Food, Drug, and Cosmetic Colors: Toxicological Considerations - ACS

20 Food, Drug, and Cosmetic Colors: Toxicological Considerations

Downloaded by UNIV OF ARIZONA on April 25, 2017 | http://pubs.acs.org Publication Date: October 25, 1983 | doi: 10.1021/bk-1983-0234.ch020

JOSEPH F. BORZELLECA Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298 JOHN HALLAGAN and CAROLINE REESE The Offices of Daniel R. Thompson, 900 17th St. N.W., Washington, DC 20006

The Food, Drug and Cosmetic (FD&C) Colors have been studied extensively. The most recent have been chronic toxicity/oncogenicity studies in Charles River CD rats and Charles River CD-1 mice. The colors evaluated and the dietary levels employed were: Dietary Levels (%) Color Rat Mouse FD&C Blue 1 0.0, 0.1, 1.0, 2.0 0.0, 0.5, 1.5, 5.0 FD&C Green 3 0.0, 1.25, 2.5, 5.0 0.0, 0.5, 1.5, 5.0 FD&C Blue 2 0.0, 0.5, 1.0, 2.0 0.0, 0.5, 1.5, 5.0 FD&C Yellow 6 0.0, 0.75, 1.5, 3.0, 5.0 0.0, 0.5, 1.5, 5.0 FD&C Yellow 5 0.0, 0.1, 1.0, 2.0, 5.0 0.0, 0.5, 1.5, 5.0 FD&C Red 3 0.0, 0.1, 0.5, 1.0, 4.0 0.0, 0.3, 1.0, 3.0 Many parameters were measured during the course of these studies including reproductive performance (rats only), body weights, feed consumption, clinical chemistries (blood, urine), hematology, gross and histological examination of tissues. Data were subjected to extensive statistical analyses. There were no consistent statistically significant and biologically relevant compound related effects, including tumors. These studies were supported by the Certified Colors Manufacturers Association and were conducted by Bio-dynamics Laboratory and International Reseach and Development Corporation. C o l o r s have been an e s s e n t i a l p a r t o f o u r e x i s t e n c e . N a t u r e i s c o l o r f u l . C o l o r s have been used t h r o u g h o u t h i s t o r y b y man i n a t l e a s t t h r e e m a j o r a r e a s - f o o d , d r u g s and c o s m e t i c s . C o l o r e d c a n d y h a s been i d e n t i f i e d i n p a i n t i n g s i n E g y p t i a n tombs d a t i n g 0097-6156/83/0234-0311$06.50/0 © 1983 A m e r i c a n C h e m i c a l S o c i e t y

Finley and Schwass; Xenobiotics in Foods and Feeds ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


