I GREAT L - · PDF fileof phosphate in detergents have led to an increase in the use of alternative detergent ... Detergent Builders, final report ... phosphates used as detergent

I GREAT L I SCIENCE ADVlSMW . - BOARD

IrnNAJIONAL I

JOINT C ~ S I O N

HEALTH IMPLICATIONS OF NON =NTA DETERGENT BUILDERS

(+

Statements and views presented in this report are those of the Task Force members and do not necessarily reflect the views and policies of the International Joint Commission or the Great Lakes Science Advisory Board.

GREAT LAKES SCIENCE ADVISORY BOARD

October 1980

Great Lakes Science Adv i so r y Board I n t e r n a t i o n a l J o i n t Commission Canada and t h e U n i t e d S ta tes

Members o f t h e Board:

The Task Force on t h e Hea l t h E f f e c t s o f Non-NTA Detergent B u i l d e r s as a requ i rement o f i t s Terms o f Reference, submits t h e f o l l o w i n g r e p o r t on i t s f i n d i n g s prepared by t h e members.

G.C. Becking

d - 7 L. F i s h b e i n

A.S. Kraus

sAd{ /u ) .I. Shibko Ad junc t Member

The Task Force wishes t o acknowledge t h e i n v a l u a b l e c o n t r i b u t i o n s o f resource persons Drs. Raymond Shapi ro and Rober t T a r d i f f t o d i scuss ions r e l a t i n g t o t h e human s a f e t y o f Type A Zeol i t e .

PREFACE

ACKNOWLEDGEMENTS

SUMMARY

INTRODUCTION

CARBONATES

TABLE OF CONTENTS

CARBOXYMETHY LOXY SUCC I NATE (CMOS)

CARBOXYME'THYLTARTRONATE ( Bu i.1 der "M" )

C ITRATES

PHOSPHATES

SOLUBLE SILICATES

ALUMINOSIL ICATES (TYPE A SODIUM ZEOLITE)

APPEND.IX A - Terms o f Reference f o r t h e Task Force on t h e H e a l t h E f f e c t s of Non-NTA Detergent B u i l d e r s

APPENDIX B - Membership, Task Force on t h e H e a l t h E f f e c t s o f Non-NTA Dete rgen t B u i l d e r s

APPENDIX C - Terms o f Reference f o r t h e Science A d v i s o r y Board

APPENDIX D - Membership, Sc ience Adv iso ry Board

PREFACE

The I n t e r n a t i o n a l J o i n t Commission G r e a t Lakes Sc ience A d v i s o r y B o a r d ' s Task F o r c e on t h e H e z l t h E f f e c t s o f Non-NTA D e t e r g e n t B u i l d e r s p r e s e n t s i t s f i n a l r e p o r t . The f o l l o w i n g b u i l d e r s were s t u d i e d and Chap te rs c o n t r i b u t e d b y i n d i v i d u a l members o f t h e Task Force, v i z :

0 Carbonates; 0 Carboxymethy loxsucc i n a t e (CMOS) ; 0 Carboxymethyl t a r t r o n a t e ( B u i l d e r "M"); 0 C i t r a t e s ; 0 Phosphates; 0 S o l u b l e S i l i c a t e s ; and 0 A1 umi n o s i 1 i c a t e s (Type A Sod i um Zeo l i t e ) .

ACKNOWLEDGEMENTS

The Task Fo rce i s i n d e b t e d t o those c o - o p e r a t i n g Soap and D e t e r g e n t A s s o c i a t i o n Member I n d u s t r i e s o f Canada and t h e U n i t e d S t a t e s f o r t h e i r i n v a l u a b l e a s s i s t a n c e i n p r o v i d i n g r e f e r e n c e m a t e r i a l on t h e d e t e r g e n t b u i l d e r s s t u d i e d . We a p p r e c i a t e a l s o t h e c o n t r i b u t i o n made b y M i s s A p r i l Welsh, S p e c i a l A s s i s t a n t t o Dr. Day, K i n g s t o n General H o s p i t a l , f o r h e r r e v i e w o f t h e d r a f t Task Fo rce r e p o r t and o f t h e b i b l i o g r a p h y c i t e d .

S p e c i a l thanks a r e due t o Dr. I r v i n g J. S e l i k o f f and h i s s t a f f a t t h e Mount S i n a i School o f Med ic ine , New York City, f o r h a v i n g g e n e r o u s l y h o s t e d two mee t ings f o r t h e Task F o r c e on f i b r o u s m i n e r a l s .

F i n a l l y , we express o u r a p p r e c i a t i o n t o t h e s t a f f o f t h e G r e a t Lakes Reg iona l O f f i c e , Windsor, o f t h e I n t e r n a t i o n a l J o i n t Commission f o r t h e i r a s s i s t a n c e i n p r e p a r i n g t h i s r e p o r t .

SUMMARY

I n t r o d u c t i o n ------------

Under t h e 1972 Great Lakes Water Q u a l i t y Agreement between Canada and t h e

U n i t e d Sta tes, measures were taken t o reduce t h e i n p u t o f phosphorus t o t h e

l a k e s f r o m m u n i c i p a l sewage; phosphate c o n t a i n i n g household d e t e r g e n t s hav ing

been determined as major c o n t r i b u t o r s . The consequent r e s t r i c t i o n s i n t h e use

o f phosphate i n de te rgen ts have l e d t o an inc rease i n t h e use o f a l t e r n a t i v e

de te rgen t -bu i 1 ders; . .

' Three task f o r c e s were e s t a b l i shed by t h e Science ~ d v i s o r ~ Board ( f o r m e r l y

t h e Research A d v i s o r y Board) ' t o r e v i e w t h e h e a l t h e f f e c t s o f these m a t e r i a l s

r e s u l t i n g from man's exposure t o t h e a q u a t i c env i ronment and t o r e v i e w t h e

e c o l o g i c a l s a f e t y o f 'a1 t e r n a t i v e b u i l d e r s i n c u r r e n t or p r o j e c t e d use, v i z : . . . , . : . . . . '1..

Task Force on t h e H e a l t h I m p l i c a t i o n s o f NTA ( n i t r i l o t r i a c e t i c a c i d ) ,

f i n a l r e p o r t pub l ished, May, 1977;

Task Force' on t h e E c o l o g i c a l E f f e c t s o f Non-Phosphate De te rgen t

B u i l d e r s , a r e p o r t on NTA, December, 1978, s t u d i e s o f o t h e r b u i l d e r s

a re s t i l l underway; and

e Task Force on t h e H e a l t h E f f e c t s o f Non-NTA Dete rgen t B u i l d e r s , f i n a l

r e p o r t due i n 1980.

B u i l d e r s S t u d i e d

The l a t t e r t a s k f o r c e . s t u d i e d t h e f o l l o w i n g b u i l d e r s :

1. Carbonates

2. Carboxymethyloxysuccinate (CMOS - Lever B r o t h e r s )

3. Carboxymethyl t a r t r o n a t e ( f o r m e r l y Bu i 1 der "M" - Monsanto Co. )

4. C i t r a t e s

5. Phosphates

6. s o l u 6 l e s i l i c a t e s

7. Type A Z e o l i t e ( a s y n t h e t i c a l u m i n o s i l i c a t e )

The task f o r c e was a ided i n i t s quest by . in format ion p rov ided under t h e

auspices o f t h e Canadian and U.S. Soap and Detergent Assoc ia t ions ,

r e s p e c t i v e l y . Conclusions were based on p resen t knowledge u s i n g c u r r e n t

s t a t e - o f - t h e - a r t techniques i n t o x i c o l o g i c a l assessment.

Resu l ts and Conclusions

A summary i s p rov ided below o f t h e f i n d i n g s o f t h e Task Force on t h e

Hea l th E f f e c t s o f Non-NTA Detergent B u i l d e r s as l i s t e d above.

1. Carbonates. The range o f a v a i l a b l e t o x i c i t y s t ud ies i n exper imenta l

animals i s l i m i t e d . No mutagenic o r t e r a t o g e n i c e f f e c t s have been

repor ted . Carbonates occur n a t u r a l l y i n water. They have a l ong h i s t o r y

o f use as f ood a d d i t i v e s and as such a re c l a s s i f i e d as Gene ra l l y

Recognized as Safe (GRAS). Carbonates have a l s o been used a t h i g h l e v e l s

f o r t h e t rea tment o f p e p t i c u l ce rs . It i s concluded t h a t t h e use o f

carbonates as de te rgen t b u i l d e r s poses no human h e a l t h hazard th rough

t h e i r c o n t r i b u t i o n o f carbonate t o d r i n k i n g water.

2. Carboxymethyloxysuccinate - CMOS (Lever Bro thers ) . The t o x i c o l o g i c a l

s t ud ies r e p o r t e d by Lever Bro thers i n d i c a t e t h a t CMOS i s e s s e n t i a l l y

non- tox ic and produces no demonstrable e f f e c t s o f c a r c i n o g e n i c i t y ,

mu tagen i c i t y o r t e r a t o g e n i c i t y . It was concluded t h a t , based on t h e Lever

Bro thers r e p o r t , CMOS poses no h e a l t h hazard t o man f rom ch ron i c i n g e s t i o n

f rom d r i n k i n g water.

3. Carboxymethy l ta r t rona te CMT - Former ly B u i l d e r "M" (Monsanto Co.). Th i s

m a t e r i a l i s n o t p r e s e n t l y c o m m e r c i a l l y a v a i l a b l e b u t may s t i l l be a -

candidate b u i l d e r . T o x i c o l o g i c a l s t u d i e s have been r e p o r t e d by t h e

Monsanto Company.

The task f o r c e concluded t h a t , f rom i t s chemical s t r u c t u r e . . and p r o p e r t i e s

and t h e r e p o r t e d r e s u l t s o f acute and subchronic t o x i c i t y t e s t s , CMT would

n o t be expected t o pose an undue h e a l t h hazard t o man. The types o f t e s t s

performed on CMT have been app rop r i a t e f o r s a f e t y e v a l u a t i o n b u t t h e lack

o f p r ima ry da ta i n most areas, i n c l u d i n g ch ron i c t o x i c i t y da ta and

r e p r o d u c t i v e s t ud ies i n a d d i t i o n t o t h e unknown g e n e t i c r i s k t o man,

prec ludes f u l l assessment o f t h e p o t e n t i a l h e a l t h a f f e c t s o f t h i s

substance f o l l o w i n g pro longed exposure by man t o t h e chemical i n d r i n k i n g

water.

C i t r a t e s . C i t r i c a c i d and i t s potassium, sodium and ca l c i um s a l t s a r e

GRAS substances, o c c u r r i n g bo th n a t u r a l l y and as a d d i t i v e s i n many foods

and a re a1 so normal human metabol i t e s o f carbohydrates. Acute, subchron ic

and ch ron i c t o x i c i t y t e s t s o f c i t r a t e s show no o r a l o r dermal e f f e c t s o r

eye i r r i t a t i o n . No mutagenic o r t e r a t o g e n i c e f f e c t s have been r e p o r t e d

no r i s p o t e n t i a l c a r c i n o g e n i c i t y suspected o f c i t r a t e s .

I n acknowledgment o f t h e f i n d i n g s o f these s t u d i e s and o f t h e World Hea l t h

O r g a n i z a t i o n ' s endorsement o f an " u n l i m i t e d " acceptab le d a i l y i n t a k e of

c i t r a t e s , t h e task f o r c e concludes t h a t t h e r e i s no ev idence t h a t

i n g e s t i o n of c i t r a t e s i n d r i n k i n g water would pose a h e a l t h hazard t o

humans .

5. Phosphates. Phosphates a r e u b i q u i t o u s i n n a t u r e and w i d e l y used i n

i n d u s t r y . They a re GRAS substances w i t h a l l owab le d a i l y i n t akes o f 800mg

o f phosphorus per day. Est imates o f phosphorus i n t a k e s i n f ood range from

300 t o 1500mg per day. Worst-case es t imates o f phosphorus i n t a k e s i n

d r i n k i n g water, assuming ex tens i ve use o f phosphate i n detergents ,

suggests i n t akes o f l e s s than 0.01 mg o f phosphorus per day. I n view o f

t h i s t . r i v i a l i n take , and because animal s t ud ies show t h a t ve r y l a r g e

q u a n t i t i e s by va r i ous r o u t e s o f a p p l i c a t i o n show no t o x i c i t y ,

mutagen ic i t y , t e r a t o g e n i c i t y o r c a r c i n o g e n i c i t y , i t i s concluded t h a t

phosphates used as de te rgen t b u i l d e r s should produce no adverse h e a l t h

e f f e c t s through t h e i r c o n t r i b u t i o n t o phosphorus i n d r i n k i n g water.

6. Solub le S i l i c a t e s . So lub le s i l i c a t e s f i n d a wide d i v e r s i t y o f uses,

i n c l u d i n g t h e f ood and med i c i na l i n d u s t r i e s . Sodium s i l i c a t e i s used as a

d e t e r g e n t b u i l d e r . I n t h e body, sodium s i l i c a t e i s m e t a b o l i z e d t o and

e x c r e t e d as s i l i c i c ac id , wh ich i s r e l a t i v e l y abundant i n n a t u r e and a

normal c o n s t i t u e n t o f human u r i n e .

Acute, subchron ic and c h r o n i c t o x i c i t y t e s t s i n d i c a t e t h a t sodium s i l i c a t e

i s e s s e n t i a l l y non- tox i c . No mutagenic e f f e c t s were observed and no d a t a

a r e a v a i 1 a b l e on e i t h e r t e r a t o g e n i c o r c a r c i n o g e n i c e f f e c t s . ,

The S e l e c t Committee of t h e F e d e r a t i o n o f American S o c i e t i e s f o r

Exper imenta l B i o l o g y (FASEB) conc luded i n a 1979 s t u d y t h a t sodium

s i l i c a t e s and c e r t a i n o t h e r s i l i c a t e s used as f o o d i n g r e d i e n t s do n o t

p r e s e n t a p u b l i c h e a l t h hazard under c u r r e n t usage. T h i s c o n c l u s i o n

suppor ted t h e r e s u l t s o f an e a r l i e r (1974) FAO/WHO t o x i c o l o g i c a l

e v a l u a t i o n o f s i l i c a and c e r t a i n s i l i c a t e s used as f o o d a d d i t i v e s , wh ich

e s t a b l i s h e d no l i m i t f o r t h e accep tab le d a i l y i n t a k e o f t h e s i l i c a t e s

s t u d i e d excep t f o r magnesium s i l i c a t e and t a l c . The t a s k f o r c e concurs

w i t h these c o n c l u s i o n s i n r e g a r d t o t h e human h e a l t h s a f e t y o f s o l u b l e

s i l i c a t e s used as d e t e r g e n t b u i l d e r s and t h e i r p o t e n t i a l c o n t r i b u t i o n o f

s i l i c o n t o d r i n k i n g water .

7. Type A Z e o l i t e ( a s y n t h e t i c a l u m i n o s i l i c a t e ) . A l u m i n o s i l i c a t e s a r e w i d e l y

u t i l i z e d i n t h e f o o d i n d u s t r y and i n t r e a t i n g d r i n k i n g water , n o t p o s i n g a

human h e a l t h hazard under c u r r e n t c o n d i t i o n s o f use. Cubic Type A

Z e o l i t e , w i t h a Na:Si :Al r a t i o o f 1 : l : l i s the rmodynamica l l y l e s s s t a b l e

than f o o d grade a l u m i n o s i l i c a t e , w i t h i t s co r respond ing r a t i o o f 1:1:13,

r a p i d l y fo rming s o l u b l e a lumina tes and s i l i c a t e s i n aqueous suspensions a t

a pH <8; hence r a r e l y b e i n g found -in t h e env i ronment .

Type A Z e o l i t e i s e s s e n t i a l l y n o n - t o x i c i n c h r o n i c t o x i c i t y t e s t s on

animals, t h e behav iou r b e i n g r e p r e s e n t a t i v e o f t h e s i l i c a t e s formed on

h y d r o l y s i s r a t h e r t h a n t h a t o f t h e a luminates . No c a r c i n o g e n i c o r

t e r a t o g e n i c e f f e c t s r e s u l t f r o m Type A Z e o l i t e exposure and i t i s u n l i k e l y

t o produce mutagenic behav iour .

C o n s i d e r i n g t h e normal exposure o f man t o n a t u r a l s i l i c o n compounds

w i t h o u t e v i d e n t h e a l t h hazards and t h e m i n i s c u l e i n c r e a s e i n s i l i c o n

l e v e l s i n d r i n k i n g w a t e r r e s u l t i n g f r o m t h e proposed use o f Type A Z e o l i t e

i n d e t e r g e n t s , t h e t a s k f o r c e conc ludes t h a t use o f t h i s z e o l i t e i n

d e t e r g e n t s i s n o t a n t i c i p a t e d t o l e a d t o adverse human h e a l t h e f f e c t s .

1. INTRODUCTION

Dur ing t h e l a s t two decades i t has become c l e a r t h a t phosphorus i s one of

t h e p r i n c i p a l n u t r i e n t s c o n t r i b u t i n g t o t h e process o f e u t r o p h i c a t i o n observed

i n many i n l a n d waters, i n c l u d i n g The Great Lakes. Whi le phosphorus l oad ings

t o t h e lakes have many o r i g i n s , t h e c o n t r i b u t i o n th rough domestic wastewater

was i d e n t i f i e d as one o f t h e p r i n c i p a l sources. I n r e c o g n i t i o n o f t h i s , t h e

1972 Great Lakes Water Qua1 i t y Agreement between Canada and t h e U n i t e d S ta tes

c a l l e d f o r t h e development and imp1 ementat ion o f waste t r ea tmen t programs and

o t h e r measures t o reduce i n p u t s o f phosphorus t o t h e l akes f rom mun i c i pa l

sewage. Phosphate-conta in ing de te rgen ts were i d e n t i f i e d as one o f t h e main

sources o f c o n t r o l l a b l e wastewater phosphorus. It was though t t h a t

r e s t r i c t i o n s on t h i s de te rgen t use o f phosphate would immediate ly reduce

phosphorus load ings t o t h e lakes i n t h e absence o f t h e wastewater t rea tment

technology and t r ea tmen t p l a n t s w i t h t h e c a p a b i l i t y t o reduce t h e phosphorus

f r om a l l sources i n mun i c i pa l wastewater t o an acceptab le e f f l u e n t l e v e l . The

r e s t r i c t i o n s which were t h e r e f o r e imposed on t h e use o f phosphate i n

de te rgen ts have r e s u l t e d i n t h e increased use o f a l t e r n a t i v e de te rgen t b u i l d e r

m a t e r i a l s and t h e i r consequent r e l e a s e t o t h e aqueous environment.

The I n t e r n a t i o n a l J o i n t Commission Science Adv i so r y Board c rea ted t h r e e

task f o r c e s t o i n v e s t i g a t e t h e s t a t e o f knowledge o f t h e h e a l t h and e c o l o g i c a l

effects of the builder materials being used or that were anticipated to be

used as a r e s u l t o f t h e r e s t r i c t i o n on t h e use o f t h e phosphate m a t e r i a l s .

A Task Force on t h e HEALTH IMPLICATIONS OF NTA AS A DETERGENT BUILDER has

completed i t s s t udy and r e p o r t e d i t s f i n d i n g s t o t h e IJC i n J u l y 1977.

(Reference: "A Report t o The Great Lakes Research Adv iso ry Board o f t h e

I n t e r n a t i o n a l J o i n t Commission on t h e Hea l t h Imp1 i c a t i o n s o f NTA lYay 1977". )

I n response t o t h i s r e p o r t , t h e Science Adv iso ry Board c'oncluded, " t h e Board 's

conc lus i on t h a t on t h e b a s i s o f h e a l t h hazard t h e r e i s no reasonable cause f o r

r e s t r i c t i n g t h e use o f NTA as a replacement f o r phosphate i n de te rgen ts i n The

Great Lakes Basin". (Reference: Annual Report o f t h e Research Adv i so r y

Board, IJC, J u l y 1977).

A second Task Force on t h e ECOLOGICAL EFFECTS OF NON-PHOSPHATE DETERGENT

BUILDERS has comple ted i t s s t u d y o f NTA and recommended, " t h a t NTA shou ld n o t

be p r o h i b i t e d f r o m use as a d e t e r g e n t b u i l d e r . " (Reference: E c o l o g i c a l

E f f e c t s o f Non-Phosphate De te rgen t B u i l d e r s : F i n a l Repor t on NTA, IJC

December 1978.) T h i s second t a s k f o r c e has c o n t i n u e d i t s s t u d y o f m a t e r i a l s

o t h e r t h a n NTA.

T h i s t h i r d Task Force on t h e HEALTH EFFECTS OF NON-NTA DETERGENT BUILDERS

was e s t a b l i s h e d t o c o n s i d e r t h e h e a l t h e f f e c t s of d e t e r g e n t b u i l d e r m a t e r i a l s

o t h e r t h a n NTA t h a t a r e c u r r e n t l y i n use o r a r e l i k e l y t o come i n t o use. T h i s

t h i r d t a s k f o r c e c o n s i s t e d o f s c i e n t i s t s s e l e c t e d from areas t h a t address t h e

h e a l t h e f f e c t s o f such m a t e r i a l s . . . I n a d d i t i o n , t o f a c i l i t a t e awareness o f

unpub l i shed d a t a and ongoing r e s e a r c h b e i n g conducted b y i n d u s t r y and

governments, l i a i s o n members were s o l i c i t e d f r o m t h e Soap and D e t e r g e n t

A s s o c i a t i o n s o f Canada and t h e U n i t e d S t a t e s and a p p r o p r i a t e f e d e r a l agenc ies

f r o m t h e two c o u n t r i e s . A d j u n c t members w i t h s p e c i f i c areas o f e x p e r t i s e were

added t o a s s i s t t h e t a s k f o r c e i n i t s rev iew. Appendix B l i s t s t h e t a s k f o r c e

and l i a i s o n members and Appendix A 1 i s t s t h e terms o f r e f e r e n c e o f t h e t a s k

f o r c e .

