-soft) Gouda D

15

Container

NMOR

MOR

NMOR

3.2 0.9 Ν 0.4 Ν 3.3 3.1 0.7 1.4 1.6

58 77 38 44 26 8.7 9.7 4.9 8.0 35

1.9 a Ν 5.4 3.1 Ν 1.6 1.2 Ν Ν N

a

Ν = None detected (). T h i s l e d H o t c h k i s s and V e c c h i o (5) t o analyze a v a r i e t y o f food grade paper and paperboard packaging m a t e r i a l s f o r the p r e s e n c e o f t h e above-mentioned c o n t a m i n a n t s . Most o f t h e s e paper p r o d u c t s were o f the type t h a t a r e used f o r packaging d r y foods such as o a t s , c e r e a l , r i c e , p a s t a , sugar, f l o u r , s a l t , and c o r n m e a l . Of t h e 34 samples a n a l y z e d , n i n e c o n t a i n e d t r a c e s (1 t o 33 ppb) o f NMOR (unconfirmed by mass spectrometry); t h e r e s t were n e g a t i v e . The above r e s e a r c h e r s a l s o a n a l y z e d s i x each o f the NMOR-positive and NMOR-negative samples f o r t h e i r MOR c o n t e n t s . A l l contained f a i r l y h i g h l e v e l s o f MOR ( T a b l e I I I ) . I n some c a s e s , t h e l e v e l s o f NMOR c o r r e l a t e d w i t h those o f MOR.

Table I I I .

MOR and NMOR Contents o f Food Grade Paper and Paperboard Packaging M a t e r i a l s

Sample

MOR

(ppb)

A Β C D Ε F

426 223 560 347 812 238

Χ

434

G H I J K L

98 132 329 445 113 842

X

327

NMOR

a

t r a c e ( Ν Ν Ν Ν Ν

3


150

FOOD AND PACKAGING INTERACTIONS

Hotchkiss and Vecchio (_5) also investigated the possible migration of these chemicals from packaging papers to foods. Traces (~1 ppb) of NMOR were observed in flour samples taken closest to the bag wall which i t s e l f contained about 33 ppb NMOR. Homogenized flour from another bag was found to contain 18 ppb MOR but no NMOR, suggesting migration of MOR from the bag to the f l o u r . When pieces of paper and paperboard packagings containing NMOR were incubated for 72 hr at 100°C with flour or pasta in a closed container, traces of NMOR migrated from the packagings to these foods. These workers emphasized, however, that since the conditions used for the above migration experiments were quite d r a s t i c , the data should be i n t e r preted with caution. Further work i s obviously needed to determine migration patterns for these chemicals from packaging materials to foods under normal storage conditions. I t would be advisable to replace MOR as a corrosion inhibitor in b o i l e r water with an amine that does not form a stable N-nitroso derivative (5^· More recently, Sen and Baddoo ( 7 ^ reported further evidence of migration of NMOR from packaging papers to margarine. Margarines and a variety of wrappings (parchment paper, s p e c i a l l y coated paper, waxed paper, aluminum-backed paper) were analyzed for their NMOR content. NMOR ranging from 5 to 73 ng per wrapping was detected i n some of the wrappings. Furthermore, margarines taken from the outer ~5 mm layer of sample packaged in NMOR-positive wrappings were mostly positive for NMOR, while those taken from the center of the margarine blocks (1 lb) were always negative. This suggested migration of NMOR from the wrappings to the outer layer of the margarine blocks. Not a l l margarines wrapped i n NMOR-positive wrappings were, however, contaminated with NMOR. In fact, the brand of paper containing the highest levels of NMOR (62 to 73 ng/wrapper) did not transfer any NMOR to margarine. This was attributed to the presence of a special p l a s t i c coating on the innerside of these wrappings that prevented NMOR migration. No NMOR was detected i n margarines packaged i n aluminum-backed paper or p l a s t i c tubs.

MOR and NMOR Contamination of F r u i t s from Liquid Waxes The application of l i q u i d wax as an edible protective coating on f r u i t s and vegetables i s an old practice (&). Its main purpose i s to prevent moisture loss and thus extend shelf l i f e of f r u i t s and vegetables ( 8 K Since MOR and f a t t y acid derivatives of MOR (e.g., morpholine oleate) are widely used as solvents or emulsifying agents for waxes ( 9 ) , such a practice can inadvertently contaminate waxcoated f r u i t s and vegetables with MOR and NMOR. Unfortunately, not a great deal of information i s available i n this regard. Only very recently, Sen and Baddoo (10) investigated the possible presence of MOR and NMOR in apples coated with l i q u i d waxes. As expected, up to 3.8% MOR and 140 to 670 ppb of NMOR were detected i n 9 samples of l i q u i d waxes. In apples coated with such waxes, 0.25 to 7.7 ppm of MOR but no NMOR were detected. Neither MOR nor NMOR were detected i n uncoated apples.