312

X E N O B I O T I C S IN F O O D S A N D

FEEDS

back t o a b o u t 1500 B.C. A r t i f i c i a l l y c o l o r e d w i n e s were r e p o r t e d b y P l i n y t h e E l d e r i n a b o u t 400 B.C. Ebers Papyrus, t h e o l d e s t r e c o r d o f d r u g s , i d e n t i f i e s c o l o r s t h a t were used i n drugs. A b o u t 5000 B.C., E g y p t i a n s were u s i n g g r e e n c o p p e r f o r eye shadow. A l s o u s e d were henna t o dye h a i r , c a r m i n e t o r e d d e n l i p s , k o h l (an a n t i m o n y compound) t o b l a c k e n e y e b r o w s , l i d s a n d l a s h e s . A r o u n d 500 B.C., s a f f r o n was u s e d t o make f a c e s y e l l o w and henna t o dye f e e t r e d i n I n d i a . C h i n e s e used v e g e t a b l e d y e s on f e e t , c h e e k s , and t i p s o f t h e i r t o n g u e s f o r v a r i o u s r e a s o n s . The Romans u s e d w h i t e l e a d and c h a l k o n t h e i r f a c e s and b l u e and g o l d dye o n t h e i r h a i r . The s o u r c e s o f d y e s u s e d b y man i n c l u d e a n i m a l , v e g e t a b l e , and m i n e r a l . S i r W i l l i a m H e n r y P e r k i n s , i n 1856, synthesized t h e f i r s t a n i l i n e dye. I n I 8 6 0 , a t r i p h e n y l m e t h a n e dye, f u c h s i n e , was u s e d b y t h e F r e n c h t o c o l o r w i n e . On A u g u s t 2, 1886, t h e U.S. C o n g r e s s a u t h o r i z e d t h e a d d i t i o n o f c o l o r t o b u t t e r . On J u n e 6, 1896, C o n g r e s s a p p r o v e d c o l o r a n t s i n c h e e s e , a n d b y 1900 c o l o r a n t s were added t o c a t s u p , j e l l i e s , c o r d i a l s , c a n d i e s , sausage and noodles. However, t h e r e were some c o n c e r n s b y t h e p u b l i c . F o r example, chrome y e l l o w , m a r t i u s y e l l o w a n d q u i c k s i l v e r v e r m i l l i o n were added t o f o o d s t o h i d e p o o r q u a l i t y o r t o i n c r e a s e w e i g h t . T h e r e was no c o n t r o l o v e r t h e p u r i t y o f c o l o r a n t s u s e d . F o r e x a m p l e , i t h a s been n o t e d t h a t r e j e c t e d t e x t i l e d y e s were sometimes added t o f o o d s . Use o f a r s e n i c a c i d and m e r c u r y i n t h e m a n u f a c t u r e o f c o l o r a n t s a l s o c r e a t e d some concerns. In 1899, t h e N a t i o n a l C o n f e c t i o n e r s A s s o c i a t i o n p u b l i s h e d a l i s t o f u n f i t c o l o r a n t s f o r f o o d s . T h i s was t h e f i r s t t i m e t h a t any g r o u p a d d r e s s e d t h e i s s u e o f s a f e t y o f c o l o r a n t s . Unfort u n a t e l y , t h i s was n o t v e r y e f f e c t i v e . I n A u g u s t , 1904, t h e U.S.D.A. i s s u e d a F o o d I n s p e c t i o n D e c i s i o n w h i c h s t a t e d , "Food i s a d u l t e r a t e d i f i t i s c o l o r e d , powdered o r p o l i s h e d w i t h attempt t o deceive." A n o t h e r F o o d I n s p e c t i o n D e c i s i o n was i s s u e d i n September 1905 i n w h i c h t h e U.S.D.A. r e q u i r e d t h a t c o l o r s must b e d e c l a r e d on l a b e l s . I n 1906 t h e U.S.D.A. d e c l a r e d m a r t i u s y e l l o w i n m a c a r o n i t o be an u n s a f e c o l o r ; a n d i n 1907 t h e F.D.A. p r o h i b i t e d t h e u s e o f d a n g e r o u s and impure c o l o r a n t s i n f o o d . T h e Food a n d Drug A c t was p a s s e d i n 1906. Dr. B e r n a r d C. H e s s e o f t h e U.S. D e p a r t m e n t o f A g r i c u l t u r e had e v a l u a t e d t h e c h e m i s t r y and p h y s i o l o g y o f a p p r o x i m a t e l y 700 c o a l t a r d y e s . O n l y c o l o r s o f known c o m p o s i t i o n were examined p h y s i o l o g i c a l l y . T h o s e s h o w i n g n o n - f a v o r a b l e r e s u l t s c o u l d be u s e d i n f o o d s . The U.S.D.A. began t o c e r t i f y s y n t h e t i c o r g a n i c f o o d c o l o r s i n A p r i l 1908. T h e c o s t o f t h e c e r t i f i c a t i o n was t o b e b o r n e b y i n d u s t r y (and s t i l l i s ) . T h e c o l o r s a p p r o v e d a t t h a t t i m e were amaranth (Red 2 ) , p o n c e a u 3R ( O r a n g e 1 ) , e r y t h r o s i n e (Red 3 ) , n a p h t h o l y e l l o w S ( Y e l l o w 7 ) , l i g h t g r e e n SF y e l l o w i s h , and i n d i g o d i s u l f o a c i d s o d i u m s a l t ( B l u e 2 ) . O t h e r c o l o r s were added: i n 1916, t a r t r a z i n e ( Y e l l o w 5 ) ; i n 1927, FCF g r e e n



20.

BORZELLECA ET AL.