Seven m a t e r i a l s were i d e n t i f i e d f o r examina t ion b y t h e t a s k f o r c e : t h e

o r g a n i c p o l y c a r b o x y l a t e b u i l d e r s o t h e r t h a n NTA - c i t r a t e , carboxymethy loxy-

s u c c i n a t e (CMOS), and carboxymethy l t a r t r o n a t e ( B u i l d e r M), and t h e i n o r g a n i c

b u i l d e r s - carbonate , s i 1 i c a t e , a1 uminosi 1 i c a t e (Type A Zeo l i t e ) and phosphate.

One procedure f o l l o w e d b y t h e t a s k f o r c e was t o a r range i n d u s t r y and/or

company p r e s e n t a t i o n s on t h e c u r r e n t , known, i n f o r m a t i o n a v a i l a b l e on t h e

h e a l t h e f f e c t s o f t h e s e m a t e r i a l s . These were ar ranged e i t h e r as meet ings

w i t h w r i t t e n summaries o r as summaries p r o v i d e d o n l y .in w r i t t e n form. Task

f o r c e and a d j u n c t members rev iewed t h i s i n f o r m a t i o n and d i scussed and q u e r i e d

p e r t i n e n t aspects . Another procedure was t o under take r e s e a r c h o f a v a i l a b l e

i n f o r m a t i o n t h r o u g h computer a s s i s t e d r e v i e w s o f t h e pub1 i s h e d l i t e r a t u r e and

t h r o u g h s p e c i a l l y ar ranged conferences.

The f i n d i n g s o f t h e Task Force on t h e H e a l t h E f f e c t s o f Non-NTA D e t e r g e n t

Bu i l d e r s a r e p r e s e n t e d i n t h e f o l l o w i n g chap te rs .

I n t r o d u c t i o n

The a v a i l a b l e i n f o r m a t i o n on t h e b i o l o g i c a l e T f e c t s o f " ca rbona tes " has

been summarized i n t h e GRAS Monograph and i n t h e SCOGS ( S e l e c t Committee on

GRAS Substances) Repor t . These r e p o r t s were prepared f o r t h e U.S. FDA, as

p a r t of i t s ongoing su rvey o f t h e s a f e t y o f GRAS ( G e n e r a l l y Recognized as

Safe) f o o d chemica ls . The documents a r e a v a i l a b l e f r o m t h e N a t i o n a l T e c h n i c a l

I n f o r m a t i o n Serv ice , U. S. Department o f Com~nerce, VA 22151. The f o l l o w i n g

i n f o r m a t i o n has been a b s t r a c t e d f r o m t h i s document. I t i s cons ide red t o be

t h e most r e l e v a n t f o r e v a l u a t i n g t h e p o s s i b l e h e a l t h e f f e c t s o f carbonates t o

man.

Env i ronmenta l L e v e l s

The ma jo r source o f exposure o f man t o ca rbona tes and b i c a r b o n a t e s i s

th rough t h e d i e t ( f o o d and w a t e r ) . The average d i e t a r y i n t a k e o f carbonates

and b i c a r b o n a t e s b y a d u l t s th rough t h e i r use i n f o o d may exceed l g l d a y . T h i s

may be a gross ove res t ima te , s i n c e t h i s i s based on ( a ) t o t a l usage based on

t h e amount used i n foods and ( b ) t o t a l consumpt ion i n 1970 and a U.S.

p o p u l a t i o n o f 210 m i l l i o n . The a c t u a l l e v e l depends on t h e n a t u r e o f t h e d i e t

and f requency w i t h which c e r t a i n foods a re eaten, as w e l l as t h e

c h a r a c t e r i s t i c s o f t h e f o o d p r e p a r a t i o n process s i n c e carbonates and

b i ca rbona tes , wh ich a r e o f t e n used as l e a v e n i n g agents, a r e no l o n g e r . p r e s e n t

i n t h e processed f o o d ( 1 ) . The normal l e v e l o f ca rbona te and b i c a r b o n a t e i n

raw d r i n k i n g wa te r ranges f r o m 0 - 1 mg/L, a t 15-322 mg/L, r e s p e c t i v e l y ( ( 2 )

Tab le 1).

Es t ima tes o f t h e c o n t r i b u t i o n o f d e t e r g e n t carbonates t o env i ronmenta l

l e v e l s o f carbonates, based on an a v e r a g e ' l e v e l o f . 20% on a l l g r a n u l a r l a u n d r y

de te rgen t , show t h a t t h e c o n t r i b u t i o n t o raw sewage would be 9.3 mg/L, and t o

s u r f a c e water, 0.0093 mg/L (Tab le 2, ( 3 ) ) .

* C o n t r i b u t e d b y S. I . Shibko

TABLE 1

C03- AND HC03- CONCENTRATIONS IN RAW DRINKING WATER SUPPLIES

Avg . 118

Great Lakes mg /L

- co 3 HC03-

Milwaukee, Wisc. 0 134

Chicago, 111. 1 132

D e t r o i t , Mich. 1 95

Bu f fa lo , N.Y. 0 11 1

A v ~ . 25 . - Avg .

Eastern Coast mg/L

co3- HC03-

Newark, N.J. 0 2 3

Richmond, VA. 0 4 1

Char lo t te , N.C. 0 2 0

A t lan ta , Ga. 0 - 15

M i d-Wes t mg /L

co3- HC03-

.,Topeka, Kan. 0 322

Des Moines, Iowa 0 340

Kansas City, Mo. 0 198

Omaha, Neb. 0 - 238

TABLE 2

Bases

U.S. Laundry Detergent Market Volume1: 3 x l o 9 l b . / y r . f1974)

Produc t Composit ion: 20% Na2C03

U.S. ~ o p u l a t i o n ~ : 211, 381, 000 ( J u l y 1, 1974)

U.S. Sewage F.low3: 100 ga l /cap i ta /day CL CL

U.S. Sewage E f f l u e n t D i l u t i o n (Avg.) = 1:100

11. C a l c u l a t i o n - Raw Sewage

l b de te rgen t 0,20 Na2C03 3 3 x 10 year de te raen t x 454 g / l b x 10 mg/g ., e

= 9.3 mg/L 211 x l o 6 c a p i t a x 100 gal /cap/day x 365 days /year x 3.79 l i t r e s / g a l

111. C a l c u l a t i o n - Su r f ace Waters

Acute T o x i c i t y

(Dosage mg/kg Substance Animal No. Route body we igh t ) Ref. Po tass i um carbonate r a t s unk. o r a l 1870 Sodi um

(4 )

b ica rbona te r a t s unk. o r a l 4300 (a ) Sod i llm

( 5

b ica rbona te r a t s unk. o r a1 6000 ( b ) Sodi llm

( 5

b ica rbona te r a t s unk. o r a l 5500 ( c ) Sodi um

(5 )

b ica rbona te r a t s unk. o r a l 4850 ( d ) Sodi um

( 5

b ica rbona te r a t s u r~k . o r a l 5900 ( e ) ( 5

a i n a 20% s l u r r y b i n a 50% s l u r r y c dose volume 20 mL/kg d dose volume 50 mL/kg e dose vo lu~ne 20 rnL/kg + 30 NIL water

Subchronic T o x i c i t y and 'Metabol ism

The a v a i l a b l e da ta i n mammalian spec ies i s ex t reme ly l i m i t e d . Calc ium

carbonate f e d t o r a t s a t a d i e t a r y l e v e l o f 3% f o r 4 months r e s u l t e d i n

suppression o f growth. The decrease i n growth may have been due t o an

imbalance i n t h e Ca/P04 r a t i o , s i nce no a d d i t i o n a l phosphate was added t o

t h e exper imenta l d i e t s ( 6 ) . C f rom C 1 4 carbonates, i s r e a d i l y i nco rpo ra ted

i n t o t h e metabo l i c poo l . I t i s m a i n l y exc re ted b y r e s p i r a t i o n , b u t some i s

i nco rpo ra ted i n t o 1 i v e r glycogen, f a t s and p r o t e i n s ( 7 ) .

Reproduct ion S tud ies

Swiss w h i t e mice were f e d d i e t s c o n t a i n i n g 0, 0.5, 1 and 1.9% ca l c i um

carbonate. There was a s i g n i f i c a n t decrease i n t h e t o t a l weight o f t h e young

a t weaning i n t h e 1.9% group. The same e f f e c t was observed i n subsequent

l i t t e r s . Autopsy o f t h e o f f s p r i n g a t 21 days o f age, i n t h e 1.9% group,

showed p a l e speckled l i v e r s , en la rged h e a r t and smal l thymus glands ( 8 ) .

Chron ic T o x i c i t y and C a r c i n o g e n i c i t y

No d a t a a v a i l a b l e .

M u t a g e n i c i t y

The g e n e t i c a c t i v i t y o f sodium b i c a r b o n a t e and po tass ium ca rbona te was

assessed i n m i c r o b i a l assays, w i t h and w i t h o u t t h e a d d i t i o n o f mammalian

m e t a b o l i c enzymes. The i n d i c a t o r organisms used f o r t h e t e s t s were

Saccharomyces ce rv i seae , s t r a i n D4, and Sa lmone l la typh imur ium, s t r a i n s

TA-1535, TA-1537 and TA-1538. Sodium b i c a r b o n a t e and po tass ium ca rbona te were

n o t mutagenic e i t h e r d i r e c t l y o r i n t h e presence o f organ homogenates i n any

of t h e -- i n v i t r o systems t e s t e d ( 9 ) .

Te ra togen i c i t y

The f o l l o w i n g s t u d i e s have been c a r r i e d o u t t o e v a l u a t e t h e p o s s i b l e

t e r a t o g e n i c e f f e c t s o f . sodium ca rbona te and sodium b ica rbona te :

Sodium b i c a r b o n a t e

A l b i n o mice (CD-1 o u t b r e d m ice ) were dosed on day 6-15 of g e s t a t i o n b y

o r a l i n t u b a t i o n a t dose l e v e l s o f 5.80, 27.0,125.0, o r 580.0 . mg/kg. .

A l b i n o r a t s ( W i s t a r d e r i v e d s t o c k ) were dosed on day 6-15 o f g e s t a t i o n b y

o r a l i n t u b a t i o n a t dose l e v e l s o f 3.40, 15.8, 73.3, o r 340.0 mg/kg.

Sodium ca rbona te

A l b i n o mice (CD-1 o u t b r e d m ice ) were dosed on day 6-15 o f g e s t a t i o n b y

o r a l i n t u b a t i o n w i t h dose l e v e l s o f 3.40, 15.8, 73.4, o r 340.0 mg/kg.

A l b i n o r a t s ( W i s t a r d e r i v e d s t o c k ) were dosed on day 6-15 g e s t a t i o n b y

o r a l i n t u b a t i o n a t dose l e v e l s o f 2.45, 11.4, 52.9, o r 240.0 mg/kg.

Sodium b icarbonate

Dutch-bel ted r a b b i t s were dosed on day 6-18 o f g e s t a t i o n by o r a l

i n t u b a t i o n a t dose l e v e l s o f 3.30, 15.3, 71.2, o r 330.0 mg/kg. '

Parameters eva lua ted i nc l uded f e t a l m o r t a l i t y , i n t e r n a l , e x t e r n a l o r

s k e l e t a l a1 t e r a t i o n s . No f e t a c i d a l o r t e r a t o g e n i c e f f e c t s were r e p o r t e d (10) .

Stud ies w i t h Man

The avai 1 ab le i n f o r m a t i o n i s ' p r i m a r i l y de r i ved f rom t h e e f f e c t o f ' an

ext remely h i g h dosage carbonate t rea tment on p e p t i c u l c e r p a t i e n t s . 2,300

mglkg NaHCO3 admin is te red d a i l y f o r 3 weeks t o 33 p a t i e n t s r e s u l t e d i n marked a l k a l o s i s b u t no o the r adverse e f f e c t s . A l though t h e g lomeru lar

f i 1 t r a t i o n r a t e increased on dosing, no r e n a l damage was de tec ted (11) .

I n another study, one i n d i v i d u a l r ece i ved 32,000 g o f sodium b icarbonate

over a p e r i o d o f 20 months w i t h o u t any e f f e c t on acid-base balance, urea

clearance, o r r e d and wh i t e b lood c e l l counts o f hemoglobin (12) .

Normal humans absorbed 8-18% o f a s i n g l e o r a l dose o f 16.6-200 mglkg

CaC03 (13) . P a t i e n t s w i t h m i l d a l k a l o s i s absorbed 12-37% o f t h e dose

(14) . At plasma l e v e l s below 24 pM/L i n man, e s s e n t i a l l y a l l b i ca rbonate

f rom sodium b icarbonates e n t e r i n g t h e r e n a l t u b u l e i s absorbed. Above t h i s

l e v e l , t h e excess b ica rbonate i s excreted. I n g e s t i o n o f h i g h l e v e l s o f sodium

b icarbonate has caused potassium r e t e n t i o n and decreased e x c r e t i o n o f ca l c i um

i n t he u r i ne .

Summary

The range o f a v a i l a b l e i t u d i e s i n mammalian species i n c l u d i n g 'man i s q u i t e . ,

l i m i t e d , and does n o t meet t h e usual requi rements f o r s a f e t y eva lua t i on .

However, t h e use o f carbonates and b icarbonates a t ex t reme ly h i g h l e v e l s f o r

t h e t rea tment o f i n d i v i d u a l s w i t h p e p t i c u l c e r a t i o n i n d i c a t e s no adverse

e f f e c t s o t h e r than t r a n s i e n t changes i n acid-base r a t i o . I n normal

i n d i v i d u a l s , b i c a r b o n a t e i s r e a d i l y m e t a b o l i z e d and e x c r e t e d th rough t h e lungs

as Con o r th rough t h e k idneys. Abnormal e f f e c t s r e p o r t e d i n exper imen ta l

an imals f e d c a l c i u m carbonate appear t o be r e l a t e d t o t h e excess ca lc ium,

caus ing a m i n e r a l imbalance, r a t h e r t h a n t o ca rbona te o r b i .carbonate per - se.

Conc lus ions

The a v a i l a b l e b i o l o g i c a l d a t a i n d i c a t e t h a t t h e p resen t -day human exposure

t o carbonates and b ica rbona tes f r o m f o o d and o t h e r sources does n o t pose a

h e a l t h hazard. No hazard i s a n t i c i p a t e d f r o m t h e use o f carbonates and,

b i ca rbona tes as d e t e r g e n t b u i l d e r s , th rough t h e i r c o n t r i b u t i o n t o t h e loads o f

carbonates and b ica rbona tes i n d r i n k i n g water.

References

1. SCOGS-26 ( S e l e c t Corr~mi t t e e on GRAS Substances)-Eva1 u a t i o n o f t h e H e a l t h

Aspects o f Carbonates and B ica rbona tes as Food I n g r e d i e n t s (1975).

C o n t r a c t No. FDA 223-75-2004.

2. U.S.C.S. Paper (1962).

3. The P r o c t e r and Gamble Company. Communication t o Research A d v i s o r y Board

Task Force on t h e H e a l t h E f f e c t s o f Non-NTA Dete rgen t Powders. J u l y 15,

4. Smyth, H.F., Jr., C.P. Carpenter, C.S. N e i l , U.C. Pozzani, J.A. S t r l e g a l ,

and J.S. Nycurn. Range- f ind ing t o x i c i t y data. V I I . Am. Ind. Hyg. Ass.,

J. (1969), - 30, ( 5 ) , 470-476.

5. Food Ingred ients-Carbonates. Repor t p repared f o r U.S. F.D.A. b y

I n f o r m a t i c s , Inc., R o c k v i l l e , MD. C o n t r a c t No. FDA 72-104. 1972, p. 24.

6. Dalderup, L.M. N u t r i t i o n and c a r i e s . I X . The i n f l u e n c e o f c a l c i u m

carbona te on r a t c a r i e s induced by a c a r c i n o g e n i c d i e t . J. Dent. Res.,

(1959), 38, 1173-1177.

7. Skipper, H.E., L. White, Jr., and C.E. Bryan. S tud ies on t h e hazard

i nvo l ved i n t h e use o f c'*. J. ~ i ' o l . Chem., (1949), , 180, 1187-1195.

8. Richards, M.B., and W.A. Gre ig . The e f f e c t s o f a d d i t i o n s o f ca l c i um

carbonate t o t h e d i e t of b reed ing mice. E f f e c t s on r e p r o d u c t i o n and on

t h e h e a r t and thymus weights o f weanl ings. B r i t . J. N u t r i t i o n (1952), - 6,

265-280.

9. L i t t o n B ione t i c s , Inc . Mutagenic e v a l u a t i o n o f sodium b i ca rbona te

(compound FDA 71-79). Prepared f o r Food and Drug A d m i n i s t r a t i o n under

c o n t r a c t no. 223-74-2104. Kensington, MD. (36 pp. ) .

10. Food and Drug Research Labora to r ies , I n c . ~ e i a t o l o ~ i c e v a l u a t i o n o f FDA

71-84 (sodium carbonate) and FDA 71-79 (sodium b i ca rbona te ) i n m ice a n d

r a t s . Four f i n a l r e p o r t s prepared under DHEW c o n t r a c t no. FDA 71-260.

Waverly, N.Y. (54 pp.). . . , , . . . " - .

11. Van Goldsenhoven, G.M.T., O.V. Gray, A.V. Pr i ce , and P.H. Sanderson. The

e f f e c t of pro longed a d m i n i s t r a t i o n o f l a r g e doses o f sodium b i ca rbona te i n

men. C l i n . Sc i . (London), (1954), - 13, ( 3 ) , 383-401.

12. K i r sne r , J.B., and W.L. Palmer. S tud ies on t h e e f f e c t o f massive

q u a n t i t i e s o f sodium b ica rbona te on t h e acid-base e q u i l i b r i u m and on r e n a l

f u n c t i o n . Ann. I n t e r n a l Med., (1943), 2, ( I ) , 100-104.

13. Ivanov ich, P., H. Fe l lows, and C. Rich. The abso rp t i on o f ca l c i um

carbonate. Ann. I n t e r n . Med., (1967), 66, (5) , 917-923. -

14. P i t t s , R.F., J.L. Ayer, and W.A. Schiess. The r e n a l r e g u l a t i o n o f

acid-base ba lance i n man. 111. The r e a b s o r p t i o n and e x c r e t i o n o f

b icarbonate. J. C l i n . Invest . , (1949), - 28, 35-44.

3. CARBOXYMETHYLOXYSUCCINATE (CMOS)'


A p o t e n t i a l de te rgen t b u i l d e r developed r e c e n t l y , i t i s e m p i r i c a l l y

i somer i c w i t h c i t r i c ac id . The s t r u c t u r e i s shown i n F i g u r e 1. It should be

noted t h a t t h e a b b r e v i a t i o n "CMOS" stands f o r t h e t r i c a r b o x y l i c anion.

Sodium CMOS** Sodium C i t r a t e

FIGURE 1

Lever B ro the rs have c a r r i e d ou t t h e development work on CMOS and i t i s

t h e i r v iew t h a t t h i s m a t e r i a l may be used as a phosphate replacement. L , I

i I :

Data i n t h i s r ev i ew have been taken f r om a summary r e p o r t by Lever . . . . .

B ro the rs presented i n t h e Un i t ed S ta tes Department o f Heal th , Educat ion and

Welfare Committee t o Coord ina te Tox ico logy and Re1 a ted Programs, January '25, '

1977, as we1 1 as p r ima ry da ta suppl i e d by t h e Company. A l though t h e Company

has presented t h e t o x i c o l o g y i n f o rma t i on i n some d e t a i l , t h e m a t e r i a l has n o t

been pub1 i shed f o r peer rev iew.

Environmental Leve l s

A l though t h e t r i s o d i u m s a l t o f CMOS i s used i n de te rgen t products , t h e

sodium ca l c i um s a l t (NaCaCMOS) w i l l be t h e chemical spec ies found i n t h e wash

- - - --

* Con t r i bu ted by G.C. Becking ** Tr i sod ium 2-oxa-2,3,4-Butanetricarboxylate

water and t h e env i ronment . The p o l a r i t y and m e t a b o l i c f a t e i n t h e env i ronment

p r e c l u d e s b i o a c c u m u l a t i o n o r b i o m a g n i f i c a t i o n i n mammals. Env i ronmenta l

l e v e l s w i l l range from 0.015 t o 0.18 mg CMOS/L i n r e c e i v i n g streams depending

on whether secondary o r p r i m a r y sewage t r e a t m e n t i s u t i l i z e d . Based on t h e

m e t a b o l i c f a t e o f CMOS, l e v e l s i n d r i n k i n g wa te r a r e u n l i k e l y t o exceed 0.05

mg/L.


L e v e r B r o t h e r s h a v e . s t u d i e d i n some d e t a i l t h e a c u t e t o x i c i t y o f CMOS

s a l t s i n s e v e r a l animal spec ies . The r e s u l t s o f t h e s e t e s t s a r e summarized i n

Tab le 1. It i s apparent t h a t CMOS s a l t s a r e n o t a c u t e l y t o x i c t o mammals.

. % . ' . TABLE 1

ACUTE TOXICITY OF SODIUM CMOS

De te rgen t f o r m u l a t i o n s c o n t a i n i n g sodium CMOS were t e s t e d f o r consumer

s a f e t y . Powdered f o r m u l a t i o n s , s i m i l a r t o t h o s e a v a i l a b l e commerc ia l l y , b u t

c o n t a i n i n g CMOS, were e s s e n t i a l l y n o n - t o x i c w i t h an o r a l LC >5g/kg i n . s o

r a t s . They were n o n c o r r o s i v e i n an esophageal c o r r o s i v i t y t e s t , were o n l y

m i ld - to -modera te i r r i t a n t s i n an occ luded r a b b i t s k i n t e s t and were o n l y

Tes t

O r a l LDso

S k i n i r r i t a t i o n

Eye i r r i t a t i o n

Acu te Dermal

Species (M&F)

Rat

R a b b i t

R a b b i t

R a b b i t

R e s u l t

2.4-3.5 g /kg

N o n i r r i t a n t

N o n i r r i t a n t

LDSo>5.9g/kg

Acute I n h a l a t i o n Rat

Comments

LD,, NaCa CMOS ( s p e c i e s i n t h e env i ronment ) = 29.5 g /kg

I n t a c t and abraded s k i n u t i l i z e d

Cornea, I r i s and C o n j u n c t i v a s t u d i e d

No l e t h a l i t y a t 5.9 g /kg

6 -h r LCSo , >8.25 g/m

N o n s e n s i t i z i n g S e n s i t i z a t i o n

No l e t h a l i t y a t 8.25 g/m3

I n t r a d e r m a l i n j e c t i o n Guinea P i g

s l i g h t l y i r r i t a t i n g t o r a b b i t eyes. Human p a t c h t e s t s f u r t h e r con f i rmed t h e

s a f e t y of CMOS-containing de te rgen ts . De te rgen t f o r m u l a t i o n s c o n t a i n i n g

sodium CMOS were b o t h n o n i r r i t a t i n g and n o n s e n s i t i z i n g .