12. SEN

Migration & Formation of Ν-Nitrosamines

151

S i n c e MOR i s an e a s i l y n i t r o s a t a b l e amine ( 1 1 ) , t h e above r e s e a r c h e r s (10) a l s o i n v e s t i g a t e d t h e p o s s i b i l i t y o f t h e f o r m a t i o n o f NMOR i n t h e human stomach f o l l o w i n g i n g e s t i o n o f wax-coated apples. In v i t r o incubation studies with wax-coated apple homogenates ( i n c u b a t e d w i t h 10 ppm n i t r i t e s o l u t i o n a t pH 3.4 f o r 2 h r s a t 37°C) gave m o s t l y n e g a t i v e r e s u l t s , whereas e q u i v a l e n t amounts o f MOR under i d e n t i c a l c o n d i t i o n s i n t h e absence o f a p p l e , produced t r a c e s o f NMOR. The n e g a t i v e r e s u l t s w i t h a p p l e s were a t t r i b u t e d t o t h e presence o f n a t u r a l l y o c c u r r i n g N - n i t r o s a t i o n i n h i b i t o r s ( e . g . , p h e n o l i c compounds, a s c o r b i c a c i d ) i n t h e s e f r u i t s (11-13). I n view o f t h e s e f i n d i n g s , t h e u s e o f l i q u i d waxes on f r u i t appears t o be o f l i t t l e h e a l t h h a z a r d s i g n i f i c a n c e t o man, a t l e a s t i n t h e c o n t e x t o f NMOR c o n t a m i n a t i o n o r i t s f o r m a t i o n . Nitrosamines

i n Rubber-Based Food C o n t a c t M a t e r i a l s

Recent r e s e a r c h has p r o v i d e d c o n c l u s i v e e v i d e n c e f o r t h e p r e s e n c e o f v a r i o u s v o l a t i l e n i t r o s a m i n e s i n a v a r i e t y o f rubber p r o d u c t s such as t i r e s and rubber t u b e s , rubber g l o v e s , baby b o t t l e r u b b e r n i p p l e s and infant pacifiers, and i n some m e d i c a l devices (14-19). The n i t r o s a m i n e s d e t e c t e d i n t h e s e p r o d u c t s a r e l i s t e d i n T a b l e I . The best evidence i n d i c a t e s t h a t t h e s e n i t r o s a m i n e s a r e formed as a result of the interaction of various vulcanization accelerators (amine d e r i v a t i v e s ) i n t h e rubber and n i t r o g e n o x i d e s from a i r . Some o r g a n i c n i t r o and n i t r o s o compounds ( e . g . , N-nitrosodiphenylamine) used i n t h e manufacture o f rubber can a l s o a c t as n i t r o s a t i n g a g e n t s . The r e a d e r i s a d v i s e d t o c o n s u l t a r e c e n t r e v i e w (16) o n t h e s u b j e c t for further d e t a i l s . The f i n d i n g o f n i t r o s a m i n e s i n baby b o t t l e r u b b e r n i p p l e s r a i s e d a g r e a t d e a l o f c o n c e r n because o f t h e p o s s i b l e m i g r a t i o n o f t h e s e compounds t o i n f a n t f o r m u l a s and i n t o b a b i e s ' s a l i v a d u r i n g t h e i r normal usage. Furthermore, many mothers s t e r i l i z e i n f a n t f o r m u l a s i n b o t t l e s w i t h r u b b e r n i p p l e s p l a c e d i n them, and o f t e n s t o r e them together f o r a prolonged p e r i o d i n the r e f r i g e r a t o r . Therefore, the o p p o r t u n i t y f o r m i g r a t i o n o f n i t r o s a m i n e s as w e l l as o f t h e c o r r e sponding amine d e r i v a t i v e s from rubber t o i n f a n t f o r m u l a s i s q u i t e great. I n t h e U.S.A., r e s e a r c h by Havery and F a z i o (Γ7, 20) demonstrated t h a t 5 t o 38% o f t h e n i t r o s a m i n e s i n rubber n i p p l e s migrated to liquid i n f a n t formulas or milk during sterilization (Table I V ) . They a l s o found t h a t n o t a l l t h e n i t r o s a m i n e s leached out d u r i n g a s i n g l e s t e r i l i z a t i o n p r o c e s s . These compounds tended t o l e a c h o u t c o n t i n u o u s l y , a l t h o u g h i n p r o g r e s s i v e l y d e c r e a s i n g amounts, on r e p e a t e d s t e r i l i z a t i o n . Sen e t a l ^ . (19) a l s o r e p o r t e d s i m i l a r r e s u l t s except t h a t they n o t e d m i g r a t i o n o f o n l y 1-5% o f n i t r o s a m i n e s from rubber n i p p l e s t o i n f a n t f o r m u l a s o r orange j u i c e ( T a b l e I V ) . The d i f f e r e n c e s observed i n t h e two s t u d i e s (Γ7, 19^ and 20) c o u l d be a t t r i b u t e d t o t h e f a c t t h a t i n t h e study o f Sen €ît_ a l . (19) t h e n i p p l e s were n o t s t e r i l i z e d w i t h t h e i n f a n t foods b u t were shaken w i t h i n f a n t f o r m u l a s o r orange j u i c e f o r 1 h r a t 40°C. I t has been suggested t h a t a d d i t i o n a l amounts o f n i t r o s a m i n e s might be formed i n b a b i e s ' stomachs due t o t h e i n t e r a c t i o n o f s a l i v a r y n i t r i t e with i n g e s t e d amine a d d i t i v e s leached o u t from rubber n i p p l e s . S p i e g e l h a l d e r and Preussmann (21) r e p o r t e d t h a t 10y