Food,

Drug,

and Cosmetic

Colors

313

G r e e n 3 ) ; a n d 1 9 2 9 p o n c e a u SX ( R e d 4 ) , s u n s e t y e l l o w SCF Y e l l o w 6 ) , a n d b r i l l i a n t b l u e SCF ( B l u e 1 ) . I n 1938, t h e F e d e r a l F o o d , Drug and C o s m e t i c A c t was p a s s e d . I t s t a t e d t h a t u n c e r t i f i e d c o a l t a r c o l o r s i n food, drugs and cosmetics could n o t b e s h i p p e d i n i n t e r s t a t e commerce. U s e o f c o l o r s was l i m i t e d . A l l c o l o r s h a d t o be c e r t i f i e d a n d h a r m l e s s . T h r e e c a t e g o r i e s o f c o a l t a r c o l o r s were e s t a b l i s h e d : F o o d , Drug a n d C o s m e t i c c o l o r s , Drug and C o s m e t i c c o l o r s , a n d E x t e r n a l Drug and C o s m e t i c c o l o r s . T h e S e r v i c e and R e g u l a t o r y Announcement, FD and C No. 3, September 1940, l i s t e d c o l o r s t h a t were a p p r o v e d a t t h a t time and t h e s p e c i f i c a t i o n and r e g u l a t i o n s concerning manufacturing, c e r t i f i c a t i o n , sale, etc. T h e F o o d and Drug A d m i n i s t r a t i o n began t e s t i n g c o l o r s i n t h e e a r l y 1950s f o l l o w i n g an i n c i d e n t i n w h i c h c h i l d r e n became s i c k a f t e r e a t i n g c a n d y and colored popcorn. Unfavorable f i n d i n g s r e s u l t e d i n the banning o f FD a n d C Orange 1, FD and C Orange 2, and FD and C Red 3 2 . The FDA's p o s i t i o n was t h a t t h e t e r m h a r m l e s s n e s s a s d e f i n e d i n t h e 1938 A c t meant s a f e r e g a r d l e s s o f t h e amount u s e d . Later, t h e Supreme C o u r t r u l e d t h a t t h e F o o d a n d Drug A d m i n i s t r a t i o n could n o t e s t a b l i s h l i m i t s unless t h e c e r t i f i e d c o l o r i n any q u a n t i t y c a u s e d harm. T h e C o l o r A d d i t i v e s Amendment o f 1960 (PL-86-618) r e q u i r e d t h e f o l l o w i n g : e x i s t i n g c o l o r s c o u l d be u s e d p e n d i n g f u r t h e r t e s t i n g ; l i m i t s o f u s e were e s t a b l i s h e d ; a l l c o l o r s were t o be i n c l u d e d , n o t j u s t t h e c o a l t a r c o l o r s ; t h e S e c r e t a r y was t o d e t e r m i n e w h i c h c o l o r s were t o be c e r t i f i e d and w h i c h w o u l d b e exempted; p r o d u c e r s and c o n s u m e r s were t o p r o v i d e d a t a t o o b t a i n permanent l i s t i n g s ; and p r o v i s i o n a l l i s t i n g r e f e r r e d t o c o l o r s f o r w h i c h a d d i t i o n a l d a t a were n e c e s s a r y t o s e c u r e permanent l i s t i n g . Uses o f C o l o r s F o o d s . C o l o r s a r e added ( 1 ) t o f o o d s t h a t have no c o l o r o f t h e i r own ( b e v e r a g e s , g e l a t i n d e s s e r t , c a n d i e s , i c e c r e a m ) ; (2) where t h e n a t u r a l c o l o r h a s been l o s t i n p r o c e s s i n g o r s t o r a g e ; (3) where c o l o r o f t h e f o o d v a r i e s w i t h t h e s e a s o n o f the y e a r (geographic o r i g i n , f o r example d a i r y products, oranges); ( 4 ) t o make f o o d s r e c o g n i z a b l e and a t t r a c t i v e , e n h a n c i n g t h e i r a e s t h e t i c v a l u e . T h e meat i n s p e c t i o n stamp i s also colored. D r u g s . C o l o r s a r e added t o d r u g s f o r p u r p o s e s o f i d e n t i f i c a t i o n , s t a n d a r d i z i n g b a t c h e s , t o mask u n s a t i s f a c t o r y n a t u r a l c o l o r s , and f o r a p p e a l ( c o l o r l e s s p r o d u c t s a r e not a e s t h e t i c ) . Cosmetics. Cosmetics r e q u i r e the a d d i t i o n o f c o l o r s f o r e f f e c t i v e n e s s . C o l o r s may b e added t o e n h a n c e t h e a e s t h e t i c v a l u e , f o r example t o a f t e r s h a v e l o t i o n a n d shampoo, o r t o s e r v e a f u n c t i o n a l p u r p o s e , f o r example i n eye brow p e n c i l , n a i l p o l i s h ,


314


l i p s t i c k , e t c . T h e amounts u s e d i n c o s m e t i c s i s used i n f o o d s and d r u g s . Acceptable

i s greater

FEEDS

than

D a i l y Intake (API)