Subchron ic T o x i c i t y and Metabo l ism ------------------ ---------------

-Subchronic s t u d i e s i n r a t s a t doses o f sodium CMOS up t o 1.0 g/kg f o r 30

days and 4.5 g/kg f o r 10 days i n d i c a t e d m in ima l t o x i c i t y f o r t h i s m a t e r i a l .

I n t h e t e n day r a t s t u d i e s , marked d i a r r h e a , decreased g rowth r a t e and

inc reased sp leen we igh t were no ted o n l y a t doses approach ing t h e LDS0

(2.6-4.5 g/kg) . No changes i n h i s t o p a t h o l o g y , hematology o r u r i n a l y s i s were

r e p o r t e d , b u t an i n c r e a s e i n b l o o d u r e a n i t r o g e n and a decrease i n serum

g l o b u l i n was observed i n male r a t s f e d 1.0 g/kg/day f o r 30 days. The

c o n c l u s i o n t h a t CMOS e x e r t s i t s min imal t o x i c i t y v i a a n o n - s p e c i f i c

d i s t u r b a n c e o f pH, m i n e r a l and wa te r ba lance r e l a t e d t o i t s c h e l a t i n g

p r o p e r t i e s seems reasonable , a1 though d a t a s u b s t a n t i a t i n g t h i s h y p o t h e s i s a r e

l a c k i n g .

The b i o l o g i c a l f a t e o f sodium CMOS was i n v e s t i g a t e d i n t h e r a t , monkey a n d ' . , .

man. T i ssue l e v e l s were determined o n l y i n t h e r a t .

No a l t e r a t i o n s i n t i s s u e l e v e l s o r metabo l ism o f CMOS were seen i n r a t s

fed CMOS f o r s i x months compared t o c o n t r o l s . his i n d i c a t e s t h a t CMOS does -

n o t i nduce enzyme systems i n v o l v e d i n metabol i z i n g t h i s chemica l .

R e s u l t s of t h e a b s o r p t i o n / e x c r e t i o n s t u d i e s a r e p resen ted i n T a b l e 2.

A f t e r 72 hours, o n l y t r a c e s o f CMOS were found i n t h e r a t s k e l e t o n and

v i t a l organs; i t i s t h e r e f o r e apparent t h a t , even if absorbed, CMOS i s r a p i d l y

and c o m p l e t e l y c l e a r e d from t h e mammalian body. A p p r o x i m a t e l y 55% o f t h e CMOS

absorbed b y t h e r a t s was metabo l i zed , p r i m a r i l y t o o x a l a t e s and oxa loace ta tes ,

whereas i n p r ima tes , i n c l u d i n g man, l i t t l e i s absorbed and t h a t which i s

absorbed i s e x c r e t e d as unchanged CMOS.

TABLE 2

MAMMALIAN ABSORPTION AND EXCRETION OF CMOS

Chronic S tud ies

Species

Rat

Monkey

Man

Al though t h r e e separate ch ron i c s t u d i e s were c a r r i e d ou t i n r a t s , t h e , .

appropr ia teness o f t h e maximum dose u t i l i z e d (300 mg/kg) and t h e m a t e r i a l

t e s t e d should be examined. It i s t r u e t h a t no p a t h o l o g i c a l l e s i o n s were no ted

i n 6, 12 and 24 months, b u t i s unusual t o c a r r y o u t a ch ron i c t o x i c i t y s t udy

where no o v e r t s igns of t o x i c i t y were noted i n t h e h i g h dose animals. The

*average recove ry fromfhe G I . t r a c t s of monieyr a t nec!opsy 72 h r p o s t dos ing ( range 24-45%)

No. o f Sub jec ts Dose

- 3 : 25 mg; 12 I J C ~

3 487 mg; 232 uCi

3 500 mg

l ack o f observed t o x i c i t y may s imp l y be an i n d i c a t i o n o f t h e r e l a t i v e

n o n - t o x i c i t y o f CMOS, b u t such an hypo thes is r e q u i r e s exper imenta l

v e r i f i c a t i o n . The use o f NaCaCMOS i n c h r o n i c t o x i c i t y s t u d i e s would seem

appropr ia te . From t h e phys i ca l chemical p r o p e r t i e s o f CMOS i t can be

c a l c u l a t e d t h a t man w i l l be exposed t o t h e CaCMOS ion, n o t t o t h e CMOS species.

No t o x i c i t y was noted i n male o r female r a t s f e d d i e t s c o n t a i n i n g 63, 250,

1000 o r 4000 mg CMOS/kg d i e t f o r s i x months. I n a 16 month s t udy NaCaCMOS

( t h e p robab le env i ronmenta l spec ies) was f e d a t 1000 and 5000 mg/kg d i e t t o

male and female r a t s p r i o r t o and a f t e r mat ing, as w e l l as t o t h e progeny f o r

16 months. No t r e a t m e n t - r e l a t e d t o x i c response was noted. I n t h e f i n a l

ch ron i c t o x i c i t y t e s t , male and female r a t s were f e d d i e t s c o n t a i n i n g 22, 216

and 3600 mg CMOS/kg f o r one year and d i e t s c o n t a i n i n g 25, 246 and 4100 mg

NaCaCMOS f o r another year . A smal l decrease i n ova ry we igh t was noted, b u t no

Percent o f Dose Excre ted

morpholog ica l changes were noted i n t h e t i s s u e sec t i ons .

G. I. T r a c t

- - 30* - -

T o t a l

102.3

96.

U r i n e 24 h r

71.2

. 2

2

Feces 2 4 h r 24-72 h r 24-72 h r

2.3

2 .

.1

26.9

9

1.9

5 3

n o t assayed

When evaluated on the basis of growth rate, food consumption, survival,

gross observations, hematology and bross and microscopic observations of

tissue, it was concluded that levels of CMOS as high as 3600/4100 sg

Na3CMOS/NaCaCMOS/kg of diet caused no significant chronic adverse effects

in rats.

The effect of CMOS salts on reproduction in rats was studied in a three

generation study. No alterations in fertility, gestation, viability or

lactation indices were reported when Na3CMOS and NaCaCMOS were fed at

dietary levels of 63, 250, 1000 and 4000 mg/kg. In a second study, these

results were corroborated. Also in the latter study, no teratogenic effects

were reported in the F1, generation after feeding diets containing 3600 mg

Na3CMOS/kg of diet. The Company concludes that CMOS salts do not

adversely effect the reproductive ability, nor the embryonic and fetal

development in rats. Such a conclusion seems reasonable, in view of the

results of specific teratogenic experiments to be reported later in this

review.

Carcinoqenicity

The Company has reported no significant differences in tumour incidence

between control and animals consuming diets containing levels of Na3CMOS

and IVaCaCMOS as high as 3600 and 4100 mg/kg. The lack of tumour pathology in

the 16 month, two-generation chronic toxicity study can be taken as furter

evidence of the non-carcinogenicity,of CMOS salts. Before one can fully

accept such negative data, it is imperative to ascertain whether these doses

approached the maximum tolerated level. That is, a dose where some minimal

target organ toxicity, or other manifestation of minimal general toxicity was

noted.

Mutagenic i ty

The mutagenicity of Na3CMOS and NaCaCMOS was studied in Salmonella

typhimurium strains TA200, 1538, 1535, 98, and 1537 at levels up to

4000 pg/plate with and without activation by mammalian microsomes. Both

compounds were nonmutagenic. I n t h e host -media ted assay u t i l i z i n g - S.

typh imur ium-TA 1530 and 6-46, as w e l l as Saccharomyces c e r e v i s i a e D-3, no

m u t a g e n i c i t y was no ted a f t e r d o s i n g m ice w i t h 4, 40 o r 400 mg/kg body

No chromosome a b e r r a t i o n s were no ted i n male r a t s f e d d i e t s c o n t a i n i n g

l e v e l s o f NaCMOS as h i g h as 500 mg/kg f o r 3 g e n e r a t i o n s .

A f t e r s i x months exposure o f male r a t s t o d i e t a r y l e v e l s o f Na3CMOS o r

NaCaCMOS o f 4000 mg/kg, no mutagenic a c t i v i t y was no ted i n a dominant ' l e t h a l

t e s t . - .

I t was conc luded t h a t CMOS d i d n o t pose a mutagenic hazard t o man. The

n e g a t i v e m u t a g e n i c i t y d a t a a1 so suppor t t h e n e g a t i v e c a r c i n o g e n i c i t y d a t a

d iscussed p r e v i o u s l y . . .

T e r a t o l o g y

E x t e n s i v e t e r a t o l o g y exper imen ta t ion , u s i n g s e v e r a l p r o t o c o l s , was

r e p o r t e d by Lever B r o t h e r s . The t e r a t o l o g i c a l p o t e n t i a l o f Na3CMOS,

sodium c i t r a t e , d i s t i l l e d wa te r and V i t a m i n A were compared i n r a t s . Wh i le

V i t a m i n A caused a s i g n i f i c a n t number o f t e r a t o g e n i c changes, no such adverse

e f f e c t s were seen i n t h e water c o n t r o l , CMOS o r c i t r a t e dosed animals. Doses

of-NaCMOS up t o 300 mg/kg were g i v e n between days 6-15 o f g e s t a t i o n , and doses

o f NaCMOS as h i g h a s 1000 mg/kg were a d m i n i s t e r e d t o r a t s between days 1-7,

7-14, 14-21 and 1-21 o f g e s t a t i o n ( p e r i o d o f organogenesi s ) . No mobi 1 i z a t i o n

o f heavy m e t a l s b y CMOS was r e p o r t e d , n o r was any p o t e n t i a t i o n o f cadmium

t o x i c i t y n o t e d i n ' t h e hamster.

Lever B r o t h e r s have concluded, on t h e b a s i s o f t h e i r t o x i c o l o g i c a l

examinat ion, t h a t CMOS poses no hazard t o man f r o m c h r o n i c i n g e s t i o n f r o m

d r i n k i n g water. Acute t o x i c i t y was s i m i l a r t o o t h e r b u i l d e r s now i n use.

Based on t h e i r summary r e p o r t , and t h e p r i m a r y d a t a a v a i l a b l e t h i s c o n c l u s i o n

i s p r o b a b l y v a l i d .

4. CARBOXYMETHY LTARTRONATE (Builder 'M')*


Monsanto has developed a new p o l y c a r b o x y l i c a c i d de te rgen t b u i l d e r , c a l l e d

carboxymethyl t a r t r o n i c a c i d (CMT) . Th i s b u i l d e r has o f t e n been r e f e r r e d t o as

B u i l d e r "Mu, and t h e s t r u c t u r e s o f t h e major components a re shown i n F i g u r e 1.

COONa FOONa COONa COON a COONa FOONa 1 I 1 . . I

H$-0 - CH 2 HC-0- CH 2HC-0 -CH2 I

COONa 100Na . .

COON a

Sodium Carboxy- Sodium D i t a r t r o n a t e Sodium D i g l y c o l a te methyl t a r t r o n a t e (7%) ( 3%) (NaCMT - 76%)

F i g u r e 1 -

The b u i l d e r i s composed o f a l l t h r e e chemicals shown i n F i g u r e 1. The term

CMT used i n t h i s r e p o r t r e f e r s t o t h e m i x t u r e used i n detergents .

A t present , t h i s m a t e r i a l i s n o t commerc ia l ly ava i l ab le ; b u t ' g i v e n t h e

proper economic s i t u a t i o n , t h e chemical p r o p e r t i e s o f CMT i s a b u i l d e r m igh t

p l ace i t i n a c o m p e t i t i v e p o s i t i o n w i t h o the r chemicals. For t h i s reason, . . a

d i scuss ion o f t h e human h e a l t h aspects o f t h i s b u i l d e r seems i n order . . .

. . . > , ,

Monsanto Company has in formed t h e Task Force t h a t research i s s t i l l

proceeding on CMT, b u t w i t h a v e r y low p r i o r i t y . The o n l y r e p o r t a v a i l a b l e on

CMT was pr.epared by Monsanto ( B u i l d e r "IY", Environmental and Human Safety,

March 1978). No p r ima ry t o x i c o l o g i c a l da ta have been reviewed, nor have any

o f t h e t e s t r e s u l t s been pub l i shed f o r peer review.

Environmental Level s

It has been es t imated t h a t d r i n k i n g water cou ld c o n t a i n l e s s than 0.02 mg . .

CMT/L under use c o n d i t i o n s where a l l d e t e r g e n t s t o n t a i n e d 25% w/w CMT. Based

* Con t r i bu ted by G.C. Oecking

on chemical p r o p e r t i e s and economic f a c t o r s , CMT would never be used a t t h i s

1 eve1 .


The o r a l LDS0 f o r CMT i n r a t s has been r e p o r t e d as 2-3 g/kg w h i l e t h e

dermal MLD i n r a b b i t s was found t o be g r e a t e r than 8 g/kg. CMT was repo r ted

as n o n - i r r i t a t i n g t o r a b b i t eyes and sk in . No evidence o f p r ima ry i r r i t a t i o n ,

f a t i g u i n g o r s e n s i t i z a t i o n was found i n 200 human sub jec ts .

Subchronic T o x i c i t y and Metabol ism - -

Monsanto has c a r r i e d ou t 90-day f eed ing s tud ies i n dogs and r a t s . The r a t

appeared t o be more s e n s i t i v e t o CMT than dogs. No adverse e f f e c t s were

repo r ted i n dogs f e d d i e t s c o n t a i n i n g 10,000 mg CMT/kg f o r 90 days, whereas a

no -e f f ec t l e v e l i n r a t s o f 3000 mg/kg d i e t was repor ted . The o n l y adverse

e f f e c t i n r a t s f e d CMT a t 10,000 mg/kg d i e t was an increased u r i n a r y e x c r e t i o n

o f calc ium. I n a 30-day study, r a t s were f e d d i e t s c o n t a i n i q g 3000 mg CMT/kg

d i e t and no enhancement o f methyl mercury t o x i c i t y by CMT was noted. I n a l l

subchronic s tud ies , t h e i n d i c a t q r s o f t o x i c i t y were m o r t a l i t y , gross and

h is topa tho logy , hematology and u r i n a l y s i s .

14 Metabolism da ta on CMT are minimal, based o n l y on s i n g l e doses of

C - l abe l l ed CMT admin is te red t o r a t s . I n such experiments, 90 percen t o f

t h e dose was excre ted i n 48 hours; 58 percen t i n t h e feces and 32 percen t i n

t h e u r i ne . I t i s s t i l l n o t c e r t a i n whether t h e excre ted m a t e r i a l i s unchanged

CMT o r va r i ous metabo l i tes .

Chronic T o x i c i t y and C a r c i n o g e n i c i t y

The ch ron i c t o x i c i t y and c a r c i n o g e n i c i t y t e s t s have n o t been r e p o r t e d i n

f i n a l form. A 2-year r a t s t udy and an 18-month mouse s tudy a t NaCMT d i e t a r y

l e v e l s between 1 and 10 g/kg were t o be completed i n 1979. A 2-year s tudy i n

r a t s , where d r i n k i n g water con ta ined 1.7g/L o f N ~ C ~ C M T , was a l so due t o be

completed i n 1979. The o n l y i n f o r m a t i o n rece i ved t o da te i n d i c a t e s t h a t no

compound-related, i n - l i f e t o x i c s igns were noted i n these ch ron i c s tud ies .


The sodium and c a l c i ~ ~ m s a l t s o f CMT have been t e s t e d f o r p o t e n t i a l

m u t a g e n i c i t y i n f i v e s t r a i n s of Sa lmone l la t yph imur ium and Saccharomyces

c e r e v i s i a e D-3 w i t h and w i t h o u t m e t a b o l i c a c t i v a t i o n . Even when 5 p e r c e n t

s o l u t i o n s o f NaCMT were s t u d i e d , r e s u l t s were n e g a t i v e .

Dominant l e t h a l t e s t s i n m ice f e d d i e t s c o n t a i n i n g 5 g NaCMT/kg o r

p resen ted d r i n k i n g water c o n t a i n i n g 1.7 mg CaCMT/L were n e g a t i v e . A lso, a f t e r

8 weeks o f dos ing, no chromosome a b e r r a t i o n s were found i n bone marrow c e l l s .

A t a l e v e l o f 1.7 g NaCaCMT/L i n d r i n k i n g water, two r e c i p r o c a l

t r a n s l o c a t i o n s were no ted i n 400 F1 male mice. Nega t i ve r e s u l t s were

o b t a i n e d a t 0.17 g NaCaCMT/L. The s i g n i f i c a n c e o f t h e s e r e s u l t s i s as y e t

unknown.

T e r a t o g e n i c i t y

The t e r a t o g e n i c p o t e n t i a l o f CMT was s t u d i e d i n r a t s and r a b b i t s , u s i n g

f e t a l m o r t a l i t y , i n t e r n a l , e x t e r n a l o r s k e l e t a l a l t e r a t i o n s 9 - a s i n d i c a t o r s of

t e r a t o g e n i c i t y . Doses o f 100-1000 mg NaCMT/kg were g i v e n o r a l l y t o r a t s

between days 6-18 o f g e s t a t i o n . No f e t a c i d a l o r t e r a t o g e n i c e f f e c t s were

noted. S i m i l a r l y , no f e t a c i d a l o r t e r a t o g e n i c e f f e c t s were r e p o r t e d i n

r a b b i t s g i v e n o r a l doses o f 100-300 mg/kg between days 6-18 o f g e s t a t i o n .

I n t h e r a t , an o r a l dose o f 100 mg/kg o f NaCMT d i d n o t a l t e r t h e c l a s s i c a l

t o x i c i t y and t e r a t o g e n i c e f f e c t s o f me thy l mercury.

Monsanto Company has r e p o r t e d t h a t m u l t i g e n e r a t i o n r e p r o d u c t i v e s t u d i e s

a r e i n progress. No e x p e r i m e n t a l r e s u l t s a r e a v a i l a b l e .

Summary

From i t s chemica l s t r u c t u r e and p r o p e r t i e s , and t h e r e s u l t s o f a c u t e and

subchron ic t o x i c i t y t e s t s , one would n o t expec t ClYT t o pose an undue h e a l t h

hazard t o man. The t y p e s o f t e s t s c a r r i e d o u t on CMT have been a p p r o p r i a t e

f o r s a f e t y e v a l u a t i o n but , g i v e n t h e l a c k o f p r i m a r y d a t a i n most areas, t h e

l a c k o f c h r o n i c t o x i c i t y d a t a and r e p r o d u c t i v e s t u d i e s , as w e l l as t h e unknown

g e n e t i c r i s k t o man one cannot assess f u l l y t h e p o t e n t i a l h e a l t h e f f e c t s o f

CMT a f t e r c o n t i n u a l exposure t o t h i s c h e m i t a l i n d r i n k i n g water .


T h i s r e p o r t concerns t h e h e a l t h aspects o f u s i n g c i t r i c a c i d and i t s s a l t s

as b u i l d e r s i n househo ld -de te rgen ts . The most e x t e n s i v e uses f o r c i t r a t e s a r e

i n t h e f o o d and pharmaceut ica l i n d u s t r i e s . C i t r a t e s e f f e c t i v e l y c h e l a t e most

d i v a l e n t and t r i v a l e n t i o n s ( I ) , t h u s making e f f e c t i v e d e t e r g e n t b u i l d e r s .

Other i n d u s t r i a l uses i n c l u d e meta l c l e a n i n g , e l e c t r o l y t i c p o l i s h i n g and

p l a t i n g , dyeing, water t r e a t m e n t and o t h e r m i s c e l 1 aneous i n d u s t r i a l processes.

C i t r a t e s ( p a r t i c u l a r l y sodium and potass ium) a r e u b i q u i t o u s i n nature ,

appear ing i n smal l amounts i n most organisms. C i t r a t e i s a normal m e t a b o l i t e

i n most l i f e f o r m s d u r i n g t h e metabol ism o f carbohydrate .

Env i ronmenta l L e v e l s

I n genera l , ambient c i t r a t e l e v e l s i n t h e a q u a t i c env i ronment range

between0.025 - 0.145 mg/L, w h i l e va lues as h i g h as 8.7 mg/L have been

r e p o r t e d ( 2 ) . The median c i t r a t e c o n c e n t r a t i o n i n sewage e f f l u e n t has been

found t o be 0.2 mg/L. C i t r a t e l e v e l s as h i g h as 10 mg/L a re r a p i d l y degraded

t o normal ambient l e v e l s ( 2 ) . . .

Long-term human exposure t o c i t r a t e r e s u l t i n g f r o m d e t e r g e n t use would be:'

p r i m a r i l y o r a l , t h rough i n g e s t i o n o f d r i n k i n g water. On t h e average, d r i n k i n g

water c o n t a i n s 0.002 - 0.005 mg c i t r a t e / L and t h i s would i n c r e a s e t o 0.0085

mg/L i f a l l d e t e r g e n t s were b u i l t w i t h 25% c i t r a t e ( 2 ) . I f t h i s occur red

w i t h o u t degradat ion, man would consume 0.02 mg c i t r a t e / d a y f r o m h i s d r i n k i n g

water, compared t o 4.5 g from food sources ( 3 ) .

............................ * C o n t r i b u t e d by G.C. Becking


A succ inc t summary o f t h e acute t o x i c i t y o f c i t r a t e s i s presented i n a

r e p o r t t o t he Food and Drug Admin i s t r a t i on (3 ) . The o r a l LDso o f sodium .-

c i t r a t e i n mice was 7.1 g/kg. A l l mice r e c e i v i n g 4.8 g c i t r a t e / k g surv ived .