IV.

(g) (h)

N i p p l e shaken w i t h orange j u i c e

(Adapted from R e f .

Ν = none d e t e c t e d

(g) (h) (i) (j)

N i p p l e shaken w i t h i n f a n t formula

a

(d) (e) (f)

Nipple s t e r i l i z e d i n b o t t l e with infant formula

17, 19, 20.)

(i)

(a) (b) (c)

in

Nipple s t e r i l i z e d b o t t l e with milk

Nipple used

from Rubber N i p p l e s

4 5

204

4 5

2

64

NDMA

58 83

58 83

29 12 27

28 57 11

NDEA

2052

1030

1030 2052 15

47

2

NDBA

459 180

459 180

114

165

281

Ν Ν

1.4

4 9

18

17

NDMA

1.9 1.5

3.5 1.4

18 17 19

20 20 5

NDEA

a

2.5

2

5 3.6 N

4

29

NDBA

% Migration into i n f a n t foods

Ν 3.8

1.1 4.5

6

5

8

NPIP

(19)

(.19) (L9)

(19) (19) (19) (19)

(20) (20) (20)

(17) (17) (20)

Reference

t o I n f a n t F o r m u l a , M i l k , and Orange J u i c e

NPIP

Levels of nitrosamines i n n i p p l e s (ppb)