The amount o f t h e m a t e r i a l t h a t c a n be i n g e s t e d w i t h o u t u n r e a s o n a b l e r i s k o f a d v e r s e h e a l t h e f f e c t s may be c o n s i d e r e d an a c c e p t a b l e d a i l y i n t a k e . This r e f e r s p r i m a r i l y t o food c h e m i c a l s . T o a r r i v e a t an a c c e p t a b l e d a i l y i n t a k e , a p p r o p r i a t e t o x i c o l o g i c a l t e s t s a n d s a f e t y f a c t o r s a r e i n v o l v e d . ADIs h a v e been e s t a b l i s h e d b y t h e U.S. F o o d a n d Drug A d m i n i s t r a t i o n , t h e W o r l d H e a l t h O r g a n i z a t i o n , t h e J o i n t E x p e r t Committee o n F o o d A d d i t i v e s , and t h e E u r o p e a n E c o n o m i c Community. B a c k g r o u n d o f t h e C u r r e n t T e s t i n g Program The Food and Drug A d m i n i s t r a t i o n d e t e r m i n e d t h a t t h e p r o v i s i o n a l l i s t i n g o f c o l o r s was t o be e l i m i n a t e d . C o l o r s were t o be e i t h e r p e r m a n e n t l y l i s t e d o r t o b e p r o h i b i t e d f r o m u s e . A l s o , t h e r e was c o n c e r n a b o u t c o l o r s t h a t were p e r m a n e n t l y l i s t e d . The c o n c e r n was n o t b a s e d o n a d v e r s e h e a l t h e f f e c t s n o r on t h e g e n e r a t i o n o f a s i g n i f i c a n t amount o f t o x i c o l o g i c a l d a t a , but p r e s u m a b l y o n a t e r a t o l o g y s t u d y o f Aramanth (Red No. 2) t h a t a p p e a r e d i n R u s s i a n l i t e r a t u r e . The f i n d i n g s were n o t c o n f i r m e d when t h e s t u d y was r e d o n e b y t h e Food and Drug A d m i n i s t r a t i o n and by t h e C e r t i f i e d C o l o r s Manufacturers A s s o c i a t i o n . T h e r e was some c o n c e r n t h a t c o l o r s were n o t n e c e s s a r y s i n c e t h e y are non-nutrive. This neglects t h e aesthetic value o f foods. C o l o r s were a l s o r e - e v a l u a t e d , p r e s u m a b l y b e c a u s e o f t h e c y c l i c r e v i e w a n d r e - e v a l u a t i o n p r o g r a m a t FDA. T h e i n d u s t r y was r e q u e s t e d b y FDA t o r e - t e s t a l l FD a n d C and D and C c o l o r s . S p e c i f i c a l l y , t h e c o l o r m a n u f a c t u r e r s were r e q u e s t e d t o p r o v e s a f e t y . I f s a f e t y i s d e f i n e d as t h e absence o f t o x i c i t y , then i t can never be proved s i n c e one cannot prove a n e g a t i v e . I f s a f e t y i s d e f i n e d a s t h e v e r y l o w p r o b a b i l i t y t h a t an a d v e r s e e f f e c t w i l l o c c u r under c e r t a i n c o n d i t i o n s o f u s e , t h e n a p p r o p r i a t e s t u d i e s c a n b e d e s i g n e d and l e v e l s d e t e r m i n e d . H a r m l e s s n e s s must b e d e f i n e d under c e r t a i n c o n d i t i o n s o f u s e . I n o r d e r t o r e s p o n d t o FDA's r e q u e s t , l i f e - t i m e s t u d i e s were c o n d u c t e d i n t h e mouse a n d t h e r a t t o e s t a b l i s h s a f e t y ( r e a s o n a b l e c e r t a i n t y t h a t no harm w i l l o c c u r when t h e m a t e r i a l i s used under certain conditions). P r i o r t o i n i t i a t i n g these s t u d i e s , a thorough search o f the l i t e r a t u r e was c o n d u c t e d a n d t h e e x t e n t o f o r a l t o x i c i t y t e s t s was d e t e r m i n e d . I t was f o u n d t h a t t h e c o l o r s have a v e r y l o w o r d e r o f a c u t e o r a l t o x i c i t y . An e x p e r i m e n t a l d e s i g n was t h e n developed. P o t e n t i a l r e p r o d u c t i v e t o x i c i t i e s were e v a l u a t e d i n multigeneration r e p r o d u c t i v e and t e r a t o l o g i c a l s t u d i e s . No a d v e r s e e f f e c t s were r e p o r t e d a t any o f t h e l e v e l s e x a m i n e d .


20.

BORZELLECA ET

Experimental

AL.

Food,

Drug,

and Cosmetic

Colors

315

Design

The FD and C c o l o r s e v a l u a t e d a r e l i s t e d i n Table I. The c h e m i c a l s t r u c t u r e s , m o l e c u l a r w e i g h t s and c h e m i c a l names a p p e a r i n Table i i . The suppliers o f t h e colors a r e i d e n t i f i e d i n Table i n . O t h e r e x p e r i m e n t a l d e t a i l s a r e summarized i n Tables i v


through V I I .

The c h r o n i c t o x i c i t y / c a r c i n o g e n i c i t y s t u d i e s were d e s i g n e d as d e f i n i t i v e s t u d i e s t o a d d r e s s t h e i s s u e o f s a f e t y . T h e e x p e r i m e n t a l d e s i g n i n v o l v e d j_n u t e r o e x p o s u r e o f r a t s and t h e use o f w e a n l i n g m i c e . O n l y c e r t i f i e d b a t c h e s o f c o l o r f r o m t h e v a r i o u s s u p p l i e r s were u s e d . Two l a b o r a t o r i e s were s e l e c t e d f o l l o w i n g an e x t e n s i v e e v a l u a t i o n o f t h e f a c i l i t i e s a v a i l a b l e at that time. The c o l o r s were a n a l y z e d on a r e g u l a r b a s i s t o e v a l u a t e s t a b i l i t y , and m i c r o b i o l o g i c a l contamination. Feed analyses were c o n d u c t e d o n a w e e k l y b a s i s f o r t h e f i r s t 13 weeks o f t h e s t u d y , and t h e n a t m o n t h l y i n t e r v a l s t h e r e a f t e r b y t h e c o n t r a c t l a b o r a t o r y a n d b y i n d e p e n d e n t l a b o r a t o r i e s . Good l a b o r a t o r y p r a c t i c e s monitoring occurred a t l e a s t monthly. Results The r e s u l t s o f t h e s e s t u d i e s a r e summarized i n T a b l e s V I I I through XIII. These data f a i l e d t o i d e n t i f y any carcinogenic p o t e n t i a l o f t h e F o o d , Drug and C o s m e t i c c o l o r s . T h e r e were no c o n s i s t e n t , b i o l o g i c a l l y s i g n i f i c a n t compound-related e f f e c t s a t any l e v e l in e i t h e r species. Future