Another s tudy i n d i c a t e d t he o r a l LDso f o r c i t r i c a c i d i n mice was 5 g/kg

and i n r a t s as 12 g/kg. The s igns o f acute t o x i c i t y f r om c i t r i c a c i d i n mice

and r a t s are those o f o rgan ic ac idos i s and ca lc ium de f i c i ency .

Acute o r a l t o x i c i t y s t u d i e s o f c i t r i c a c i d i n man have n o t b e e n repor ted ,

b u t d a i l y doses o f potassium c i t r a t e as h i g h as 10 g have been used t o render

u r i n e l e s s a c i d and as a m i l d d i u r e t i c ( 4 ) .

Subchron i c T o x i c i t y

Rats admin is tered c i t r i c a c i d i n t h e d i e t (0.6 g/kg body we igh t ) f o r 90

days e x h i b i t e d no s i g n i f i c a n t changes i n body weight gain, b lood parameters,

h i s t opa tho logy o r reproduc t i o n (5 ) . No behav ioura l , biochemica l o r h i s t o -

p a t h o l o g i c a l abno rma l i t i es were produced i n dogs f e d c i t r i c acid, 1.38 g/kg,

f o r 112-120 days (4 ) .

It has been repo r ted t h a t c i t r i c a c i d f e d t o r a t s a t a l e v e l o f 4.67 g/kg

body weight f o r 6 weeks produced a s l i g h t thynus a t rophy and mic roscop ic

s p l e n i c f o l l i c l e s (3 ) .

Chronic T o x i c i t y

Horn, -- e t al., ( 6 ) f e d c i t r i c a c i d t o r a t s a t l e v e l s o f 1.2 and 2.0 g/kg

body weight f o r 2 years. Su rv i va l r a t e s were n o t a f f ec ted , b u t t r e a t e d

animals grew more s l o w l y t h a n c o n t r o l s . A f t e r 2 years, organ weights we re ' no t

a f f e c t e d and no h i s t o p a t h o l o g i c a l changes were seen i n t h y r o i d , lung, hear t ,

l i v e r , spleen, k idney, adrenal , stomach, sma l l and l a r g e i n t e s t i n e , pancreas,

bone marrow o r t e s t i c u l a r t i s sue .

Rats f e d d i e t s c o n t a i n i n g 1 . 2 % ' c i t r i c a c i d ( d a i l y i n t a k e 0.8 g /kg) stiowed

no h a r m f u l e f f e c t s w i t h r e s p e c t t o g rowth i n , 2 success ive g e n e r a t i o n s ove r a

90 week p e r i o d . No r e p r o d u c t i v e e f f e c t s were noted, n o r were s i g n i f i c a n t

changes no ted i n hematology o r h i s t o p a t h o l o g y ( 4 ) .

C a r c i n o g e n i c i t y

No c a r c i n o g e n i c i t y b i o a s s a y has been c a r r i e d o u t on c i t r i c a c i d o r i t s

s a l t s . If c i t r a t e was c a r c i n o g e n i c t o r a t s , one would have expected

s i g n i f i c a n t h i s t o p a t h o l o g i c a l changes i n t h e c h r o n i c s t u d i e s s i n c e such h i g h

doses were u t i l i z e d (4,6).


C i t r i c ac id , po tass ium and sodium c i t r a t e have been s t u d i e d i n a v a r i e t y

o f systems, b o t h m i c r o b i a l and mammalian, w i t h and w i t h o u t m e t a b o l i c

a c t i v a t i o n . M i c r o b i a l t e s t s i n Salmonel 1 a t yph imur ium ( s t r a i n s TA-1535, 1537

and 1538) and Saccharomyces c e r e v i s i a e , 04 were n e g a t i v e f o r sodium and

potass ium c i t r a t e .

. .

C i t r i c a c i d was found t o be non-mutagenic i n a host -media ted assay u s i n g

S. t yph imur ium TA-1530 and 6-46, and & c e r e v i s i a e D 3 . Doses up t o - 3.5 g /kg body we igh t were u t i l i z e d . C i t r i c a c i d g i v e n o r a l l y t o r a t s a t 3 g!k~!d?.~-

f o r 5 days d i d n o t produce s i g n i f i c a n t chromosome a b e r r a t i o n s . S i m i l a r l y , a t

0.6 mg/rr~L o f niedia, c i t r i c a c i d d i d n o t produce s i g n i f i c a n t chromosome aber-

r a t i o n s i n human embryo , l u n g c e l l s (WI-38). C i t r i c a c i d was a l s o found t o be

n e g a t i v e in t h e dominant l e t h a l assay, i n r a t s a t doses o f 3 g ' /kg /da j f o r 5 days ( 3 ) .

T e r a t o g e n i c i t y

The t e r a t o g e n i c p o t e n t i a l o f c i t r i c a c i d has been s t u d i e d i n , m i c e , r a t s ,

hamsters, and r a b b i t s by a d m i n i s t r a t i o n o f doses between 241 - 425 mg/kg

d u r i n g t h e p e r i o d o f organogenesis. No adverse e f f e c t s on o v a l i m p l a n t a t i o n ,

m a t e r n a l o r f e t a l s u r v i v a l were noted. The number of a b n o r m a l i t i e s seen i n

e i t h e r s o f t o r s k e l e t a l t i s s u e s d i d n o t d i f f e r i n c o n t r o l o f t r e a t e d an imals ( 3 ) .

Summary

No evidence e x i s t s t o i n d i c a t e man's p r e s e n t d a i l y i n t a k e o f a p p r o x i m a t e l y

4.5 g o f c i t r a t e poses a h e a l t h hazard. Even i f c i t r a t e s were used a t t h e

l e v e l o f 25% i n a l l d e t e r g e n t s ( h i g h l y u n l i k e l y ) , man's d a i l y i n t a k e would

inc rease b y l e s s t h a n 0.001% (0.4 mg/day). The World H e a l t h O r g a n i z a t i o n ( 4 )

i n d i c a t e d t h a t an accep tab le d a i l y i n t a k e f o r c i t r a t e s was " n o t l i m i t e d " . The

use o f c i t r a t e s i n d e t e r g e n t s poses no hazard t o man.

References

1. A. Davidson, B.M. M i lw idsky . S y n t h e t i c de te rgen ts , 5 t h ed; CRC Press,

1972, p. 78.

2. P f i z e r and P r o c t o r & Gamble Companies. Long-term s a f e t y o f d e t e r g e n t

c i t r a t e s . Repor t t o t h e IJC Task Force on H e a l t h E f f e c t s o f Non-NTA

Dete rgen t B u i l d e r s . March 1, 1979.

3. Fed. Am. Soc. Expt. B i o l . E v a l u a t i o n of t h e h e a l t h aspects o f c i t r i c ac id ,

sodium c i t r a t e , potass ium c i t r a t e , c a l c i u m c i t r a t e , ammoniuni c i t r a t e ,

t r i e t h y l c i t r a t e , i s o p r o p y l c i t r a t e and s t e a r y l c i t r a t e as f o o d

i n g r e d i e n t s . Repor t t o Food and Drug A d m i n i s t r a t i o n C o n t r a c t #FDA

223-75-2004, 1977.

4. World H e a l t h Organ iza t ion , A n t i o x i d a n t s . C i t r i c A c i d and i t s Calcium,

Potassium, and Sodium S a l t s , T o x i c o l o g i c a l E v a l u a t i o n o f Some Food

A d d i t i v e s i n c l u d i n g A n t i c a k i n g Agents, A n t i m i c r o b i a l s , A n t i o x i d a n t s ,

E m u l s i f i e r s and Th icken ing Agents. Geneva, World H e a l t h O r g a n i z a t i o n

1974. W I WI4H, NO. 5, (1974), 170-172.

5. Krop, S., and H. Gold. On t h e t o x i c i t y of h y d r o x y a c e t i c a c i d a f t e r

p ro longed a d m i n i s t r a t i o n : con~par i son w i t h i t s s o d i ~ ~ m s a l t and c i t r i c and

t a r t a r i c ac ids . J. Am. Pharm. Assoc. Sc i . ~ d . ' , (1945), - 34, 86-89,

6. Horn, H.J., E.G. H o l l a n d and L.W. Haz le ton. S a f e t y o f a d i p i c a c i d as

compared w i t h c i t r i c a c i d and t a r t a r i c ac id . J. A g r i c . Food Chem.,

(1957), - 5, 759-761. 30

6. PHOSPHATES *

I n t r o d u c t i o n -----------

Phosphorus i s an element e s s e n t i a l t o a l l f o r m s - o f l i f e , b o t h animal and

p l a n t . Phosphorus i s p resen t i n water as orthophosphate, and i n s o i l s as

s o l u b l e or thophosphate and t h e i n s o l u b l e a p a t i t e form. Enough CO2 i s

p r e s e n t i n s o i l water, i n e q u i l i b r i u m w i t h t h e C02 i n t h e a i r , t o c r e a t e

s l i g h t l y a c i d i c c o n d i t i o n s , and t h u s p e r m i t c o n t i n u i n g s o l u b i l i z a t i o n of t h e

a p a t i t e t o . . t h e or thophosphate f o r m t h a t can be u t i l i z e d by organisms ( 1 ) .

Many o t h e r chemical forms o f phosphorus an ion e x i s t ; t h e r e l e v a n t ones a r e

d iscussed below.

Phospha te - t rans fe r r e a c t i o n s a r e v i t a l t o energy t r a n s f e r and t o t h e

metabol ism o f l i p i d , p r o t e i n and carbohydrate . Phosphate i s a l s o an e s s e n t i a l

p a r t o f t h e n u c l e i c a c i d s t r u c t u r e . Phosphorus i s a major component o f t h e

body, p redominan t l y i n t h e bones and t e e t h . The b lood serum l e v e l s o f

phosphorus i n a d u l t s a r e u s u a l l y i n t h e 2.5-4.5mg/100mL range (1, 2, 3 ) .

Phosphates have many i m p o r t a n t uses i n i n d u s t r y and a g r i c u l t u r e . S a l t s o f

v a r i o u s forms o f phosphate have been used e x t e n s i v e l y i n d e t e r g e n t s and

c l e a n i n g agents f o r many years . I n d e t e r g e n t s t h e condensed and p o l y m e r i c

phosphate s a l t s f u n c t i o n as detergency b u i l d e r s w h i l e t h e s a l t s o f

or thophosphate p r o v i d e a l k a l i n i t y and emu1 s i f y i n g a c t i o n ( 4 ) . Approx imate ly

95% o f t h e phosphate used as d e t e r g e n t b u i l d e r i s sodium t r i p o l y p h o s p h a t e ,

Na5P3010, and most o f t h e r e s t i s t e t r a p o t a s s i u m pyrophosphate, K4P207,

and t e t r a s o d i um pyrophosphate, Na4P207 ( 5 ) . T r i sod ium orthophosphate, Na3P04,

has been used i n heavy d u t y c l e a n i n g compounds o r , i n t h e dodecahydrate form,

i s s o l d as such f o r t h a t purpose ( 4 ) .

There have been t h r e e genera l rev iews r e l a t i n g t o t h e s a f e t y o f phosphates

t o humans. A 1978 r e v i e w ( 5 ) by t h e FMC Corpora t ion , Monsanto, O l i n and

* C o n t r i b u t e d b y R.D. O ' B r i e n

P r o c t e r 81 Gamble dea ls s p e c i f i c a l l y w i t h de te rgen t phosphates, t h e i r

chemist ry , i n d u s t r i a l p roduc t i on methods and amounts and l e v e l s achieved i n

water and sewage. The Food and Drug A d m i n i s t r a t i o n rev iewed i n 1975 ( 3 ) t h e

h e a l t h e f f e c t s o f phosphates i n foods. The Na t i ona l Academy o f Sciences

surveyed ( 6 ) i n 1972 t h e e x t e n t o f use o f phosphate and o t h e r f o o d chemicals

" g e n e r a l l y recogn ized as safe."

Leve ls

S ince no known organisms can syn thes i ze t h e phosphate anion, i t has t o be

absorbed th rough t h e f ood supply. Animal and ce rea l p roduc ts are q u i t e h i g h

i n phosphorus. Fo r example, i n approximate f i g u r e s , cheddar cheese has 524

mg/100g, oatmeal 395mg/100gY eggs 224mg/100gY lean beef 240mg/100g. P l a n t

p roduc ts have cons ide rab l y l e s s - - l e t t u c e 28mg/100g, po ta toes 56mg/100gY

oranges 21mg/100g ( 2 ) .

It has been es t imated t h a t t h e t o t a l f ood supp l i es i n t h e U n i t e d Kingdom

p rov i de about 1500nig o f phosphorus p e r person p e r day ( 7 ) . The 1972 NAS s tudy

( 6 ) es t imated t h e average U.S. i n t a k e o f phosphorus was 300mg pe r day, w i t h

one t h i r d as ca l c i um phosphates. The Food and N u t r i t i o n Board o f t h e N a t i o n a l

Research Counci l (USA) r'ecommends a d i e t a r y a l lowance o f 800mg o f phosphorus

p e r day.

We now cons ider phosphorus i n t a k e f r om water. The t o t a l phosphorus

con ten t i n waters can be d i v i d e d i n t o t h a t which i s a v a i l a b l e and t h a t which

i s unava i l ab l e f o r b i o l o g i c a l a s s i m i l a t i o n . P a r t o f t h e phosphorus assoc ia ted

w i t h any s o i l p a r t i c l e may be chem ica l l y o r p h y s i c a l l y bound t o t h e p a r t i c l e

and t h e r e f o r e unava i l ab l e . Based on r i v e r mouth data, t h e t o t a l phosphorus

l o a d i n t h e Great Lakes (presumably i n t h e absence o f de te rgen t c o n t r i b u t i o n )

c o n s i s t s o f a s o l u b l e f r a c t i o n and a p a r t i c u l a t e f r a c t i o n . The s o l u b l e

f r a c t i o n i s e s s e n t i a l l y a l l r e a d i l y a v a i l a b l e , b u t o r l l y a p o r t i o n o f t h e

p a r t i c u l a t e f r a c t i o n i s a v a i l a b l e .

The average c o n t r i b u t i o n o f household c leaners t o t h e t o t a l . phosphorus

load i n domest ic sewage was about 53% i n 1969 and had been reduced t o 38% b y

1976 ( 5 ) . Other ma jo r c o n t r i b u t o r s o f phosphorus t o r e c e i v i n g waters i n

a d d i t i o n t o households are t h e non-po in t sources which i n c l u d e a g r i c u l t u r a l ,

f o r e s t and urban r u n o f f and atmospher ic sources. .The phosphorus c o n t r i b u t i o n

f rom d e t e r g e n t s f l o w i n g i n t o t h e Grea t Lakes i s 10% o f t h e t o t a l phosphorus

l o a d t o t h e Lakes.

Another c a l c u l a t i o n , b y t h e d e t e r g e n t manu fac tu re rs ( 5 ) , was based on a

"wors t -case scenar io " i n which t h e r e was no phosphorus removal a t m u n i c i p a l

sewage t r e a t m e n t and o n l y a hundred- fo ld d i l u t i o n o f t h e phosphorus

p r i o r t o d i scharge i n t o r e c e i v i n g waters; t h e c a l c u l a t i o n a l s o assumed t h a t

phosphates made up 20% o f de te rgen ts , which i s no l o n g e r t h e case. T h i s

c a l c u l a t i o n showed 0.023.9 o f d e t e r g e n t phosphorus per 1 i t r e as t h e averaged

v a l u e o f phosphorus c o n t r i b u t i o n t o s u r f ace waters; l o c a l c o n c e n t r a t i o n c o u l d

o f course v a r y s u b s t a n t i a l l y .

If t h e above c a l c u l a t i o n s are c o r r e c t , an i n d i v i d u a l d r i n k i n g two l i t r e s

of water a day would t a k e i n 0.046mg o f a v a i l a b l e phosphorus f r o m de te rgen t ,

and about h a l f as much f r o m o t h e r sources. Another more s p e c i f i c c a l c u l a t i o n

f rom t h e same source computed i n t h e case o f Lake E r i e i s an i n t a k e o f 0.008mg

per day d e r i v e d f r o m de te rgen t . E i t h e r amount i s sma l l compared w i t h t h e

300mg of phosphorus e s t i m a t e d above as t h e i n t a k e i n t h e U:S.A. f r o m f o o d

sources.


The d e t e r g e n t phosphates a r e c a t e g o r i z e d as hav ing s l i g h t t o moderate

acu te t o x i c i t y ( 8 ) . Massive i n g e s t i o n o f phosphor ic a c i d and i t s s a l t s

r e s u l t s i n a c i d o s i s and hypocalcemia. Ora l doses t o produce death a r e v e r y

la rge , e.g. t h e LDSO ( t h e dose l e t h a l t o 50% o f t h e an imals) o f monobasic

sodium phosphate f o r t h e gu inea p i g i s over 449mg o f phosphorus per k g o f body

weight ( 3 ) . The acu te o r a l LDSO o f pentasodium t r i p o l y p h o s p h a t e i n mice

i s 811mg o f phosphorus p e r k g of body we igh t ( 2 ) . The acu te o r a l LDso f o r

r a t s o f sodium t r i p o l y p h o s p h a t e i s 6.50g/kg; of t e t r a s o d i u m pyrophosphate,

4.00g/kg; o f tri sod i um or thophosphate dodecahydrate, 7.40g/kg ( 9 ) . Compar-abl e

p u b l i s h e d acu te t o x i c i t y d a t a on potass ium phosphates a r e n o t a v a i l a b l e , b u t

t h e y a r e expected t o be more t o x i c t h a n t h e co r respond ing sodium s a l t s due t o

t h e i n h e r e n t l y g r e a t e r t o x i c i t y o f po tass ium ( 8 ) . The t ypes o f d e t e r g e n t s

t h a t c o n t a i n phosphate b u i l d e r s , i .e . l a u n d r y de te rgen ts , au tomat i c d ishwasher

de te rgen ts , and ha rd s u r f a c e c l e a n e r s and c leansers , a r e o f l ow t o x i c i t y

hav ing a c u t e o r a l L D S O ' S f o r r a t s o f 3 t o 13g/kg (10 ) .

These l e v e l s f o r acu te t o x i c i t y can be compared w i t h t h e above d a t a on

human i n t a k e s , r e c a l c u l a t e d on a body w e i g h t b a s i s and assuming a body-weight---

o f 70kg. The phosphorus i n t a k e f r o m f o o d ( u s i n g t h e U.S. v a l u e o f 300mg p e r

day) would be 4mg/kg, o r about one-hundredth o f t h e gu inea p i g o r a l LD50.

The i n t a k e f r o m water , assuming a q u a n t i t y o f 0.075mg d a i l y (wh ich i n c l u d e s

p o t e n t i a l d e t e r g e n t ) , wou ld be O.OOlmg/kg, wh ich i s l e s s t h a n t h e gu inea p i g

o r a l LD50 by a f a c t o r o f 450,000.

Weaver and G r i f f i t h (11) have shown t h a t sodium t r i p o l y p h o s p h a t e , g r a n u l a r

d e t e r g e n t s t h a t c o n t a i n 50-60% o f t h i s b u i l d e r , and po tass ium pyrophosphate

a r e po ten t , prompt a c t i n g emet ics when g i v e n o r a l l y t o beagles. As i n d u c t i o n

of v o m i t i n g i s w i d e l y used as a f i r s t a i d measure i n p r o d u c t i n g e s t i o n , t h e s e

au tho rs suggested t h a t t h e emet i c a c t i o n o f t h e phosphate b u i l d e r s p r o v i d e s a

s a f e t y f a c t o r i n p r e v e n t i n g t h e r e t e n t i o n o f d e t e r g e n t i n t h e stomach.

Gosse l in , -- e t al . , (8 ) c o n f i r m t h a t nausea and vomi t i ng , and d i a r r h e a as w e l l ,

a r e p r o b a b l e a f t e r i n g e s t i o n o f t r i p o l y p h o s p h a t e o r pyrophosphates. These

phosphates a r e though t t o be h y d r o l y z e d t o o r thophospha te be fo re a b s o r p t i o n .

I f a p p r e c i a b l e amounts o f complex phosphate a r e absorbed, t h e r e may be b i n d i n g

o f i o n i z e d serum c a l c i u m w i t h a danger o f hypoca lcemic t e t a n y . One such

ep isode a p p a r e n t l y o c c u r r e d i n a case i n v o l v i n g a w a t e r so f tener .

T r i s o d i u m o r thophospha te o r TSP, which has been s o l d i n t h e dodecahydrate

f o r m as a c l e a n i n g agent, fo rms s t r o n g l y a l k a l i n e s o l u t i o n s i n wa te r and i s

r e p o r t e d t o have produced i n j u r i e s on i n g e s t i o n s i m i l a r t o t h o s e caused by

l y e ( 8 ) .

I As f o r o t h e r r o u t e s o f e n t r y , t h e r e i s an example o f a c u t e o r thophospha te

t o x i c i t y i n wh ich a 2 1/2 y e a r o l d g i r l developed marked hyperphosphatemia,

hypernat remia, hypoca lcemia and a c i d o s i s a f t e r two p e d i a t r i c sodium d ihyd rogen

phosphate enemas o f 67.5mL each which con ta ined 3.79 o f phosphorus (12) .

Symptoms s t a r t e d t o appear a f t e r 90 minutes and were r e l i e v e d w i t h t h e

a d m i n i s t r a t i o n o f ca lc ium gluconate.

On t h e o the r hand, severa l thousand cases o f acc iden ta l i n g e s t i o n o f

de te rgen ts by c h i l d r e n occur annua l l y i n t h e Un i t ed S ta tes (13) . Many o f t h e

products i nvo l ved c o n t a i n phosphates, and f o l l ow -up s t u d i e s c o n f i r m t h a t

. compl icat ion-s (o ther . than nausea, vomi t ing, or_di .arrhea) _ _ r a r e l y occur- (14) .

Top ica l exposure o f s k i n and eyes t o phosphate b u i l d e r s u s u a l l y occurs i n

t h e con tex t o f hand l i ng o r us ing t h e de te rgen t products t h a t c o n t a i n them.