M i g r a t i o n o f Nitrosamines

Experiment

Table


C/3

2

Ο

U

η

>

S

2 S

2 S

§ J Ο >

>

£ §


12. SEN


Ν-Nitrosamines

153

22,000 ppb (expressed in terms of the weight of a nipple) of certain nitrosamines were formed when rubber nipples were incubated with a r t i f i c i a l s a l i v a under simulated gastric conditions. Since the n i t r o s a t i o n rate of a secondary amine is inversely proportional to i t s b a s i c i t y (11 ), the most weakly basic amines l i k e methylphenylamine and ethyphenylamine were found to produce the largest amounts of nitrosamines under the above conditions. These findings led the German government to pass a regulation that put a limit of 200 ppb t o t a l leachable amines from baby bottle rubber nipples as determined by the above method (21). Recent studies by Sen £t a l . (22) suggest that in vivo n i t r o s a tion i s unlikely to occur in the presence of infant formulas or f r u i t juices. A l l infant formulas and f r u i t juices tested markedly inhibited (up to 99%) the formation of nitrosamines, including that from the weakly basic ethylphenylamine. Cow's milk was somewhat less e f f i c i e n t in this respect. The presence of various N-nitrosation inhibitors such as vitamin C, ascorbyl palmitate, α-tocopherol, and naturally occurring phenols (e.g., chlorogenic acid, phloridzin) i n these products (12, Γ3, 22-24) was believed to be responsible for this observed inhibition. A summary of the findings (22) i s presented in Table V. As was observed by Havery and Fazio (17) for nitrosamines, Sen et a l . (22) also noted that amines i n rubber nipples continued to migrate into l i q u i d infant foods even after repeated s t e r i l i z a t i o n (nipple boiled i n water for 5 min for each s t e r i l i z a t i o n ) . For example, enough amines migrated into a r t i f i c i a l s a l i v a from a nipple, which had already been s t e r i l i z e d six times, to y i e l d up to 2,200 ppb NEPhA and 226 ppb NDMA when tested by the German a r t i f i c i a l s a l i v a method (21). In the presence of orange juice or infant formula, however, nitrosamine formation was markedly i n h i b i t e d . Therefore, the health hazard, i f any, that could arise due to the formation of nitrosamines in babies' stomachs from ingested amines, might not be as great as previously thought because of the modulating effect of various food ingredients. It should be mentioned that recent survey data from both the USA (25) and Canada (22^, 26 ) suggest a s i g n i f i c a n t reduction in the levels of both nitrosamines and amine precursors i n baby b o t t l e rubber nipples from that observed previously. It i s believed that this has been achieved by modifying rubber curing formulations, probably involving the use of nonamine accelerators or of amines that do not form carcinogenic nitrosamines. Other rubber products that may come i n contact with foods include rubber gloves used during handling of foods, rubber hoses and tubings used in food processing industries or in milking machines (18), and e l a s t i c rubber nettings used for packaging both cured and uncured meats. Although traces of certain v o l a t i l e nitrosamines and diphenylamine have been detected, respectively, i n rubber gloves and water flowing through rubber tubing (1_5, 18), no data are available with regard to the migration of these chemicals to foods. Further research might be desirable in this area. E l a s t i c rubber nettings are often used for packaging cured pork products (e.g., ham, cottage r o l l s , pork picnic shoulders, sweet pickled pork cottage r o l l s ) as well as some uncured meats (e.g., roast beef). They are used mainly for holding the meat pieces



NDEA NPIP

brand Β

not tested

96-100 26-63 30-90 15-37

cow's milk

by Various

3

Liquid

Infant Foods under

97 91

97-100 65-99 100 99-100

saliva,

100 100

100 100 100 97

99-100 94-100

100 94-100 100 94-99

100 100

100 100 100 99

apple juice

Simulated

Percent i n h i b i t i o n of nitrosamine formation from amines leached out from nipple soy-based milk-based orange juice formula^ formulab

Formation

Compared to that formed i n the absence of food, i . e . , i n a r t i f i c i a l b Contains ascorbyl palmitate and α-tocopherol as additives. (Source: Reproduced from ref. 22. Copyright 1985 American Chemical Society.)

a

NDMA NDBA NPIP NEPhA

Nitrosamine detected

of Nitrosamine

brand A

Nipple used

Table V. Inhibition Gastric Conditions


C/5

Η Ο Ζ

> η

w

s Η

> ο > ο ζ ο

•τ

© > ζ

Ο Ο



12. SEN

Ν-Nitrosamines

155

together during processing and cooking. Consumers usually keep the nettings on the products during warming or cooking (for raw products) at home. Sen et^ aj_. (27) recently reported finding NDEA and NDBA i n rubber nettings. Analysis of cured meats packaged i n such nettings indicated the presence of higher levels of nitrosamines than could be accounted f o r from that o r i g i n a l l y found i n the unused nettings. This suggested formation of additional amounts of nitrosamines due to the interaction of n i t r i t e , used i n the meat curing process, with migrating amine derivatives (e.g., dibutyldithiocarbamate) from the rubber netting. When unused nettings were incubated with n i t r i t e under mildly acidic conditions, excessively high levels of the same nitrosamines were formed suggesting the presence of the corresponding amine precursors i n the nettings. No nitrosamines were found i n similar cured pork products packaged i n cotton nettings or p l a s t i c wrappings. The researchers concluded that the use of rubber nettings was the main reason for the occurrence of NDEA and NDBA (the predomi nant nitrosamine found) i n the cured meats. These workers did not extend their studies to uncured meats because the chance of formation of nitrosamines i n such cases would be very remote, due to lack of nitrite. Sen ο ζ ο ζ

>

Ζ σ

ο >

Ο

12. S E N

Migration

& Formation

of

Ν-Nitrosamines

157

Literature Cited 1.

2.


3.

4.

5. 6. 7. 8. 9. 10. 11. 12. 13.

14.

15. 16. 17. 18.

19. 20. 21. 22. 23.

24.

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