Studies

The g e n e t i c t o x i c o l o g i c a l a s p e c t s o f t h e c o l o r s a r e b e i n g evaluated. The data generated t o date f a i l e d t o demonstrate g e n o t o x i c i t y o f t h e s i x F D and C c o l o r s e v a l u a t e d . Comparative b i o t r a n s f o r m a t i o n and k i n e t i c s t u d i e s a r e e s s e n t i a l and t h e s e are i n p r o g r e s s . Special studies are being considered i n c l u d i n g i n t e r a c t i o n s , s e n s i t i z a t i o n o r a l l e r g i e s , and a s s e s s m e n t o f t h e v a l u e o f c o l o r i n human n u t r i t i o n . Summary and

Conclusions

The F o o d , Drug a n d C o s m e t i c c o l o r s h a v e been e x t e n s i v e l y e v a l u a t e d ( f e w f o o d c h e m i c a l s have been s o e x t e n s i v e l y s t u d i e d ) . The F o o d , Drug and C o s m e t i c c o l o r s d o n o t p o s e a t h r e a t t o human health a t l e v e l s c u r r e n t l y i n use o r a t l e v e l s greater than t h o s e c u r r e n t l y u s e d . T h e r e i s no b i o l o g i c a l e v i d e n c e i n a n i m a l s o r human t h a t t h e F o o d , Drug and C o s m e t i c c o l o r s a r e u n s a f e o r h a z a r d o u s t o human h e a l t h .



FD and C B l u e No. 1 FC and C G r e e n No. 3 FD and C B l u e No. 2 FD and C Y e l l o w No. 6 FD and C Y e l l o w No. 5 FD and C Red No. 3

T r i phenylmethane:

Indigoid:

Monoazo:

Pyrazolone:

Xanthene:

Chemical C l a s s

(Erythrosine) (Tetraiodo Fluorescein)

(Tartrazine)

(Sunset Yellow FCF)

(Indigotine)

1907

1916

1929

1907

1929 1927

Year approved by FDA/USDA ( B r i l l i a n t Blue FCF) ( F a s t Green FCF)

Chronic Toxicity Studies 1977-1981

FD AND C COLORS

Table I


20.

BORZELLECA E T AL.

Table

II.

Food,

and Cosmetic

x

Empirical

FD&C Red Red No. No. 40 FD&C 40 ( A l l u r a Red AC) FD&C Red No. : 3 (Erythrosine)

H

N

Formula

C

18 14°8 2 2

C

20 6 4

H

I

N a

S

N a

2

2°5

FD&C Y e l l o w No. 5

n

Q

Weights

M o l e c u l a r Weijght

496.40

9 1 2

C,,H N.Na 0 S 16 9 4 3 9 2

\

317

879.87

VeWs frr,

Colors

Çhem i ç a^l _S t^uc^jur e s . Name sj,. _ a n d __Mo 1 e çu l a r o f t h e FD&C C o l o r s E v a l u a t e d

Color


Drug,

Q

o

·

1 0

534.37

(Tartrazme) FD&C YYeellllooww No. 6 (Sunset Y e l l o w FCF) FD&C B l u e No. No 2 (Indigotine) FD&C G re ee en n Ν FD&C Gr No. 3 ( F a s t Green FCF)

C

16 10 2

H

C

16 8 2

C

37 34 2

H

H

N

N

N

N a

N a

S

2°7 2

S

2°8 2

N a

452.37

466.36

S

2°10 3

Continued

808.86

on n e x t

page


318



Table

II.

Chemical

S t r u c t u r e s ,

Color

Dye

FD&C Red No. 40 ( A l l u r a Red AC)

Monoazo

FD&C

Xanthene

Red

No.

3

Names,

Type

and

Molecular

Weights

Structure

(Erythrosine)

FD&C

Yellow

No.

5

Pyrazolone

6

Monoazo

(Tartrazine)

FD&C

Yellow

(Sunset

FD&C

No.

Yellow

Blue

FCF)

2

No.

Indigoid

(Indigotine) H

FD&C (Fast

Green Green

No.

3

FEEDS

0

Triphenylmethane

FCF)


20.

of

BORZELLECA ETAL.