Thus most r e p o r t s o f t e s t i n g i ,nvol ve f o rmu la ted products . However, Nixon, . - e t

al., (15) r e p o r t e d t h a t 50% aqueous sodium t r i po l yphospha te caused neg l i g i b l e - i r r i t a t i o n t o i n t a c t s k i n o f r a b b i t s , guinea p igs , o r humans i n four -hour

pa tch t e s t exposures. Under t h e same t e s t cond i t i ons , guinea p i g and r a b b i t

s k i n showed s l i g h t and moderate i r r i t a t i o n , r e s p e c t i v e l y , from a de te rgen t

product t h a t conta ined 50% sodium t r ipo lyphosphate , which suggests t h a t t h e

i n g r e d i e n t s o the r than t h e phosphate were more l i k e l y t h e source o f

i r r i t a t i o n . Human s k i n showed n e g l i g i b l e i r r i t a t i o n f rom t h e detergent .

A b a t t e r y of s k i n and eye i r r i t a n c y t e s t s on animals o r human sub jec t s was

used on two de te rgen ts t h a t con ta ined 50% "condensed phosphate" (sodium

t r i po l yphospha te ) t o assess e f f e c t s on s k i n and eyes (16) . Another s tudy (17) , .

i n vo l ved s i m i l a r p roduc t s t h a t a1 so con ta ined p r o t e o l y t i c eniymes. ~ 0 t h ' ' s t ud ies showed m i l d i r r i t a n t e f f e c t s f rom t h e products . ' p r e d i c t i v e , repea ted '

a p p l i c a t i o n pa tch t e s t s f o r s k i n s e n s i t i z a t i o n i nvo l ved 2055 human sub jec t s i n

t he f i r s t s e r i e s and 1478 i n t h e second. There was no evidence o f s k i n

s e n s i t i z a t i o n , thus sodium t r i po l yphospha te apears t o have no a l l e r g e n i c

p ropens i t i es ;

Subchronic S tud ies

Many s tud ies have been done t o i n v e s t i g a t e t h e sho r t - t e rm e f f e c t s o f

phosphates added t o t he d i e t s o f exper imenta l animals. One o f t h e s igns

i n d i c a t i n g a phosphate overdose i s t h e occubrence o f metastat ic - ca lc ium i n t h e - -

k idney, stomach and aor ta . Resorp t ion of bone i s a l so c h a r a c t e r i s t i c .

Male r a t s f e d d i e t s con ta i n i r l g e i t h e r 8% metaphosphate o r 8% sodium

orthophosphate f o r seven months o r u n t i l death showed inc reased u r i n a r y

e x c r e t i o n o f i n o r g a n i c phosphorus, en la rged p a r a t h y r o i d s ( 2 t o 8 t imes t h a t o f

c o n t r o l s ) , and ca lc ium depos i t s i n t h e t ubu les o f t h e o u t e r medu l la o f t h e

k i dney (18) . C a l c i f i c a t i o n occurs i n t h e area o f t h e Loop of Henle and t h e . .

t e r m i n a l p a r t o f t h e prox imal tubu le ,

Hodge c a r r i e d ou t sho r t - t e rm f e e d i n g s t u d i e s w i t h r a t s and dogs o f sodium

t r i po l yphospha te , sodium t r imetaphosphate, sodium tetrametaphosphate, and

sodium hexametaphosphate ( 19 ) . The s t u d i e s were designed t o d e t e c t and assess

r e n a l damage i n v iew o f r e p o r t e d harmfu l e f f e c t s o f l a r g e amounts o f

or thophosphate on t h e k idney. Weanling r a t s were f e d d i e t s f o r one month t h a t

con ta ined 0.2, 2.0, o r 10% of t h e t e s t phosphate. Con t ro l r a t s r ece i ved basal

d i e t alone, o r supplemented w i t h 10% sodium c h l o r i d e o r 5% sodium

orthophosphate. Growth r e t a r d a t i o n was seen w i t h t h e sodium c h l o r i d e and

sodium phosphate c o n t r o l r a t s and w i t h t h e r a t s r e c e i v i n g 10% o f condensed

phosphate. The l a t t e r r a t s a l s o had t u b u l a r degenerat ion and nec ros i s o f t h e

k idneys. The " n o - e f f e c t " l e v e l o f t h e condensed phosphates was 2% i n a l l

cases. Dogs f e d O.lg/kg/day o f t h e condensed phosphates showed no e f f e c t s .

Exposure up t o 5 months t o f rom 1 t o 4g/kg/day produced r e n a l l e s i o n s s i m i l a r

t o those seen i n r a t s a t 10% o f t h e d i e t .

Ten female a d u l t moqgrel dogs f e d d i e t s supplemented w i t h potassium

phosphate a t 2.89 phosphorus/day f o r f o u r months and then 3. lg /day f o r s i x

months showed m u l t i p l e m ic roscop ic areas o f c a l c i f i c a t i o n i n t h e k i d n e y

medul la, 'decreased u r i n a r y ca l c i um exc re t i on , increased u r i n a r y phosphate

exc re t i on , i nc reased bone r e s o r p t i o n . E i g h t ou t o f t h e t e n dogs developed

ca l c i um depos i t s i n t h e i r eye lenses. I n f i v e o f these e i g h t , t h e ca l c i um

depos i t s were assoc ia ted w i t h changes compat ib le w i t h c a t a r a c t s ( 20 ) .

I f t h e l e v e l s f e d t o dogs i n t h e above exper iments had comparable e f f e c t s

i n humans, and i f we assume t h e dogs weighed 7kg and t h e humans 70kg, t hen t h e

d a i l y amounts t h a t showed undes i r ab le e f f e c t s were e q u i v a l e n t t o 30,000mg o f

phosphorus per human, which i s 100 t imes t h e U.S. i n t a k e i n f o o d and 400,000

t imes t h e i n t a k e i n water.

Chronic Studies

There are two re levan t long-term feeding s tud ies o f condensed phosphates

used i n detergents. Hodge f e d groups o f 50 weanling male and female r a t s f o r

24 months w i t h l abo ra to ry chow d i e t s conta in ing zero, 0.05, 0.5, o r 5% sodium

t r ipo lyphosphate (19). The added phosphorus equ iva len ts were 0.012, 0.125,

and 1.25%; FASEB est imated t h a t the h ighes t l e v e l was equ iva len t t o 630mg o f

phosphorus added per kg o f body-weight (-3)-. On- the -bas is o f growth, f ood - .._.

consu~ilption, hematology, u r i n e analys is , m o r t a l i t y , organ weights, and

h is topathology, 0.05 and 0.5% sodium t r ipo lyphosphate were no e f f e c t l eve l s .

The h igh l e v e l produced g r e a t l y increased k idney weight and s i z e i n males,

accompanied by d i l a t e d convoluted tubules, i n t e r s t i t i a l and glomerular

f i b r o s i s and i n t e r t u b u l a r c a l c i f i c a t i o n .

I n t he second study, two detergents con ta in ing 50% condensed phosphate

(sodium t r ipo lyphosphate) were added t o l abo ra to ry chow d i e t s o f separate

groups o f 40 male and 40 female r a t s each f o r two years a t l e v e l s of

phosphorus equ iva len t t o 0.063% (21). There were no t o x i c e f f e c t s t o t e s t

animals compared w i t h c o n t r o l animals t h a t rece ived the basal d i e t . , -

I f the h ighes t no-effect l e v e l i n these two studies, 63mg o f phosphorus

added per kg o f body weight, i s compared w i t h t h e "worst-case" human in take of

detergent-der i ved phosphorus i n d r i n k i n g water o f 0.046mg phosphorus ( i n 2

1 i t r e s o f water per day) f o r a 50kg adu l t , t he re i s a s a f e t y f a c t o r o f more

than 68,000.

Carc inogen ic i ty and Mutagen ic i ty

I n feed ing s tud ies o f sodium t r ipo lyphosphate by Hodge (19) and Snyder, et al., (21), r a t s f e d d i e t s con ta in ing up t o 5% i n t h e f i r s t case and a t 0.25% - i n the second showed no q u a l i t a t i v e o r q u a n t i t a t i v e change from t h e normal

incidence o f tumors found i n c o n t r o l animals.

No evidence o f mutagenic e f f e c t s f o r sodium ac id pyrophosphate was

obta-ined i n a s tudy- that included: ( a ) . host-mediated assay i n mice us ing-

Salmonel la typh imur ium TA1530 and m i t o t i c recor r~b ina t ion f requency i n

Saccharomyces c e r e v i s i a e D3; ( b ) -- i n v i t r o mutagenic assay w i t h S. typh imur ium

s t r a i n s TA1535, TA1536, TA1537, and TA1538 i n t h e presence and absence o f

me tabo l i c a c t i v a t i o n ; ( c ) dominant l e t h a l t e s t i n r a t s ; and ( d ) t r a n s l o c a t i o n

t e s t i n mice ( 3 ) .

T e r a t o g e n i c i t y and Reproduc t i ve E f f e c t s

Sodium t r i po l yphospha te was embryotox ic b u t n o t t e r a t o g e n i c i n av ian

embryos a t l e v e l s up t o 32mg o f phosphorus pe r kg o f egg. Sodium

t r i p o l y p h o s p h a t e was g i ven on day 6 th rough day 15 o f g e s t a t i o n t o pregnant

mice (up t o 60mglkg as phosphorus), pregnant r a t s (up t o 43mg/kg as

phosphorus), pregnant hamsters f rom day 6 t o day 10 (up t o 36mg/kg as

phosphorus), and pregnant r a b b i t s f r om day 6 th rough day 18 (up t o 63 mg/kg as

phosphorus). No e f f e c t s on ova l i m p l a n t a t i o n o r materna l o r f e t a l s u r v i v a l

were seen. There was no s i g n i f i c a n t inc rease i n t h e number o f abno rma l i t i e s

i n s o f t o r s k e l e t a l t i s s u e ( 3 ) .

Sodium t r i po l yphospha te , sodium t r imetaphosphate, o r sodiuln hexameta-

phosphate had no e f f e c t on f e r t i l i t y o r l i t t e r s i z e nor on growth o r s u r v i v a l

o f o f f s p r i n g i n r e p r o d u c t i o n s t ud ies w i t h t h r e e genera t ions of r a t s ma in ta ined

on d i e t s contain-ing. 0.5% o f condensed phosphate (19) .

. .

Conc lus ions

The amount of phosphorus con t r - ibu ted by de te rgen ts t o human i n t a k e i s i n

t h e range o f 0.01 t o O.lmg per person pe r day, and i s t h e r e f o r e e x c e p t i o n a l l y

smal l compared w i t h t h e es t imated U.S. f o o d i n t a k e o f 300mg pe r person pe r day.

Two l i n e s o f ev idence suggest t h a t de te rgen t phosphorus de r i ved th rough

d r i n k i n g water poses no h e a l t h hazard. One i s t h a t , i n comparison w i t h t h e

above human in takes , enormously l a r g e r amounts, by f a c t o r s o f seve ra l hundred

thousand, a re needed t o produce d e t e c t a b l e t o x i c e f f ec t s (acute, subchron i c o r

c h r o n i c ) i n l a b o r a t o r y animals and even these v e r y l a r g e q u a n t i t i e s a re n o t

ca rc inogen ic , mutagenic, o r t e ra togen i c .

A second l i n e of evidence i s t h a t a 1975 rev iew ( 3 ) f o r t h e Food and Drug

Admin i s t ra t i on o f h e a l t h aspects o f phosphates i n foods showed t h a t t he re was

no hazard from t h e 300mg o f phosphorus taken i n d a i l y by humans i n food;

indeed such l a r g e amounts a re essen t i a l f o r hea l th . These food in takes of

phosphorus are 6,000 t imes g rea te r than water in takes, even under a

"worst-case" scenario. Phosphorus occurs i n numerous forms; a l l t h e 23 forms

which have any s i g n i f i c a n t rep resen ta t i on i n food and these i nc lude t h e forms

found i n detergents and n a t u r a l water, were s p e c i f i c a l l y exonerated f rom any

hazards when used a t c u r r e n t l eve l s . I n December 1979 t h e Food and Drug

Admin i s t ra t i on proposed t o a f f i r m t h a t such phosphates should be gene ra l l y

regarded as sa fe f o r a d d i t i o n t o food. They exempted ca lc ium hexameta-

phosphate and potassium polymetaphosphate'from t h i s s t a t u s because they were

no t normal ly used as food add i t i ves (22) .

It i s concluded t h a t phosphates used as detergent b u i l d e r s do no t pose a

hea l th hazard through t h e i r c o n t r i b u t i o n o f phosphorus t o d r i n k i n g water.

References

1. J.T. I r v i n g , Calcium and ~ h o s ~ h b r u s Metabol ism. Academic Press ~ n c . ,

N.Y., 1973.

. . 2. T.E. Fur ia , Ed i to r , and book o f Food Add i t i ves , 2nd ed., c.R..~. Press,

Cleveland, Ohio, 1972. Chapter 15 - Phosphates i n Food Processing, by

R.H. E l 1 inger .

3. Fed. o f American Soc ie t i es f o r Experimental B io logy, Eva lua t ion o f t h e

Heal th Aspects o f Ph0sphates .a~ Food Ingred ien ts . ~ e p o r t prepared f o r t h e

Food and Drug Admin is t ra t ion . Contract No. FDA 223-75-2004, Bethesda,

Md., 1975.

4. J.R. Van Wazer, Phosphoric Acids and Phosphates, i n Kirk-Othmer

Encyclopedia o f Chemical Technology, 2nd ed., Vol. 15, pg. 271. John

Wi ley & Sons, Inc., New York, 1968.

5. Long-term Safety o f Detergent Phosphates, b y FMC Corp., Monsanto Co., O l i n

Corp., The ~ r o c t e r and Gamble Co., December 15,' 1978.

6. Subcommittee on Review of GRAS L i s t (Phase 11). A Comprehensive Survey o f

I n d u s t r y on t h e Use o f Food Chemicals G e n e r a l l y Recognized as Safe.

N a t i o n a l Academy of Sciences, Washington, D.C., 1972.

7. S i r S t a n l e y Davidson, -- e t al . , Human N u t r i t i o n and D i e t e t i c s , 5 t h ed.

C h u r c h i l l - L i v i n g s t o n e Pub l i shers , Edinburgh. 1972.

8. R.E. Gosse l in , -- e t a l . C l i n i c a l T o x i c o l o g y o f Commercial P roduc ts - Acute

Poisoning, 4 t h ed., pg. 11-73, 83-85. W i l 1 iams & W i l k i n s , B a l t i m o r e , 1976.

9. NIOSH 1978 R e g i s t r y o f T o x i c E f f e c t s o f Chemical Substances, R.J. Lewis,

Sr. and R.L. Tatken, eds., pg. 941, 1076, 1262, U.S. Dept. o f HEW,

C i n c i n n a t i , 1979.

10. J.C. Calandra, -- e t a l . C lean ing Products and T h e i r A c c i d e n t a l I n g e s t i o n ,

4 t h ed., pg. 13. The Soap and De te rgen t Assoc ia t ion , New York, 1976.

11. J.E. Weaver, J.F. G r i f f i t h . I n d u c t i o n o f Emesis b y De te rgen t I n g r e d i e n t s

and Formu la t ions . Tox. Appl . Pharmacology, (1969), 14, 214-220.

. .

12. J.F. S&.OS, ~ ~ ~ o c a l c e m i c coma F o l l o w i n g Two P e d i a t r i c Phosphate Enemas.

P e d i a t r i c s , (1977), 60, 305.

13. NCPCC d a t a on i n g e s t i o n , Po ison C o n t r o l S t a t i s t i c s , Food and Drug

~ d m i n i s t r a t i o n , 1976.

14. A.R. Temple and J.C. V e l t r i . Outcome o f a c c i d e n t a l i n g e s t i o n s o f soaps,

de te rgen ts , and r e 1 a ted household products . V e t e r i n a r y and Human

Tox ico logy , (1979) - 21, Suppl., 31-32.

15. G.A. Nixon, C.A. Tyson, and W.C. Wertz. I n t e r s p e c i e s comparisons of s k i n

i r r i t a n c y . Tox. Appl i e d Pharmacology, (1975), - 31, 481-490.

16. D.L. Opdyke, F.H. Snyder and H.L. Rubenkoenig, Tox i co log i c S tud ies on

Household Syn the t i c Detergent 11. E f f e c t s on t h e Sk in and Eyes. Tox.

App l ied ~ h a r a m a c o l o ~ ~ , (1964), - 6, 191-196.

17. J.F. G r i f f i t h , -- e t a l . Sa fe t y e v a l u a t i o n o f enzyme detergents . O ra l and

cutaneous t o x i c i t y , i r r i t a n c y and s k i n s e n s i t i z a t i o n s tud ies . Fd.

Cosmet., (1969), - 1, 581-593.

18. J.A. Saxton, Jr., G.H. E l l i s , E f f e c t s o f Long-Continued I n g e s t i o n o f

Sodium Phosphate Upon t h e Parathyro ids, Kidneys and Bones o f Mature Rats.

Am. J. Pathol., (1941), - 17, 590.

19. H.C. Hodge. T o x i c i t y s t u d i e s on phosphates. Fd. Cosmetic Toxicol . ,

(1964), - 2, 147-154.

20. G.H. Laflamme, J. Jowsey, Bone and S o f t T issue Changes w i t h O ra l Phosphate

Supplements. J. C l i n . I n v e s t i g a t i o n , (1972), - 51, 2834.

21. F.H. Snyder, -- e t a l . Tox i co log i c s t u d i e s on household s y n t h e t i c de te rgen ts

I. Systemic E f f e c t s . Tox. Appl. Pharmacology, (1964), - 6, 133-140.

22. Department o f Health, Education, and Welfare; Food and Drug

Admin i s t r a t i on . Phosphates: Proposed A f f i r m a t i o n o f and D e l e t i o n From

GRAS Sta tus as D i r e c t and Human Food I ng red ien t s . Federal Reg is te r ,

(244) 74845-58.

7. SOLUBLE SILICATES*


s o l u b l e s i l i c a t e s possess u t i l i t y i n a spectrum o f app l iCat ions i n c l u d i n g

food packaging, medical products, t he t reatment o f d r i n k i n g water and i n h igh

phosphate, reduced phosphate and non-phosphate detergents.

The Se lec t Committee o f t h e Federat ion o f American Soc ie t i es f o r

Experimental B io logy (FASEB, 1979) i n a f i n a l eva lua t i on f o r the U.S. Food and

Drug Admin i s t ra t i on o f the h e a l t h aspects o f c e r t a i n s i l i c a t e s as food

ingred ien ts , concluded t h a t sodium s i 1 i ca te , sodium alumi nosi 1 i ca te , ca lc ium

alumi nosi 1 i ca te , ca lc ium s i l i c a t e , magnesium s i l i c a t e , potassium ' s i l i c a t e ,

t r i c a l c i u m s i l i c a t e , s i l i c a aerogel 'and t a l c do no t present a hazard t o the

pub l i c under c u r r e n t use.

. .

It should be recognized t h a t t h i s c6nclus ion was i n bas ic agreementw i th

an e a r l i e r FAO/WHO (1974) t o x i c o l o g i c a l e v a l u a t i o n which es tab l i shed no 1 i m i t

f o r the acceptable d a i l y i n t a k e o f the above s i l i c a t e s w i t h the except ion of

magnesium s i l i c a t e and t a l c .

The p r i n c i p a l o b j e c t i v e o f t h i s r e p o r t i s t o rev iew the a v a i l a b l e

l i t e r a t u r e on the t o x i c i t y o f the so lub le s i l i c a t e s w i t h a p r imary focus on

sodium s i l i c a t e . I t i s , however, use fu l t o i n i t i a l l y rev iew the germane . .

aspects of t he chemistry, use p a t t e r n s and environmental aspects of t h e '

'

s o l u b l e s i l i c a t e s .

Chemistry, Use Pat te rns and Environmental 'Aspects

The so lub le s i l i c a t e s cover a range o f composit ions. On the high. a l k a l i n e

side, species are s t o i c h i o m e t r i c and c r y s t a l l i n e , e.g., sodium m e t a s i l i c a t e

* Cont r ibu ted by L. F ishbe in

. :.. ,

(Na2Si03). On t h e h igh s i l i c a ' s i d e , commercial m a t e r i a l s are non -s to i ch io -

m e t r i c . These are a v a i l a b l e as v iscous s o l u t i o n s o r as amorphous s o l i d s .

They are s p e c i f i e d i n terms o f t h e i r weight r a t i o s o f Si02/Na20. Sodium

s i l i c a t e , canging f rom 2.0 t o 2.5 Si02/IVa20, i s most f r e q u e n t l y used i n

l aund ry de te rgen ts (Sturm, -- e t a l , 1978). The c o l l o q u i a l te rm "wate rg lass" i s

now obsolete. It had been a p p l i e d t o v iscous sodium s i l i c a t e s o l u t i o n s o f

about 3.3 Si02/Na20 as used f o r egg p rese rv i ng ( W i l l s , 1969).

As a de te rgen t b u i l d e r sodium s i l i c a t e p lays severa l r o l e s , depending on

t h e f u n c t i o n and composi t ion o f t h e detergent . For example, i n phosphate-

b u i l t detergents , sodium s i l i c a t e ma in ta ins s o i l p a r t i c l e s i n suspension and

i s no t a water so f tener . I n con t ras t , i n t h e c a r b o n a t e / s i l i c a t e b u i l d e r

combinat ion, t h e s i l i c a t e b u f f e r s t he s o l u t i o n a t an a l k a l i n e pH where ca l c i um

carbonate and magnesium hydrox ide p r e c i p i t a t e most e f f e c t i v e l y . The s i l i c a t e

may sequester magnesium i n carbonate and zeo l i te-bu i 1 t detergents .

A d d i t i o n a l l y , sodium s i l i c a t e a l so d e f l o c c u l a t e s p a r t i c u l a t e s o i l , e m u l s i f i e s

and s a p o n i f i e s greasy o i l , absorbs l i q u i d de te rgen t i ng red ien t s , p rov ides

c r i s p , f r e e - f l o w i n g g ranu les when spray d r i e d and may a l so i n h i b i t t h e

c o r r o s i o n o f metal i n t h e washing machine (Sturm, e t al., 1978).

. . . .

The l e v e l s o f sodium s i 1 i c a t e ( ~ a 2 0 * 2 ~ i 0 ) 2 i n detergent based: on va r i ous

use p a t t e r n s are as f o l l ows (Sturm, -- e t al., 1978): (1 ) based on h i s t o r i c a l

use: 5%; (2 ) based, on curr .ent use i n reduced phosphate de te rgen t : 10%; (3 )

based on p o s s i b l e use i n non-phosphate detergent : 20%. A t concen t ra t i ons

below 120 ppm, t h e o n l y s t a b l e species i n aqueous s o l u t i o n i s monomeric and i s

i n d i s t i n g ~ ~ i s h a b , l e f rom n a t u r a l l y . . d i s so l ved s i l i c a (Sturm, e t a1 ., 1978; Stumm, . . --

1970).

Sodium s i l i c a t e ( a t a concqn t ra t i on o f 8 mgLL SiO,) i s added t o . .

mun ic ipa l and domestic water supp l i es to' i n h i b i t t h e c o r r o s i o n of pipes, pumps

and tanks (Sturm, -- e t al., ,1978). . . . .

It i s impor tan t t o no te t h a t s i l i c a , s i l i c i c a c i d and t h e calc ium,

magnesium and aluminum s a l t s are ub iqu i t ous i n t h e environment and hence i t

can be cons idered u n l i k e l y t h a t man can avoid s i l i c o n exp.osure. A t l e a s t 25%

o f the e a r t h ' s c r u s t i s composed o f s i l i c o n i n the form o f s i l i c o n d iox ide

(sand and quar tz ) and t h e s a l t s of s i l i c i c ac id (FASEB, 1979).

. .

S i 1 icon, i s found i n a1 1 na tu ra l waters ' (Krauskopf, 1967). Ground waters

conta in t h e h ighest concentrat ions o f na tu ra l s i l i c a . Streams and r i v e r s

conta in more d isso lved s i l i c a than do the lakes and oceans. For example, t h e

worldwide concentrat ion o f s i l i c a i s 13.1 mg/L wh i l e t h a t o f t h e Great Lakes,

i s about 4 mg/L (Sturm, -- e t a1 ., 1978). S i l i c a l e v e l s found i n sur face waters

as a r e s u l t o f detergent use ( a t t h e 20% l e v e l ) are o f t h e order o f 0.064 mg/L

(6.4 mg/L raw sewage, assuming a sewage e f f l u e n t d i l u t i o n o f 1:100) (Sturnl, - e t

a1 ., 1978). -

. , . . ,

A shrv.ey b f the minera l c o n t e n t o f ' f i n i s h e d water i n p u b l i c .. water . . iuppl i e s . . .

o f 100 l a r g e s t U:S. c i t i e s i n 1962 i nd i ca ted t h a t t he median,h igh and.,low. . .

' '

concentrat ions o f ' s i 1 i c a were 7.1, 7.2 and 0.07 . . mg/L r e s p e c t i v e l y ( ~ ~ r f o r andA

Becker, 1964).

S i l i c o n i s found i n almost a l l t e r r e s t r i a l and aquat ic organisms (A l l i son ,

1968). I n humans, t h e lungs and pe r ib ronch ia l lymph nodes have the h ighes t

s i l i c a content, 14-2000 mg/100g and 27-5000 mg/100g r e s p e c t i v e l y (King and

Be l t , 1938). The s i l i c a content o f these t i ssues increases w i t h age and t h i s

has been suggested t o be due p r i m a r i l y t o t he con t i nua l i n h a l a t i o n o f house

and s t r e e t dust. I n con t ras t there i s a constant low concent ra t ion i n o ther

organs% and muscle t h a t does no t appear t o vary w i t h t ime (e.g., psoas muscle

and k idney concentrat ions are o f t h e order of 23/100 mg/lOOg and 11-27 mg/100g

r e s p e c t i v e l y ) (King and Be1 t, 1938).

It should be a d d i t i o n a l l y noted t h a t foods conta in n a t u r a l l y occu r r i ng

s i l i c a t e s . For example, l e v e l s o f s i l i c o n ( i n t he form o f s i l i c o n d iox ide ) i n

raw potatoes are about 10.1 mg/kg, i n m i l k 2.1 mg/L and i n beer 131 mg/L

(FASEB, 1979). S i l i c a compounds used i n food packaging inc lude s i 1 i con

dioxides, sodium s i l i c a t e and t a l c . The est imated poss ib le i n take o f sodium

aluminosi 1 i ca te , t he p r i n c i p a l s i 1 i c a t e food add i t i ve , i s about 0.8 mg/kg/day

(FASEB, 1979). An a d d i t i o n a l human i n t a k e o f s i l i c o n can a r i s e f rom i t s

medic ina l appl i c a t i o n s : . . For example, magnesi um t r i s i 1 i c a t e ' i s used as an

an tac id i n t h e t reatment / o f hyperchl o rhyd r i a as found i n p e p t i c u l c e r s and

g a s t r i t i s .

Al though t he f u n i t i o n o f s i l i c a i'n t he body i s n o t d e f i n i t i v e l y known,

s t i i d i es w i t h i h i c k s ( C i r ' l i s l e , 1972), r a t s (Lev ie r , 1975; Schwarz and ~ i l n e ,

1972) and monkeys (Lev ie r , 1975) suggest th'at s i l i c a may p l a y a r o l e i n t h e

c a l c i f i c a t i o n process i n 'bone&.

. . . .

T o x i c i t y

Since sodium s i l i c a t e occurs n a t u r a l l y and has been used i n home laundry

p roduc ts i n t h e Un i t ed S ta tes and Un i t ed Kingdom f o r approx imate ly 120 and 150

years, r e s p e c t i v e l y , few formal t o x i c i t y s t u d i e s e x i s t r e 1 a t i ng t o sodium

s i l i c a t e p e r se o r i n any soap and/or de te rgen t f o rmu la t i on .

a. Acute T o x i c i t y

The s igns observed d u r i n g eye, sk in , esophageal and o r a l t o x i c i t y t e s t s

i nc l uded c o n j u n c t i v i t i s , erythema, sma l l b l i s t e r s on sk in , burns i n o r a l and

a l imen ta ry canal, nausea and vom i t i ng ( I n t e r n a t i o n a l Tech. Inform. I n s t . ) .

The acute o r a l LDSo f o r sodium s i l i c a t e (Na20*nSi0, x H20, n = 3.25, "water

g l ass " ) i s 1100 mg/kg. The o r a l LD,, f o r sodium s i l i c a t e ( s i l i c i c a c i d

disodium s a l t ) i s 1280 mg/kg i n t h e r a t e (NIOSH, 1975; P h i l a d e l p h i a Q u a r t z

Co., 1961). The o r a l LD,, f o r sodium s i l i c a t e (3.0 Si02/Na20) i n t h e r a t i s

1600 mg/kg . (NIOSH, 1975; Soap and Detergent Assoc ia t ion , 1972).

., . .

1; man, t h e e s t i m a t e d o r a l l e t h a l d&es are: >15g/kg f o r s i l i c a

( ' s i l i c o n d i o x i d e ) and magnesium t r i s i l i c a t e and between 0.5 arid 5g/kg f o r

sodium s i l i c a t e and i n t h e ' l a t t e r case, may we1 1 be due t o ' t h e compound's : .

a l k a l i n i t y ( ~ n o n , 1964; FAO/WHO, 1974). . .

. .

The i n t r a p e r i t o n e a l LDL, f o r sodium s i 1 i c a t e (des ignated water g l ass )

i n t he guinea p i g i s 200 mg/kg (NIOSH, 1975). The minimal l e t h a l i .v. dose of

sodium metasi 1 i c a t e (Na2Si03*9H20) f o r r a b b i t s i s 175 mg/kg. Doses between

110 and 172.5 mg/kg caused anemia. Sodium s i l i c a t e a t l e v e l s of 20.28-55.9%

was e l i m i n a t e d i n t h e u r i n e w i t h i n 11-48 hours (Ga ja t to , 1951).

I n a comprehensive r e c e n t s tudy o f t h e r a t e and e x t e n t o f u r i n a r y

e x c r e t i o n i n r a t s a f t e r o r a l a d m i n i s t r a t i o n o f magnesium t r i s i l i c a t e ,

food-grade sodium a l u m i n o s i l i c a t e and Z e o l i t e Type A admin is te red i n doses o f

0, 40, 200 o r 1000 mg/kg, and sodium s i l i c a t e i n doses o f 40 and 1000 mg/kg,

i t was found t h a t u r i n a r y s i l i c o n e x c r e t i o n increased r a p i d l y a f t e r dos ing and

peak e x c r e t i o n r a t e s occurred w i t h i n 24 hours i n a l l t e s t groups (Benke and

Osborne, 1979). Z e o l i t e A had t he most r a p i d u r i n a r y e x c r e t i o n r a t e

( h a l f - l i f e , 6-8 h r ) . The h a l f - l i v e s o f magnesium t r i s i l i c a t e , sodium s i l i c a t e

and food grade sodium a luminos i 1 i c a t e were 16-20 h r , 24 h r and 38 h r ,

r e s p e c t i v e l y . When expressed as a percentage o f dose, t h e t o t a l u r i n a r y

s i l i c o n excre ted was rough l y equal f o r magnesium t r i s i l i c a t e , sodium s i l i c a t e

and Z e o l i t e A b u t cons ide rab l y l e s s f o r f ood grade sodium a lum inos i l i ca te * .

For a l l f o u r t e s t m a t e r i a l s u r i n a r y s i l i c o n e x c r e t i o n increased w i t h dose

l e v e l . However, i t should be noted t h a t t h e magnitude o f t h i s inc rease ( two

t o e i g h t f o l d ) was n o t as g r e a t as t h e inc rease i n t he amount dosed ( 2 5 - f o l d ) .

The observa t ion t h a t t h e percentage o f s i 1 i c o n excre ted decreased as t h e dose

was increased suggested t h a t some process i n t h e absorp t ion o r e x c r e t i o n was

becoming sa tu ra ted . S i m i l a r f i n d i n g s were repo r ted by King, -- e t a1 ., (1933)

who admin is tered s i l i c i c a c i d t o dogs and found t h a t i n c r e a s i n g t h e dose

caused a sma l le r f r a c t i o n o f t h e s i l i c o n t o be excre ted i n u r i ne . Comparable

da ta i n humans i s l i m i t e d and appears t o be a v a i l a b l e o t ~ l y f o r magnesium

t r i s i l i c a t e (Page, -- e t al., 1941). When admin is tered t o vo lun teers a t a dose

l e v e l o f 35 mg/kg/day f o r 4 days and t h e u r i n e i s c o l l e c t e d f o r 48 h r s a f t e r

t h e l a s t dose, t h e t o t a l excess s i l i c o n recovered i n u r i n e averaged 5.2%. It

was noted by Benke and Osborn (1979) t h a t a l though t h e da ta o f Page, e t al.,

(1941) were n o t d i r e c t l y comparable t o t h e s ing le-dose da ta r e p o r t e d above i n

t he r a t , i t would appear t h a t man absorbs l e s s s i l i c o n f rom magnesium

t r i s i l i c a t e than does t h e r a t . The hazards o f i nges ted s i l i c a t e s a re b e l i e v e d

t o be g e n e r a l l y l i m i t e d t o e f f e c t s on t he k i dney and b ladder (Emerick, .et al.,

1963; T racor -J i t co , 1973).

.. . . . ,

I n man, . e xcep t . . f o r . non -spec i f i c i r r i t a t i o n o r c o r r o s i o n o f sk in , cornea

and mucous membranes, no appa ren t l y t o x i c ac t i ons o f sodium metas i 1 i c a t e . . a re

recognized (Gleason, - e t -* a1 9 1968; Sax, 1968; W i l l s , 1969).

*Un l i ke Z e o l i t e A, f ood grade sodium a l u m i n o s i l i c a t e i s amorphous and, d i f f e r s

i n i t s A l /S i r a t i o . 47

b. Subchronic ~ o x i c i t y

here may be species r e l a t e d s u s c e p t i b i l i t y t o r e n a l damage f rom i n g e s t i o n

o f sodium s i l i c a t e . When 15 r a t s . o f bo th sexes o f t h e Charles R i v e r CD s t r a i n

were f e d sodium s i l i c a t e (no s p e c i f i e d compos i t i on ) a t l e v e l s o f 2.4 gmlkglday

i n a semi -syn the t i c d i e t , f o r 4 weeks, t h e o n l y c l i n i c a l symptoms observed were

po l yd ips ia , po lyurea, and s o f t s t o o l s observed i n a few animals. No compound-

r e l a t e d l e s i o n s were found and a l l c l i n i c a l chemical t e s t s were w i t h i n normal

l i m i t s (Newberne and Wilson, 1970).

Pure-bred beagles o f bo th sexes about 6 months o f age were f e d 2.4g/kg/day

o f sodium s i l i c a t e i n a semi -syn the t i c d i e t f o r 4 weeks ( e q u i v a l e n t t o

0.8g/kg/day of s i l i c o n d i o x i d e as t h e end p roduc t ) . Gross c o r t i c a l l e s i o n s o f

t h e k idney were observed i n 818 male dogs and i n 718 female dogs. The l e s i o n s

appeared t o be f o c a l , subcapsular hemorrhages and on t he c u t su r f ace t h e

l e s i o n s suggested c o r t i c a l i n f a r c t s (Newberne and Wilson, 1970). A1 though t h e

na tu re o f t h e l e s i o n was t h e same i n a l l cases, t h e s e v e r i t y v a r i e d f rom one

animal t o another, and f rom one area t o another w i t h i n t h e k idney.

Hyper t rophy o f t u b u l a r ep i t he l i um, w i t h o r w i t h o u t degenerat ive changes,

in f lammatory c e l l i n f i l t r a t i o n i n t o t h e i n t e r s t i t i u m , and d i l a t a t i o n o f some

and c o l l a p s e o f o t h e r t u b u l a r e p i t h e l i u m were a1 1 observed t o v a r y i n g degrees

w i t h i n l o c a l i z e d areas o f t h e kidney. The genera l impress ion was one of

i r r i t a t i o n o f t u b u l a r e p i t h e l i u m fo l l owed by degenerat ive and r e g e n e r a t i v e

changes. These a l t e r a t i o n s were accompanied by in f lammatory c e l l i n f i l t r a t i o n

i n t o t he i n t e r s t i t i u m . Al though t h e r e was presence o f ex tens i ve r e n a l damage,

impairment o f r e n a l f u n c t i o n was n o t de tec ted by any o f t h e c l i n i c a l t e s t s

conducted on serum o r u r i ne . It should be noted t h a t magnesium t r i s i l i c a t e

admin is tered t o dogs a t 1.8g/kg/day ( a l s o e q u i v a l e n t t o 0.8g/kg/day of s i 1 i c o n

d i o x i d e ) f o r 4 weeks produced t he same l es i ons . It was speculated t h a t bo th

sodium s i 1 i c a t e and magnesium t r i s i 1 i c a t e were appa ren t l y absorbed f rom t h e

gu t and damaged the k idney as t h e y o r t h e i r metabo l i c products were excre ted

i n t h e u r i n e (Newberne and Wilson, 1970).

S e t t l e and Sauer (1960) e a r l i e r r e p o r t e d t h a t s i 1 iceous depos i t s formed i n

t h e k idneys o f gu inea p i g s g iven l a r g e dose o f s o l u b l e s i l i c a o r a l l y o r

i n t r a p e r i tonea l ly.

c. Chronic T o x i c i t y and Carc inogen ic i t y

There are no apparent r e p o r t s i n t he l i t e r a t u r e o f chron ic t e s t i n g o r

c a r c i n o g e n i c i t y o f sodium s i l i c a t e i n any form.

Sodium s i l i c a t e was n o t mutagenic whewtes ted w i t h -- E. - c o l i (Demerec, - e t

a1 ., 1951).. -

e. Teratogenic i t y

There are no e x i s t i n g t e r a t o g e n i c i t y da ta on sodium s i l i c a t e s .

f. Epidemiology

There have been no ep ide~ i i i o l og i ca l s tud ies re . la ted t o sodium s i 1 i c a t e

per - se. Endemic Balkan nephropathy (BN) i n c l u d i n g marked k idney f i b r o s i s has

been associated w i t h a long pe r i od o f human consumption o f d r i n k i n g water

be1 ieved by some t o be contaminated by s i 1 i c a t e s (Markovic, 1972a, b; Markovic

and Arambasic, 1971). However, i t should be noted t h a t o the r suggested

e t i o l o g i c agents have inc luded p l a n t and funga l t ox ins , v i ruses, lead and

uranium (Austwick, 1975; Barnes, -- e t a1 ., 1977; Georgescu, 1976; Krogh and'

E l l i n g , 1976; S a t t l e r , - e t -3 a1 1977). It was 'suggested (Markovic, 1972a,b;

Marcovic and Ararnbasic, 1971) t h a t these s i l i c a t e s decomposed i n t he body

a f t e r inges t ion , r e l e a s i n g s i l i c i c ac id which was excreted i n concentrated

form by the kidneys and appeared t o be the cause of: . the f i b r o s i s . It was

be l ieved t h a t mal ignant tumors o f t he u r i n a r y t r a c t found i n approx imate ly

one - th i rd of those autopsied i n Yugoslavia was r e l a t e d t o heavy and

r a d i o a c t i v e meta ls present w i t h t he s i l i c a t e s and re leased du r i ng t h e i r

decomposit ion i n t he body (Markovic, 1972a, b ) .

A s tudy o f Benninger, -- e t al., (1974) f a i l e d t o produce r e n a l changes i n

t he g u i n e a ' p i g by chron ic a d m i n i s t r a t i o n o f s i l i c i c acid.. The authors

suggested t h a t s ince s i l i c i c ac id was no t nephrotoxic, s i l i c a t e s i n the,

d r i n k i n g water are n o t o f p r ima ry s i g n i f i c a n c e i n t he pathogenesis o f endemic

Balkan nephropathy as has been p r e v i o u s l y proposed (Markovic, 1972a,b;.

Markovic and Arambasic, 1971).

A l l sodium s i l i c a t e species, whether o f n a t u r a l o r s y n t h e t i c o r i g i n , l ead

t o t h e same monomeric s i l i c a i n s o l u t i o n . Above t h e s o l u b i l i t y l i m i t f o r

monomeric s i l i c a , which i s pH-dependent, o l i gomer i c and f i n a l l y po lymer ic

s i l i c a form. These processes are t h e same i n t e r n a l l y as elsewhere i n na tu re

(Stumm, 1970; FASEB, 1979).

g. Metabol ism

A f t e r i nges t i on , s i l i c a t e s have been repo r ted t o be decomposed i n humans

t o s i l i c i c a c i d which i s exc re ted i n concentrated f o rm by t h e k idneys

(Markovic, 1972a,b). It has been p o s t u l a t e d t h a t when a s i l i c a t e (e.g.,

magnesium t r i s i l i c a t e ) i s inges ted o r admin is tered, p a r t o f t h e s i l i c a so

formed i s p r e c i p i t a t e d as a g e l and p a r t remains i n s o l u t i o n .

S i l i c i c a c i d has been repo r ted t o be a normal c o n s t i t u e n t o f human u r i ne .

t h e amount exc re ted i s i n t h e range o f 10-30 mg/day depending on t h e d i e t .

Ingested s i l i c i c a c i d r a p i d l y pene t ra tes t h e i n t e s t i n e and i s d i s t r i b u t e d

throughout t he e x t r a c e l l u l a r f l u i d . S i l i c i c a c i d has a l so been found i n b lood

a t l e v e l s below 1 pg sio2/cm3. It has n o t been found t o b i n d t o p r o t e i n o r t o

o the r l a r g e macromolecules (FAO/WHO, 1974).

Prev ious Eva1 ua t i ons and Summary

The FAO/WHO (1974) t o x i c o l o g i c a l e v a l u a t i o n o f s i l i c o n d i o x i d e and c e r t a i n

s i l i c a t e s i n r e l a t i o n t o f ood a d d i t i v e s concluded t h a t w i t h t h e excep t ion o f

t h e r e p o r t e d damage t o dog k idney by sodium s i l i c a t e and magnesium

t r i s i l i c a t e , any s i l i c a t e absorbed i s exc re ted by t h e k idneys w i t h o u t evidence

o f t o x i c cumula t ion , i n t h e body. The a v a i l a b l e da ta on o r a l l y admin is te red

s i l i c a and s i l i c a t e s appeared t o s u b s t a n t i a t e t h e b i o l o g i c a l i n e r t n e s s o f

these compounds.

As noted p r e v i o u s l y i n t h i s repo r t , FASEB (1979) i n a rev iew and

eva lua t i on o f t h e h e a l t h aspects of c e r t a i n s i l i c a t e s as food i ng red ien ts f o r

the U.S. Food and Drug Admin is t ra t ion concluded t h a t sodium s i l i c a t e (as w e l l

as aluminum 'calcium s i l i c a t e , ca lc ium s i l i c a t e , magnesium s i l i c a t e , potassium

s i l i c a t e , sodium a lum inos i l i ca te , t r i c a l c i u m s i l i c a t e , s i l i c a aerogel and

t a l c ) do n o t present a hazard t o t he p u b l i c under c u r r e n t use. The

"unpublished GRAS s ta tus " o f sodium s i l i c a t e f o r d i r e c t use i n food should

a l so be noted (SCOGS-61 repo r t , FASEB, 1979).

The U.S. Pub l i c Heal th Serv ice has a l so s ta ted t h a t " the u s e o f . small,

amounts of sodium s i l i c a t e added t o d r i n k i n g water would, as f a r as i s known,

produce rio ill -ef fects upon :!the users o f the.watefU (Vai 1 , 1:952)..

Conclusion

It i s concluded t h a t t he use o f sodium ' s i l i c a t e i n detergents poses no

hazard t o man.

B ib l i og raphy

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B., (1968), - 171, (13; August), 19-30.

2. Anon. 1964. Uni 1 ever Research Laboratory, Report No.. CH64888, October 21.

3. Austwick, P.K. Balkan Nephropathy. Proc. Roy. Soc. Med., (1975), 68, (4.;

A p r i l ) , 219-221. .