Drug,

t h e FD&C C o l o r s E v a l u a t e d —

Chemical


Food,

and Cosmetic

Colors

Continued

CFR

Name

Reference

Disodium s a l t of 6-hydroxy-5[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-napththalenesulfonic acid

21 CFR

74.340

Monohydrate of 9-(0-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo3H-xanthen-3-one, d i s o d i u m o r d i p o t a s s i u m s a l t , w i t h s i m i l a r amounts o f l o w e r iodinated fluoresceins

21 CFR

74.303

5-0xo-l-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3-carboxy1ic acid, trisodium salt

21 CFR

74.705

Disodium s a l t of 1-p-sulfophenylazo-2-naphthol-6-sulfonic acid

21 CFR

82.706

P r i n c i p a l l y the disodium s a l t , o f 5,5'-disulfo-3,3'-dioxo- Δ ' b i i n d o l i n e w i t h s m a l l e r amounts o f the i s o m e r i c disodium^sg].t o f 5,7 disulfo-3,3'-dioxo-Δ ' -biindoline

21 CFR

74.1102

4-[(4-Εthy1-p-sulfobenzylamino)phenyl]-(4-hydroxy-2-sulfoniumphenyl)methylene^-[l-(N-ethyl-N-p-sulfobenzyl)-A ' -cyclohexadienimine]

21 CFR

82.203

f



FEEDS

Table III FD AND C COLORS


Chronic T o x i c i t y Studies 1977-1981

SUPPLIERS OF COLORS Color

Manufacturer

FD and C B l u e No. 1

H i l t o n - D a v i s Chemical Co.

FD and C G r e e n No. 3

Warner-Jenkinson Co.

FD and C B l u e No. 2

H i l t o n - D a v i s Chemical Co.

FD and C Y e l l o w No. 6

Stange Co. H i l t o n - D a v i s Chemical Co.

FD and C Y e l l o w No. 5 Warner-Jenkinson Co. FD and C Red No. 3 H. Kohnstamm



Rat Mouse

International Research and Development C o r p .

P u r i n a Rodent L a b o r a t o r y Chow P u r i n a Rodent L a b o r a t o r y Chow A f t e r 8/79: Purina Certified L a b o r a t o r y Chow

R a t and Mouse R a t and Mouse

International Research and Development C o r p .

Feed

P o r t a g e , MI

C h a r l e s R i v e r CD R a t s C h a r l e s R i v e r CD-I M i c e

Species

W i l m i n g t o n , MA

Colony

C h a r l e s R i v e r CD R a t s C h a r l e s R i v e r CD-I M i c e

Strain

Biodynamics

Laboratory

ANIMAL FEED

Rat Mouse

Biodynamics

MATERIALS AND METHODS:

Species

ANIMALS

Laboratory

MATERIALS AND METHODS:

Chronic Toxicity Studies 1977-1981

FD AND C COLORS

T a b l e IV



322

FEEDS

Table V FD AND C COLORS Chronic T o x i c i t y Studies 1977-1981 MATERIALS AND METHODS:

MICE

( C h a r l e s R i v e r , CD-I)


Observation General changes, moribundity, m o r t a l i t y (3 χ d a i l y ) Body W e i g h t / F o o d C o n s u m p t i o n ( w e e k l y : weeks 1-14; b i - w e e k l y : weeks 16-26 e v e r y 4 weeks t h e r e a f t e r ) Detailed Physical Examination ( w e e k l y : weeks 1-14; b i - w e e k l y : weeks 16-16; e v e r y 4 weeks t h e r e a f t e r )

Pathology Gross pathology on a l l animals DOS a n i m a l s Terminal

Sacrifice

Statistical Analysis Appropriate tests

Test Diet Analysis Independent a n a l y s i s by c o n t r a c t l a b and CCMA member company l a l

C l i n i c a l Laboratory Tests H e m a t o l o g y ( 3 , 6, 12, 18 months; terminal) Hemoglobin Hematocrit Total erythrocyte E r y t h r o c y t e morphology T o t a l and d i f f e r e n t i a l l e u c o c y t e (10 Μ , 10 F f r o m each g r o u p )

Histopathology Adrenal (2) A o r t a (abdominal) Bone and bone marrow ( f e m u r ) B l o o d smear B r a i n (3 s e c t i o n s , i n c l u d i n g f r o n t a l c o r t e x and b a s a l g a n g l i a , p a r i e t a l c o r t e x and t h a l a m u s ; c e r e b e l l u m and p o n s ) Esophagus Eye ( 2 - w i t h o p t i c n e r v e ) Gall bladder Heart (with coronary v e s s e l s ) Intestine cecum colon duodenum ileum Kidneys (2) Liver (2) Lung and m a i n s t e m b r o n c h i Lymph nodes (mesenteric, mediastinal)


BORZELLECA ET AL.

Food,

Table V

Drug,

and Cosmetic

Colors

(Continued)


Histopathology Mammary g l a n d ( i n g u i n a l ) Nerve ( s c i a t i c ) Ovaries Pancreas Pituitary Prostate S a l i v a r y gland (mandibular) S e m i n a l v e s i c l e s (2) S k e l e t a l muscle (biceps femoris) Skin Spinal cord ( c e r v i c a l ) Spleen Stomach Testes with epididymides Thymus Thyroid/parathyroid Trachea Urinary bladder Uterus Gross changes o r u n c e r t a i n nature (including a s e c t i o n o f normala p p e a r i n g p o r t i o n o f same tissue) T i s s u e masses o r s u s p e c t tumors w i t h r e g i o n a l lymph nodes



324

FEEDS

T a b l e VI FD AND C COLORS Chronic T o x i c i t y Studies 1977-1981 MATERIALS AND METHODS:


In U t e r o

RATS

Segment

Group

Male

Female

M i n . No. L i t t e r s

Dosage L e v e l s

1-A

60

60

70

Control

1-B

60

60

70

Control

2

60

60

35

Low

3

60

60

35

Mid

4

60

60

35

High

RANDOM SELECTION

Chronic Feeding

Segment

Group

Male

Female

Dosage L e v e l s

1-A

70

70

Control

1-B

70

70

Control

2

70

70

Low

3

70

70

Mid

4

70

70

High


20.

BORZELLECA ET AL.

Food,

Drug,

and Cosmetic

Colors

325

Table VII FD AND C COLORS Chronic T o x i c i t y Studies 1977-1981 MATERIALS AND METHODS:

RATS ( C h a r l e s R i v e r , CD-I)


Observation General changes, moribundity,) m o r t a l i t y (3 χ d a i l y ) Body W e i g h t / F o o d C o n s u m p t i o n ( w e e k l y : weeks 1-14; b i - w e e k l y : weeks 16-26 e v e r y 4 weeks t h e r e a f t e r ) Detailed Physical Examination ( w e e k l y : weeks 1-14; b i - w e e k l y : weeks 16-16; e v e r y 4 weeks t h e r e a f t e r ) Pathology Gross pathology on a l l animals DOS a n i m a l s Interim S a c r i f i c e Terminal S a c r i f i c e

C l i n i c a l Laboratory

Tests

H e m a t o l o g y ( 3 , 6, 12, 1 8 , 24 months; t e r m i n a l ) Hemoglobin Hematocrit Total erythrocyte E r y t h r o c y t e morphology T o t a l and d i f f e r e n t i a l l e u c o c y t e (10 M, 10 F f r o m e a c h g r o u p ) B l o o d C h e m i s t r y ( 3 , 6, 1 2 , 18, 24 months; t e r m i n a l ) Serum g l u t a m i c o x a l o a c e t i c transaminase Serum g l u t a m i c p y r u v i c transaminase A l k a l i n e phosphatase Blood urea nitrogen Fasting glucose Total protein Creatinine

U r i n a l y s i s ( 3 , 6, 1 2 , 18 24 months; t e r m i n a l ) Gross appearance Appropriate tests Specific gravity pH Protein Test Diet Analysis Glucose Ketones Independent a n a l y s i s by c o n t r a c t Bilirubin l a b and CCMA member company l a i O c c u l t b l o o d Microscopic analysis Statistical Analysis

(Continued)


326


T a b l e VII


Histopathology Adrenal (2) Aorta (abdominal) B l o o d smear Bone and bone marrow ( f e m u r ) B r a i n (3 s e c t i o n s , i n c l u d i n g f r o n t a l c o r t e x and b a s a l g a n g l i a , p a r i e t a l c o r t e x and t h a l a m u s ; c e r e b e l l u m and pons) Esophagus E y e (2 - w i t h o p t i c n e r v e ) Heart (with coronary v e s s e l s Intestine cecum colon duodenum ileum Kidneys (2) Liver (2) Lung and m a i n s t e m b r o n c h i Lymph nodes (mesenteric, mediastinal) Mammary g l a n d ( i n g u i n a l ) Nerve ( s c i a t i c ) Ovaries Pancreas Pituitary Prostate S a l i v a r y gland (mandibular) Seminal v e s i c l e s ( 2 ) S k e l e t a l muscle (biceps femoris) Skin Spinal cord ( c e r v i c a l ) Spleen Stomach Testes with epididymides Thymus Thyro i d/parathyro i d Trachea Urinary bladder Uterus Gross changes o f u n c e r t a i n nature (including a s e c t i o n o f normala p p e a r i n g p o r t i o n o f same t i s s u e ) T i s s u e masses o r s u s p e c t tumors w i t h r e g i o n a l lymph nodes

FEEDS

(Continued) Ophthalmoscopic

Examination

3, 6, 12, 18, 24 months


Controls


2 Concurrent Controls

5.0% (7500 mg/kg/day)

1.5% (2250 mg/kg/day)

0 . 5 % (750 mg/kg/day)

60/Sex/Group

2 Concurrent

2.0% (1000 mg/kg/day)

1.0% (500 mg/kg/day)

0 . 1 % (50 mg/kg/day)

70/Sex/Group

Number/Group Dose L e v e l s

F e m a l e s - 2 8 — 3 0 A p r i l 1980

M a l e s - 28-30 A p r i l 1978

Termination:

26 A p r i l 1978

Initiation:

F e m a l e s - 15 November 1979

M a l e s - 28 December 1979

Termination:

11 O c t o b e r 1977

Initiation:

Initiation Termination

No c o n s i s t e n t biologically significant compound r e l a t e d adverse e f f e c t s


Effects

9

ρ

to

a.

is

fx to S

ο

?