4. Barnes, J.M., -- e t a l . Balkan (endemic) Nephropathy and a tox in -p roduc ing

s t r a i n o f p e n i c i l l i u m verrucosum var. cyclopium: An exper imenta l model i n

r a t s . Lancet, (1977), 1, (8013: 26, March), 671-675.

5. Benke, G.M. and Osborn, T.W. U r i n a r y s i l i c o n e x c r e t i o n by r a t s f o l l o w i n g

o r a l a d m i n i s t r a t i o n o f s i l i c o n compounds. Food Cosmet. Toxicol . , (1979),

17, 127-128. -

6. Benninger, J.L., Graepel, P., and Hodler, J. F a i l u r e t o produce r e n a l

changes i n t h e guinea p i g by ch ron i c a d m i n i s t r a t i o n o f s i l i c i c ac id .

E t i o l o g y o f Balkan nephropathy. Res. Exp. Med., (1974), 162, (28;

February), 215-226, (Ger. ) .

7. C a r l i s l e , E.M. S i l i c o n : An e s s e n t i a l element f o r t he ch ick . Science,

(1972), 178, 619.

8. Demerec, M., Be r tan i , G., and F l i n t , J. A survey o f chemicals f o r

mutagenic a c t i o n on E. c o l i , Am. N a t u r a l i s t , (1951), - 85, 119-136.

9. Dur for , C.N. and Becker, E. P u b l i c water supp l i es o f t he 100 l a r g e s t

c i t i e s i n t h e Un i ted States, 1962. U.S. Geologica l Survey Water-Supply

Paper No. ,1812, (1964). U. S. Government P r i n t i n g O f f i ce , Washington, D.C.

10. Emerick, R.J., Kugel, E.E. and Wallace, V. U r i n a r y e x c r e t i o n o f s i l i c o n

and the p roduc t ion o f s i l i c e o u s u r i n a r y c a l c u l i i n r a t s . Am. J. Vet.

Res., (1963), - 24, 610.

11. FAO/WHO. T o x i c o l o g i c a l Eva lua t i on o f some Food A d d i t i v e s I n c l u d i n g

A n t i c a k i n g Agents, A n t i m i c r o b i a l , An t i ox i dan t s , Emu1 s i f i e r s and Th icken ing

Agents, WHO Food A d d i t i v e Ser ies, No. 5, World H e a l t h Organ iza t ion ,

Geneva. (1974), pp. 21-27.

12. FASEB. (Federa t ion o f American S o c i e t i e s f o r Exper imenta l B i o l o g y ) 1979.

F i n a l Eva lua t i on o f t h e Hea l t h Aspects o f C e r t a i n S i l i c a t e s as Food

I ng red ien t s , Report Prepared ' f o r Food and Drug Admi n i s t r a t i o n , Con t rac t

#FDA 223-75-2004, Bethesda, MD, 18-19. .

13. Ga ja t to , S. S i l i c o n pharmacology. 11. T o x i c i t y o f sodium s i l i c a t e : I t s

u r i na ry e l imi na t ion , S t u d i Sassaresi , (1944), - 22, 27-90; Chem. Abs t r . , (1951), - 45.

14. Georgescu, L. V i ruses i n endemic (Balkan) nephropathy. Lancet, (1976),

1, 1086. -

15. Gleason, M.N., -- e t a l . " C l i n i c a l Tox ico logy o f dommercial Products-Acute

Poisoning", 3 rd ed., (1968), Wi l l i ams and Wi lk ins , Bal t imore, pp. 3, 69, . .

. . . . . . . . . -

131. . . . , . - .

16. I n t e r n a t i o n a l Technica l I n fo rma t i on I n s t i t u t e , "Tox ic and ~ a i a r d o u s .. '-

I n d u s t r i a1 Chemicals".

17. King, E.J., B e l t , T.H. The p h y s i o l o g i c a l and p a t h o l o g i c a l aspects of

s i l i c a . ' Phys. Rev., (1938), 18, 329.

18. King, E.J., S t a t i a l , H. & Dolan, M. The b iochemis t r y o f s i l i c i c ac id .

111. The e x c r e t i o n o f admin is te red s i l i c a . Biochem. J., (1933), 27, 1007.

19. Krauskopf, K.G. " I n t r o d u c t i o n t o Geochemistry", McGraw-Hi 11, New York, . .

(1967), p. 721.

20. Krogh, P., E l l i n g , F. Fungal t o x i n s and endemic (Balkan) nephropathy. . .

Lancet, (1976), 2, 40.

21. Levier , R.R. D i s t r i b u t i o n o f s i l i c o n i n the a d u l t r a t and Rhesus monkey.

B io inorg . Chem., (1975), - 4, 109-116.

22. Markovic, B. 1972a. Endemic nephropathy and cancer o f t he upper u r i n a r y

t r a c t u ro the l i um in. Yugoslavia, I s r a e l J. Med. Sci., (1972), - 8, 540-548.

23. Markovic, B. 1972b. Mal ignant diseases o f u r i n a r y t r a c t i n t he Balkan

count r ies , Uro l . In t . , (1972), - 27, 130-143.

24..Markovic, B., and Arambasic,M. Experimental ch ron i c i n d u s t r i a l n e p h r i t i s

compared w i t h endemic human nephropathy, J. Path., (1971), - 103, 35.

25. Newberne, P.M. and Wilson, R.B. Renal damage associated w i t h s i l i c o n

compounds i n dogs, Proc. Nat. Acad. Sci., (1970), - 65, 872-875.

26. NIOSH. R e g i s t r y of Toxic E f f e c t s o f Chemical Substances, U.S. ~overnment

P r i n t i n g O f f i c e , Washington, D.C. (1975), p. 1068.

27. Page, R.C., Hefner, R.R., and Frey, A. U r i n a r y exc re t i on o f s i l i c a i n

humans f o l l o w i n g o r a l admin i s t ra t i on o f magnesium s i l i c a t e , Am. J. Dig.

Dis., ,(1941), - 8, 13-15.

28. Ph i l ade lph ia Quar tz Co. 1961. Report No. 56333.

29. S a t t l e r , T.A., D imi t rov , and H a l l , P.M. Re la t i on between endemic (Balkan)

nephropathy and u r i n a r y - t r a c t tumors, Lancet, (1977), Feb. 5, 278-280.

30. Sax, N. I. "Dangerous Proper t ies o f I n d u s t r i a l Mater ia ls " , 4 t h ed.,

(1968), Van Nostrand-Reinhold, New York, p. 1118.

31. S e t t l e , W.R., and Sauer, F. Demonstration o f s i l i c e o u s depos i ts i n t h e

kidneys of t he guinea p ig , Am. J. Vet. Res.., (1960), - 21, 709.

32. Stumm, P. "Aquat ic Chemistry", Wi ley- Intersc ience, New York, (1970),

p. 396.

33. Sturm, R.W., Blumberg, J.G., and Schleyer, W.L. Heal th Aspects o f Sodium

S i l i c a t e as a Detergent Bu i lder , P.Q. Corporat ion and Proc ter & Gamble

Co., July, (1978), p. 4.

34. Soap and Detergent Associat ion. The Soap and Detergent Assoc ia t ion

S c i e n t i f i c and Technical Report No. 5R, (1972), p. 24, New York, N.Y.

35. Tracor-J i tco, Inc. S c i e n t i f i c L i t e r a t u r e Reviews on Genera l l y Recognized

as Safe (GRAS) Food Ingred ien ts -S i 1 i ca tes . Prepared f o r t h e FDA,

September, (1973), p. 65.

36. Va i l , J.G. "Soluble S i l i c a t e s n Vol. 1, ACS Monograph No. 116, (1952),

Reinhold Publ. Co., New York.

37. W i l l s , J.H. Syn the t i c Inorgan ic S i l i c a t e s , In : Kirk-Othmer Encyclopedia

o f Chemical Technology, 2nd ed., Vol. 18, (1969), Wiley, New York, 134-165.

8. ALUMlNOSlLlCATES (TYPE A SODIUM ZEOLITE)' . . . . . . . .


A1 uminosi 1 i c a t e s have a v a r i e t y o f uses, i n c l u d i n g the food i ndus t r y .

Food grade a l u m i n o s i l i c a t e i s approved f o r use i n c e r t a i n foods up t o l e v e l s

o f 2 percent. Aluminosi 1 i ca tes , a1 uminum compounds and s i 1 i c a t e s are w ide l y

used i n t he treatment o f d r i n k i n g water.

Recently, t he Federat ion o f American Soc ie t i es f o r Experimental B io logy

completed a rev iew and eva lua t i on o f t h e h e a l t h aspects o f c e r t a i n s i l i c a t e s

as food i ng red ien ts f o r the Un i ted States Food and Drug Admin is t ra t ion . (1) The conclus ion o f t he committee was t h a t aluminum calc ium s i l i c a t e , ca lc ium

s i l i c a t e , magnesium s i l i c a t e , potassium s i l i c a t e , sodium s i l i c a t e , sodium

aluminosi 1 i ca te , t r i c a l c i u m s i 1 i c a t e and s i 1 i c a aerogel, do no t present a

hazard t o the p u b l i c under c u r r e n t use. This conclus ion was i n agreement w i t h

e a r l i e r dec is ions by t h e World Hea l th Organ iza t ion (WHO) and t t ie Food and

A g r i c u l t u r e Organizat ion (FAO), which es tab l i shed no l i m i t f o r - t he acceptable

d a i l y i n take o f these same s i l i c a t e s , w i t h t h e except ion o f magnesium s i l i c a t e .

This r e p o r t concerns t h e ' h e a l t h aspects o f s y n t h e t i c Type 'A Zeol i t e

(sodium aluminosi 1 i c a t e ) u t i 1 i zed i n household detergents. A' rev iew of t h e

chemical and t o x i c o l o g i c a l data on t h i s aluminosi 1 i c a t e (2,3,4) w i 11 be made

t o asce r ta in whether t h e p o t e n t i a l h e a l t h r i s k i s markedly d i f f e r e n t f rom

o the r w ide l y used s i 1 i con compounds (e.g. sodium s i 1 i c a t e , sodium

a lum inos i l i ca te , e tc . ) .

Chemistry and Environmental Levels

A knowledge o f t he chemist ry o f Type A Z e o l i t e i s e s s e n t i a l f o r proper

eva lua t i on o f t he r e s u l t s f rom t o x i c o l o g i c a l experiments.

* Contr ibuted by G.C. Becking

, .

I t i s a s y n t h e t i c , c r y s t a l 1 i n e , i n o r g a n i c sodium a l u m i n o s i 1 i c a t e , h a v i n g a

Na:Al:Si r a t i o o f 1:1:1, and i s c u b i c i n s t r u c t u r e . Type A Z e o l i t e i s more

the rmodynamica l l y u n s t a b l e t h a n f o o d grade a l u m i n o s i l i c a t e , wh ich has a

Na:Al:Si r a t i o o f 1:1:13. I n aqueous suspensions, i t w i l l t r a n s f o r m t o

amorphous a lumina tes ( c l a y - 1 i k e m a t e r i a l s ) and sodium s i 1 i c a t e s . The presence

o f p r o t o n s o r c h e l a t o r s i n t h e env i ronment w i l l enhance t h e removal o f

s i l i c a t e s f r o m t h e c u b o i d a l s t r u c t u r e , d e s t r o y i n g t h e r i g i d . c u b i c s t r u c t u r e .

A t pH .<5 t h e t r a n s f o r m a t i o n t a k e s p l a c e i n a few seconds, and a t pH va lues

between 5 and 8, t h e r a t e i s f a s t , b u t may t a k e a few m inu tes t o complete. - A t

a pH above 8 t h e same t r a n s f o r m a t i o n occurs b u t a t a s lower r a t e .

Given t h i s i n s t a b i l i t y , c u b o i d a l Type A Z e o l i t e w i l l r a r e l y be found i n

t h e environment. . I t . w i l l r a p i d l y t r a n s f o r m t o amorphous a lumina tes and

s o l u b l e s i l i c a t e s under t h e a c i d c o n d i t i o n s o f t h e stomach a n d t h e n e u t r a l

c o n d i t i o n s o f o t h e r t i s s u e s and t h e genera l environment. Bo th t r a n s f o r m a t i o n

p r o d u c t s have an e x t e n s i v e h i s t o r y o f s a f e usage.

I n t h e U n i t e d S ta tes , t h e median l e v e l s o f s o l u b l e s i l i c a t e (measured as

SiO2) and s o l u b l e a l u m i n a t e (measured as A l ) a r e 7.1 mg/L and 0.054 mg/L

r e s p e c t i v e l y . Assuming an exaggerated use p a t t e r n , t h a t i s , where a l l

d e t e r g e n t s were b u i l t w i t h 20 p e r c e n t Type A Z e o l i t e , env i ronmenta l s t u d i e s

showed t h a t t r a n s f o r m a t i o n p r o d u c t s would r e s u l t i n 0.00003 mg/L A l / L and

0.00007 mg/L SiO2 i n p o t a b l e water . These f i n d i n g s have been conf i rmed i n

b o t h l a b o r a t o r y and p i l o t s c a l e s t u d i e s o f d r i n k i n g wa te r t r e a t m e n t processes

and c o n d i t i o n s . No p a r t i c l e s r e s e m b l i n g t h e c u b o i d a l s t r u c t u r e o f Type A

Z e o l i t e have been found i n these s t u d i e s .


E x t e n s i v e acu te t o x i c i t y s t u d i e s on Type A Z e o l i t e i n d i c a t e t h a t t h i s

m a t e r i a l i s an a c u t e l y n o n t o x i c chemica l ( 5 ) . I t i s n o n - t o x i c when i n g e s t e d

i n a s i n g l e dose and i s r e l a t i v e l y n o n - i r r i t a t i n g t o t h e eye and s k i n . Type A Z e o l i t e does n o t produce s e n s i t i z a t i o n and i s n o n - i r r i t a t i n g t o t h e

r e s p i r a t o r y system a f t e r a s i n g l e i n h a l a t i o n exposure. The s t u d i e s on which

t h e above c o n c l u s i o n s were made a r e summarized i n Tab le 1.

TABLE 1

Tes t

Ora l t o x i c i t y (Dog) 1 1 g/kg produced s l i g h t hyperemia o f stomach

Resu l t s

Ora l LD5, (Rat )

Eye i r r i t a t i o n (Rabb i t ) 3 rng un r i nsed 3 mg r i n s e d 0.1 mL o f 10% aqueous

>27.0 g/kg; no l e t h a l i t y a t 27 g/kg

Eye i r r i t a t i o n (Monkey)

35 mg unr insed

Sk in i r r i t a t i o n (Rabb i t ) Abraded and Non-Abraded S l i g h t l y moistened; 20% aqueous

s l u r r y Z e o l i t e A 24-hour, . c l osed pa t ch

Sk in i r r i t a t i o n (Human) S i n g l e patch, 50% aqueous s l u r r y

Acute Percutaneous T o x i c i t y (Rabb i t ) Abraded and Non-abraded 2 g/kg; 24-hour c losed pa t ch

S e n s i t i z a t i o n (Guinea P i g ) 50% aqueous s l u r r y (3 weekly a p p l i c a t i o n s and

cha l 1 enge)

S e n s i t i z a t i o n (~umans ) . ,

5% aqueous s l u r r y ( 9 week ly a p p l i c a t i o n s and

cha l 1 enge),

Acute i n h a l a t i o n (Rats) S i n g l e 1 -h r exposure: 2.4 and

18.3 mg/L S i n g l e 4-hr exposure; 0.08 and

0.14 mg/L

Acute i n t r a t r a c h e a l i n s t i 11 a t i o n ( ~ a t s ) . . .

S l i g h t i r r i t a t i o n which subs ided w i t h i n 48 hours

. .,

1 M i l d i r r i t a t i o n c o n s i s t i n g o f m i l d erythema

No deaths; m i l d erythema a t t rea tment s i t e

No s e n s i t i z a t i o n

No s e n s i t i z a t i o n

No observable t o x i c e f f e c t s

No observab le t o x i c e f f e c t s

I r r i t a t i o n p o t e n t i a l o f Type A Z e o l i t e i s s i m i l a r t o ca l c i um carbonate and l e s s t han s i l i c a f l o u r

I n v i t r o (Rabb i t s ) -and i n v i v o (Rats and Hamsters) a1 veol a r macrophage

T o x i c i t y r a t i n g : Type A Zeo l i te<Clay<Quar tz

Metabol ism and Subchronic T o x i c i t y S tud ies . ..

Both acute and sub-chron ic me tabo l i c s t u d i e s have been conducted on Type A

Z e o l i t e i n r a t , monkey and man t o determine i t s absorp t ion , d i s t r i b u t i o n and

e x c r e t i o n p a t t e r n . ~ d d i t i o n a l l ~ , r e a c t i o n s t o Type A Z e o l i t e i n a model human

stomach were s tud ied , as was t he r e l a t i o n s h i p between t h e c o n c e n t r a t i o n o f

s o l u b l e and p a r t i c u l a t e s i l . i c o n spec ies i n human u r i n e and t h e l e v e l of

s i l i c o n i n p o t a b l e water . A summary o f t h e v a r i o u s me tabo l i c t e s t s w a s . . .

p resented t o t h e IJC Task Force by t h e P roc te r and Gamble Company (2,3) and i s

reproduced w i t h minor changes i n Table 2.

TABLE 2

Metabol ism Stud ies

Test I Resu l t s

Stomach Model - Human

Acute ( s i n g l e dose) r a t and monkey: 0,40

Type man: 0 o r 40 mg Type --

Sub-chronic i n r a t s 0 and 2% i n d i e t - 8 weeks

- Type A Z e o l i t e i s hydro lyzed t o a luminates and s i 1 i c a t e s

- U r i n a r y s i 1 i c o n markedly ' increased, u r i n a r y a1 umi num unchanged

- 85-110% o f dosed aluminum found i n r a t feces . - I n man, b lood A1 <1 pg/mL a f t e r s i n g l e

40 mg/kg dose - S i m i l a r u r i n a r y s i l i c o n e x c r e t i o n (% o f dose)

i n a l l 3 spec ies ., . .

- ~ n c r e a s e i n u r i n a r y . s i l i c o n ; u r i n a r y aluminum unchanged

- No s i g n i f i c a n t t i s s u e s to rage o f aluminum - No k i n e t i c ev idence f o r m u l t i p l e t i s s u e .

b i n d i n g s i t e s f o r s i l i c o n

E x c r e t i o n o f u r i n a r y p a r t i c u l a t e S i l i c o n ( r a t s ) ; 0, 0.125, 0.25, 0.5,

1 and 2% i n d i e t 3 - 16 weeks

- A marked i nc rease i n e x c r e t i o n o f p a r t i c u l a t e s i l i c o n noted a t 0.125 - 0.25% Type A Z e o l i t e

Human U r i n a r y S i l i c o n - E x c r e t i o n i n r e l a t i o n t o d r i n k i n g water s i l i c o n l e v e l s

- D r i n k i n g water s i l i c o n (median l e v e l 7 mg/L) does n o t a f f e c t u r i n a r y p a r t i c u l a t e s i l i c o n e x c r e t i on

- <1 pg/L s i l i c o n c o n t r i b u t e d t o d r i n k i n g water th rough use o f Type A Z e o l i t e would i nc rease u r i n a r y e x c r e t i o n o f s o l u b l e s i l i c a <o. 02%.

Acute and sub-chronic metabol ic s tud ies have been conducted w i t h Type A

Zeol i t e and o ther s i l i con conta in ing compounds, such as sodium s i l i ca te ,

magnesium t r i s i l i c a t e and food grade sodium a lum inos i l i ca te , which have been

approved as safe f o r food use by t h e U.S. Food and Drug Admin i s t ra t i on (FDA),

t he WHO and o ther i n t e r n a t i o n a l agencies. The above s tud ies i n d i c a t e t h a t

Type A Z e o l i t e i s hydrolyzed i n t he stomach t o s i l i c a t e s and .aluminates and

on l y t he s i l i c o n moiety o f Type A Z e o l i t e i s p a r t i a l l y absorbed.

The acute s tud ies show tha t , as the dose o f Type A Z e o l i t e i s increased,

u r i n a r y s i l i c o n exc re t i on i s increased. Aluminum i s recovered i n t h e feces.

This f e c a l aluminum represents unabsorbed aluminum, s ince ana lys is o f b i l e

from animals dosed w i t h Type A Z e o l i t e show t h a t b i l e i s no t a r o u t e o f

exc re t i on f o r Type A Zeol i te .

U r ina ry exc re t i on of s i l i c o n , expressed as percent o f s i l i c o n dosed, was

s i m i l a r f o r r a t , monkey and man when dosed w i t h a s i n g l e l a r g e dose of Type A

Zeo l i t e . To t h i s ex ten t t he r a t i s an appropr ia te model f o r chron ic t o x i c i t y

s tud ies on Type A Zeo l i t e .

The sub-chronic metabol ic s tud ies conducted i n r a t s p rov ide add!iti.onal

support f o r t he conclus ion t h a t Type A Zeo l i t e . i s hydrolyzed i n . th,e .stomach t o

s i l i c a t e s and aluminates and th.at on l y t h e s i l i c o n moiety o f Type A Z e o l i t e i ,s

absorbed. These s tud ies show t h a t as the dose o f Type A Z e o l i t e i n ~ t h e r a t

d i e t i s increased, t he amount o f s i l i c o n excreted i n t he u r i n e i s markedly

increased wh i le , u r i n a r y aluminum and t i ssue , aluminum remain unchanged.

U r ina ry s i l i c o n exc re t i on i s such t h a t a t d i e t a r y concentrat ions greater than

0.125% Type A Zeo l i t e , t he u r i n a r y s i l i c o n burden becomes so g rea t t h a t t he

u r i n e becomes saturated w i t h so lub le s i l i c a t e and s i l i c a t e p r e c i p i t a t i o n

occurs i n t he u r i n e ( r e f e r r e d t o he re in as " p a r t i c u l a t e " s i l i c o n ) .