>

^

Co

S"

Cosm etic d

Mouse

Rat

Species

FD AND C BLUE NO. 1

I n t e r n a t i o n a l R e s e a r c h and D e v e l o p m e n t C o r p o r a t i o n

Table VIII


ELLECA ET


Mouse

Rat

Species


5.σ/ο (7500 mg/kg/day)

16 May 1980

Termination:

11 May 1978

0.5% (750 mg/kg/day)

1.5% (2250 mg/kg/day)

Initiation:

F e m a l e s - 18 A p r i l 1980

M a l e s - 4 March 1980

Termination:

60/Sex/Group


5.0% (2500 mg/kg/day)

2.5% (1250 mg/kg/day)

12 O c t o b e r 1977

Initiation:

Initiation Termination Effects


Statistically significant increase i n hyperplasia and t u m o r s i n u r i n a r y b l a d d e r s o f high-dose male rats.

FD AND C GREEN NO. 3 B i o / D y n a m i c s , I n c .

1.25% (625 mg/kg/day)

70/Sex/Group


T a b l e IX



2 Concurrent C o n t r o l s

5.054 (7500 mg/kg/day)

1.554 (2250 mg/kg/day)

Males - 21-22 February 1980

Termination:


*Not b i o l o g i c a l l y significant

Females - 3-4 A p r i l 1980

l b May 1978

Mammary Tumors (Males)*

Males - 18-19 February 1980

0.554 (750 mg/kg/day)

Bladder Tumors (Males)*

Termination:

Initiation:

B r a i n Gliomas and Granular C e l l Tumors (Males)*

Effects

18 October 1977

Initiation:

60/Sex/Group

2 Concurrent C o n t r o l s


1.0% (500 mg/kg/day)

0.5% (250 mg/kg/day)

70/Sex/Group


Females - 14-15 A p r i l 1980 * S t a t i s t i c a l l y s i g n i f i c a n t with high dose males only

Mouse

Rat

Species


Bio/Dynamics, Inc.

FD AND C BLUE NO. 2

Table Χ


Κ)

s

o

o

> r

H

r r m n >

Ν M

*>

Ο

Ο


Mouse

Rat

Species



Females - 30 March 1980

Males - 29 December 1979

Termination:

16 May 1978

0.5% (750 mg/kg/day)

1.5/o (2250 mg/kg/day)

Initiation:

60/Sex/Group

5.σ/ο - March 1981

Females - 7 March 1980

Males - 22 A p r i l 1980

5.σ/ο (2500 mg/kg/day) Controls

Termination:


2 Concurrent

5.σ/ο - 26 February 1979

3 November 1977

Initiation:


1.5/o (750 mg/kg/day)

0.75/o (375 mg/kg/day)

70/Sex/Group

Number/Group Dose Levels

Bio/Dynamics, Inc.

FD AND C YELLOW NO. 6

Table XI




Effects

(Λ

Ό

m m

τ]

> Ζ σ

Ό

τι Ο Ο

η

Η

X m ζ ο 2 δ

°


Mouse

Rat

Species

Termination:

2.0% (1000 mg/kg/day)


5.0% (7500 mg/kg/day)

2 May 1980

Termination:

3 May 1978

0.5% (750 mg/kg/day)

1.5% (2250 mg/kg/day)

Initiation:

5.0» - 24 F e b r u a r y 1981

60/Sex/Group


5.0% - 9 O c t o b e r 1978

1.0% (500 mg/kg/day)

31 December 1980

25 O c t o b e r 1977

Initiation:


0 . 1 % (50 mg/kg/day)

70/Sex/Group


Table XII FD AND C YELLOW NO. 5 I n t e r n a t i o n a l R e s e a r c h and D e v e l o p m e n t C o r p o r a t i o n




Effects


Mouse

Rat

Species

2 Concurrent

Controls

3.054 (4500 mg/kg/day)

1.054 (1500 mg/kg/day)

0.3% (500 mg/kg/day)

60/Sex/Group

Controls

(50 mg/kg/day) (250 mg/kg/day) (500 mg/kg/day) (2000 mg/kg/day)

2 Concurrent

0.1% 0.5% 1.054 4.054

70/Sex/Group


I n t e r n a t i o n a l Research

Table XIII

23 A p r i l 1980

Termination:

25 A p r i l 1978

Initiation:

27 March 1980 4% - 24 F e b r u a r y 1981

Termination:

18 O c t o b e r 1977 4% - 4 O c t o b e r 1978

Initiation:


and D e v e l o p m e n t C o r p o r a t i o n

FD AND C RED NO. 3




Effects

Food, Drug, and Cosmetic Colors: Toxicological Considerations - ACS

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