A human u r i n a r y s i 1 i con mon i to r ing program i n v e s t i g a t i n g t h e re1 a t ionsh ip ' * -

between na tu ra l l e v e l s o f s i l i c o n i n t h e d r i r ~ k i u g water (1-10 ppm ~ i 0 2 )

and the exc re t i on o f so lub le and " p a r t i c u l a t e " s i l i c o n ( s i l i c o n p r e c i p i t a t e > 0 . 4 ~ )

i n t he u r i n e shows t h a t d r i n k i n g water con ta in ing up t o 10 ppm SiO2 has no

e f f e c t on u r i n a r y " p a r t i c u l a t e " s i l i c o n excret ion, thus i n d i c a t i n g t h a t the

p a r t s per b i l l i o n o f s i l i c o n added t o t he d r i n k i n g water through t h e l a r g e

s c a l e use o f Type A Z e o l i t e i n t h e de te rgen t i n d u s t r y i s no t l i k e l y t o cause

an inc rease i n u r i n a r y " p a r t i c u l a t e " s i l i c o n .

The above ex tens i ve metabo l i c exper iments i n severa l species, i n c l u d i n g

man, have p rov ided ample p r o o f t h a t t h e o r a l t o x i c i t y o f Type A Z e o l i t e i s

t h a t o f so lub le s i l i c a t e s . Also, t h e sub-chronic feeding s tud ies , i n which

r a t s were f e d d i e t s c o n t a i n i n g 0.1 t o 2% Type A Z e o l i t e f o r pe r i ods o f t ime

between 90 and 200 days, i n d i c a t e t h a t Type A Z e o l i t e i s a r e l a t i v e l y

non- tox ic chemical . S i g n i f i c a n t t o x i c man i fes ta tons were o n l y noted a t doses

p roduc ing h i g h l e v e l s o f u r i n a r y p a r t i c u l a t e s i l i c o n .

I n Cox o r Loug Evans r a t s , d i e t a r y l e v e l s of Z e o l i t e A as h i g h as 2%

f a i l e d t o cause dose re1 ated e f f e c t s on organ weights, hematology, b l ood

chem is t r y o r k idney f u n c t i o n a f t e r 168 o r 200 days. Body weights o f animals

r e c e i v i n g 2% Type A Z e o l i t e were lower than c o n t r o l s . Also, an inc reased

u r i n e vo l l~me and decreased s p e c i f i c g r a v i t y were noted i n animals r e c e i v i n g 2%

Z e o l i t e i n t h e d i e t . S i l i c e o u s p a r t i c l e s were noted i n t h e u r i n e o f a l l r a t s

r e c e i v i n g >0.125% Type A Z e o l i t e i n t h e d i e t . The q u a n t i t y of p a r t i c l e s

appearing i n t h e u r i n e was dose r e l a t e d . A d d i t i o n a l l y , a t d i e t a r y l e v e l s

g rea te r than 0.125% Type A Z e o l i t e , t h e s i l i c e o u s p a r t i c l e s aggregated t o form

b ladder and k idney stones. Such stones d i d no t appear u n t i l a f t e r 90 days on

t e s t and t h e inc idence o f stones increased w i t h t i m e and d i e t a r y l e v e l s above

0.125%. Below t h i s " t h resho ld " d i e t a r y l e v e l f o r p a r t i c l e fo rmat ion , no

compound r e l a t e d stones weie observed. The p a r t i c l e s and stones were

amorphous, h i g h i n s i l i c o n content , w i t h no de tec tab le aluminum.

Compound r e 1 a ted mic roscop ic changes were observed i n t h e k idneys and/or

b ladders of animals r e c e i v i n g g r e a t e r t han 0.125% Type A Z e o l i t e i n t h e d i e t

f o r 168 o r 200 days. The mic roscop ic changes cons i s ted of hype rp las ia of t h e

t r a n s j t i o n a l c e l l e p i t h e l i u m o f t h e mucosa o f t h e u r i n a r y b ladder and t h e

k idney p e l v i c ep i t he l i um. When such changes were found p a r t i c u l a t e m a t e r i a l

o r c a l c u l i were a1 so found. A1 so,' a f t e r m ic roscop ic examinat ion o f t h e

k idney, u r e t e r s and u r i n a r y b ladder o f animals r e c e i v i n g 2% Type A Z e o l i t e i n

t h e d i e t , a l t e r a t i o n s cha rac te r i zed by an inc rease i n t h e i nc i dence and

s e v e r i t y o f i n t e r s t i t i a l n e p h r i t i s and regenera t ive ep i the1 ium were noted. No

h i s topa tho log i ca l l es ions were found i n animals f e d d i e t s con ta in ing 0.125%

Z e o l i t e A. The microscopic changes appeared t o be r e l a t e d t o t h e u r i n a r y

s i l i c a t e burden and s i l i c e o u s m a t e r i a l i n t h e t i ssues . They were s i m i l a r t o

those repo r ted f o r o ther s i l i c a t e s , such as sodium s i l i c a t e , magnesium

t r i s i 1 i c a t e and s i 1 i c i c acid.

Twenty-eight-day and 91-day dermal t o x i c i t y s tud ies conducted i n r a b b i t s

showed t h a t Type A Z e o l i t e had no systemic o r dermal e f f e c t s . A p p l i c a t i o n of

2 mL/kg bodyweight of a 10% aqueous s l u r r y of Type A Z e o l i t e t o t h e backs o f

r a b b i t s 6 hr/day, 5 days per week f o r 4 o r 13 weeks was n o n - i r r i t a t i n g t o t h e

sk in and had no adverse e f fec t on bodyweight, hematology, c l i n i c a l chemis t ry .

o r h i s to logy .

Chronic T o x i c i t y

Based on sub-chronic metabol ic s tud ies and 200 day sub-chronic feed ing

studies, t he h ighes t d i e t a r y dose l e v e l used i n ch ron i c s tud ies was 0.1%. . .

This should be considered a maximum t o l e r a t e d dose, s ince h igher l e v e l s r e s u l t

i n s i l i c e o u s m a t e r i a l causing phys ica l t i s s u e damage. The exact e f fec t of

such non-physio logica l a c t i o n on chron ic t o x i c i t y i s unknown.

Admin i s t ra t i on o f 0.001%, 0.01% and 0.1% Type A Z e o l i t e i n t h e d i e t of

Wistar r a t s f o r 78 weeks had no compound r e l a t e d e f f e c t s on phys i ca l

appearance, hematology, b lood chemist ry o r u r i n a l y s i s .

Gross necropsy of animals revea led no abnormal f i n d i n g s . 'This s tudy

cannot be considered an adequate ch ron i c t o x i c i t y study, b u t t h e

c a r c i n o g e n i c i t y bioassay (us ing a s i m i l a r dosing regimen) u t i l i zed an

experimental design, making i t a combined c a r c i n o g e n i c i t y and 104 week ch ron i c

t o x i c i t y study.

I n t h e c a r c i n o g e n i c i t y bioassay, r e s u l t s o f b lood chemistry, hematology,

u r i n a l y s i s and body weight / food consumption studies, as we1 1 as the

h i s topa tho log i ca l examinat ion f o r non-cancerous les ions , support the r e s u l t s

o f t he 78 week chron ic experiment. That i s , t h e admin i s t ra t i on o f 0.1% Type A

Z e o l i t e i n t h e d i e t f o r 104 weeks does no t produce chron ic t o x i c i t y i n ra ts* .

No evidence of f i b r o s i s was observed i n hamsters exposed t o -20 mg/m3

o f Type A Zeo l i t e , 3 days per week, 5 hours per day f o r 52 weeks. The on l y

observat ion was the presence o f t he t e s t ma te r i a l i n t h e a l veo la r macrophage

and lymph nodes.

Exposure o f Cynomol gus monkeys t o 1 and 6 mg/m3 of Type A Zeol i t e o r

Type A Z e o l i t e detergent (detergent micronized t o maximize i n h a l a t i o n ) f o r

24-months and t o 50 mg/m3 o f Type A Z e o l i t e o r quar tz f o r 12 months had no

adverse e f f e c t s on bodyweight gain, hematology, serum chemist ry o r

u r i n a l y s i s . The o n l y a l t e r a t i o n i n pulmonary f u n c t i o n was a decrease i n t he

mean v i t a l capac i t y o f t h e monkeys exposed t o quar tz f o r 12 months.

Histopathology o f t he var ious t i ssues i nd i ca ted t h a t exposure t o -1 and 6

mg/m3 o f Type A Zeo l i t e -con ta in ing detergents f o r 6 hours per day, 5 days

per week f o r 104 weeks produced o n l y an increase i n a l veo la r and septa l

macrophages. Exposure t o -1 and 6 mg/m3 Type A Z e o l i t e f o r 104 weeks and

-50 mg/m3 Type A Z e o l i t e f o r 52 weeks produced an increase i n a l veo la r and

septa l marcrophages. I n add i t ion , a t the 6 and 50 rng/m3 Type A Z e o l i t e

doses, sporadic i n f 1 ammatory reac t i ons were observed i n t he lungs o f some o f

t he t r e a t e d animals. These inf lammatory reac t i ons were observed p r i m a r i l y i n

lobes of t he lung p rev ious l y compromised by m i tes and kao l i n . Ne i ther Type A

Z e o l i t e nor Type A Zeo l i t e -con ta in ing detergents produced pulmonary f i b r o s i s

a f t e r 104 weeks o f exposure.

Compound r e l a t e d e f f e c t s were no t observed i n any o the r t i ssues . Quar tz

produced progressive pulmonary f i b r o s i s i n monkeys as e a r l y as 30 weeks a f t e r

i n i t i a l exposure. The observed increase i n a l veo la r and septa l macrophages

w i t h Type A Z e o l i t e and Type A Z e o l i t e detergents i s a c l a s s i c a l pulmonary

clearance response t o r e l a t i v e l y innocuous, inso lub le , m a t e r i a l s deposited i n

t h e lungs. These r e s u l t s support t h e conclus ion t h a t Type A Z e o l i t e and Type

A Zeo l i t e -con ta in ing detergents are r e l a t i v e l y innocuous ma te r ia l s .

* Personal Communication from t h e p r o c t e r and Gamble Company, regard ing i n fo rma t ion suppl ied t o them by t h e Henkel Company.

Carc inogen i c i t y

To determine t h e carc inogen ic p o t e n t i a l o f Type A Z e o l i t e , i t was

admin is te red a t 0.001, 0.01 and 0.1% i n t h e d i e t o f r a t s f o r 104 weeks. A t

t h e 0.1% dose t h e r e was an exacerba t ion o f glomerulonephrosis, a sponta-

neous k idney disease which develops i n ag ing r a t s . The 0.1% dose i s

cons idered a maximum t o l e r a t e d dose because o f t h e r e p o r t e d exacerba t ion o f

t h i s spontaneous k idney d isease i n female r a t s and because i t i s t h e

"b reakpo in t " a t which t h e r e i s an inc rease i n p a r t i c u l a t e s i l i c o n i n t h e u r i n e

which cou ld l ead t o s tone fo rmat ion , compromising t h e carc inogen ic assessment

i n b l adder and k idneys .

Tumor inc idence was repo r ted t o be e s s e n t i a l l y i d e n t i c a l among groups and

sexes whether broken down as t o t a l tumors, ma l ignan t tumors o r benign tumors.

No t rea tment assoc ia ted c a r c i n o g e n i c i t y was i d e n t i f i a b l e .

Mesenteric-lymphangiomas and p i t u i t a r y tumors were t h e most common tumors

i n males, whereas p i t u i t a r y tumors were t h e most p reva len t t ype o f tumor i n

females. I n bo th cases, no t rea tment assoc ia ted o r dose-response assoc ia ted

carc inogen ic e f f ec t was repor ted .

I n conc lus ion, an e s s e n t i a l l y 1 i f e t i m e f eed ing s tudy which was designed

and conducted i n a f a s h i o n s i m i l a r t o those i n t h e NCI1s bio'assay prog'rarn h i s

y i e l d e d da ta s t r o n g l y suppo r t i ng t h e conc lus ion t h a t t h e chron ic ' feeding of

h i g h doses of Type A Z e o l i t e does n o t produce cancer o r ch ron i c organ t o x i c i t y

i n rodents .

No carc inogen ic o r f i b r o g e n i c e f f e c t s were observed i n r a t s ' exposed t o

-20 mg/m3 of Type A Z e o l i t e , f o r t h r e e days pe r week, 5 hours pe r day f o r

22 months. The o n l y compound r e l a t e d e f f e c t observed was t h e presence o f t h e

t e s t m a t e r i a l i n t he a l v e o l a r macrophage and t h e lymph nodes, i n d i c a t i v e of

d e t o x i f i c a t i o n mechanisms f o r a i r bo rne f o r e i g n i n s o l u b l e p a r t i c u l a t e ma t te r .

No carc inogen ic e f f e c t s were observed i n r a t s g iven a s i n g l e 50 mg

i n t r a p e r i t o n e a l - i n j e c t i o n o f q u a r t z o r Type A Z e o l i t e and then' observed f o r

var ious t ime per iods up t o 24 months. Under t he above dosing cond i t ions , Type A Z e o l i t e produced a f ib rogen ic response w i t h i n t h e p e r i t o n e a l c a v i t y . The

response was q u a l i t a t i v e l y and q u a n t i t a t i v e l y d i f f e r e n t f rom the f i b r o g e n i c

response produced by quar tz . Speci f i c a l ly, t h e response observed w i t h Type A

Z e o l i t e regressed w i t h t ime, whereas t h e response a f t e r a d m i n i s t r a t i o n o f

quar tz progressed w i t h t ime. Unpublished, p r e l i m i n a r y s tudies, u t i l i z i n g t h i s

technique i n mice, found t h a t an i n t r a p e r i t o n e a l i n j e c t i o n o f 20 mg o f f i b r o u s

n a t u r a l z e o l i t e r e s u l t e d i n t h e produc t ion o f mesotheliomas i n l ess than one

year (Personal Communication - D r . I. Sel i k o f f ) . It i s thus a v a l i d model t o

i n d i c a t e carc inogen ic o r t o x i c p o t e n t i a l o f r e1 a t i v e l y i n s o l u b l e ma te r i a l s .

The e f f e c t s o f chron ic i n h a l a t i o n o f Z e o l i t e A con ta in ing detergent

f o rmu la t i ons were s tud ied i n monkeys exposed t o 1 and 6mg/m3 o f these

ma te r i a l s . Exposure was f o r 6 hrs/day, 5 days per week f o r 104 weeks. None

o f the t e s t m a t e r i a l s had adverse e f f e c t s on body weight gain, hematology,

serum chemist ry o r u r i n a l y s i s . The o n l y a l t e r a t i o n i n pulmonary f u n c t i o n was

noted i n monkeys t r e a t e d w i t h quar tz . H i s topa tho log i ca l examinat ion o f t he

var ious t i ssues i n d i c a t e d t h a t exposure t o approximately 1 and 6 mg/m3 o f

Type A Zeo l i t e , o r detergent f o rmu la t i ons w i t h Z e o l i t e A produced o n l y an

increase i n a l v e o l a r and septa1 macrophages, and t h e expected response t o

inha led i n s o l u b l e p a r t i c u l a t e mat te r . These i n h a l a t i o n s tud ies i n monkeys

support t h e conclus ion t h a t chron ic exposure t o Type A Z e o l i t e dusts poses a

n e g l i g i b l e h e a l t h hazard.

Mutagen ic i ty

No mutagen ic i ty t e s t s on Type A Z e o l i t e have been repor ted. Food grade

sodium a l u m i n o s i l i c a t e has been found non-mutagenic i n hos t mediated assays

w i t h Salmonel la typhimurium and Saccharomyces c e r e v i s i a e as w e l l as a dominant

l e t h a l assay i n which male r a t s were in tubated w i t h 4.25, 42.5 o r 425 mg/kg o f

sodium a l u m i n o s i l i c a t e d a i l y f o r 5 days p r i o r t o mating.

S i l i c o n d iox ide and hydrated ca lc ium s i 1 i c a t e d i d n o t ,induce n ~ u t a t i o n s i n

t he hos t mediated assay w i t h Salmonella typhimurium o r Saccharomyces

cerev is iae , nor d i d these two s i l i c o n m a t e r i a l s produce s i g n i f i c a n t

aberrations in the bone marrow metaphase chromosomes of rats; nor did they

produce abnormal changes in anaphase chromosomes of human embryonic lung cells in tissue culture.

Based on the fact that other silicates are non-mutagenic, it is unlikely

that Type A Zeolite would be positive in mutagenicity tests.

Teratol ogy

In the rat teratology study, danis were given either 74 mg/kg or 1600 mg/kg

Type A Zeolite by gavage on days 6-15 of gestation inclusive. In the rabbit

teratology study, dams were given 74 mg/kg, 345 mg/kg or 1600 mg/kg of Type A Zeolite on days 6 through 18 of gestation. Like other silicates, Type A

Zeol i te has a teratogenic potential. comparable to food grade sodium . -

aluminosil icate.

Conc 1 us i ons

The toxicological data base on 'Type A Zeolite is much more extensive-than that available for other synthetic and natural silicates, even those used by '

the food industry. Type A Zeolite is essentially non-toxic via oral, dermal, ocular and respiratory routes of exposure and adverse effects are noted only

after oral doses several million times that of calculated human exposures.

These effects are similar to those noted after administration of massive oral

doses of other widely used si 1 icates (e.g. magnesium trisi 1 icate, food grade

sodium a1 uminosil icate and sodium si 1 icate) .

Laboratory and environmental studies have shown that man will not be

exposed to cuboidal Type A Zeolite, only to soluble silicates and-insoluble a1 uminates (clay-1 ike material ) . Extensive metabol ic studies have shown that

only the silicate, but not the aluminate, moiety of Type A Zeolite is absorbed; supporting the conclusion that the oral toxicity of Type A Zeolite is that of soluble silicate.

The median level of SiO2 in drinking water is 7 mg/L. Assuming an

exaggerated use pattern for Type A Zeolite in detergents, this level of

silicon will increase by less than 0.001%.

During animal studies, marked histopathological lesions were noted only in

the kidney and bladder from animals fed diets containing Type A Zeolite at

levels exceeding 0.125 percent. Such dose levels lead to increased

particulate silicon and frank kidney and bladder stones after 90 days.

Naturally occurring levels of silicon in drinking water ,(up to 10 mg/mL) have

not been shown to lead to detectable levels of urinary particulate silicon.

Type A Zeolite is not a teratogen and is not carcinogenic orally or via ,;

the inhalation route of exposure. The negative mutagenic activity noted in

other silicates make it highly unlikely that Type A Zeolite poses a mutagenic

hazard.

-.

As with other builders, based on present knowledge and using current

state-of-the-art techniques of toxicological assessment, it is concluded that

the use of Type A Zeolite in detergents will not pose a health hazard to

humans.

. . .

Summary . .. . .

. . .

Aluminosilicates are widely utilized in the food --industry and -in treating

drinking water, not posing a human health hazard under current conditions of

use. Cubic Type A Zeolite, with a Na:Si:Al ratio of 1:l:l is thermodynami-

cally less stable than food grade aluminosi 1 icate, with its corresponding

ratio of 1:1:13 rapidly forming insoluble aluminates and soluble silicates in

aqueous suspensions at a pH <8, hence rarely being found in the environment. . . . . .

. .. . , . .

Type A Zeolite . . is essentially non-.toxic .in acute and chronic toxicity , . . . - . .

tests on animals, the behaviour being representative of the silicates formed

on hydrolysis. No carcinogenic or teratogenic effects were noted after

exposure o f experimental animals t o h igh l e v e l s o f Type A Z e o l i t e and i t i s

u n l i k e l y t o produce mutagenic e f fec ts .

Considering t h e normal exposure o f man t o na tu ra l s i l i c o n compounds

w i thout ev ident h e a l t h hazards and t h e m in i scu le increase i n s i l i c o n l e v e l s i n

d r i n k i n g water r e s u l t i n g from t h e proposed use o f Type A Z e o l i t e i n

detergents, t he Task Force concludes t h a t use o f t h i s z e o l i t e i n detergents i s

no t a n t i c i p a t e d t o l ead t o adverse human h e a l t h e f f e c t s .

References

1. FASEB. (Federat ion of American Soc ie t i es f o r Experimental B io logy) 1977.

Tenta t ive Eva lua t ion o f t h e Heal th Aspects o f Ce r ta in S i l i c a t e s as Food

Ingredients, Report Prepared f o r Food and Drug Admin is t ra t ion , Contract

#FDA 223-75-2004, Bethesda, MD., 18-19.

2. The Procter and Gamble Company. Report t o Science Advisory Board Task . Force on t h e Human Heal th E f f e c t s o f Non-NTA Detergent Bu i l de rs - Human

Safety o f Type A Zeo l i t e . December 1.4, 1978.

3. The Procter and Gamble Company. Report t o Science Advisory Board Task

Force on the Heal th E f f e c t s o f Non-NTA Detergent Bu i l de rs - Human Safe ty

o f Type A Zeo l i t e . October 15, 1979.

4. The Procter and Gamble Company. Report t o t h e Science Advisory Board Task

Force on t h e Human Heal th E f f e c t s of Non-NTA Detergent Bu i l de rs - I n h a l a t i o n Studies on Type A Z e o l i t e i n Cynomolgus Monkeys. October 15,

1979.

5. Gosselin, R.E., Hodge, H.C., Smith, R.P., and Gleason, M.N. C l i n i c a l

Toxicology o f Commercial Products, 4 t h ed., (1976), Wi l l iams and Wi l k ins

Co., Balt imore.

APPENDIX A

TERMS OF REFERENCE

f o r t h e

TASK FORCE

on t h e

HEALTH EFFECTS OF NON-NTA DETERGENT BUILDERS

The Science Adv isory Board, f o r m e r l y t h e Research Adv isory Board, has p r e v i o u s l y i n v e s t i g a t e d and made recommendations rega rd ing t h e env i ronmenta l and human h e a l t h impact o f t h e use o f NTA as a de te rgen t b u i l d e r . A task f o r c e i s now working on t h e environmental impact o f t h e non-NTA de te rgen t b u i l d e r s . The Task Force on t h e Hea l t h E f f e c t s o f Non-NTA Detergent B u i l d e r s should rev iew t h e approaches used by t h e Task Force on Hea l t h E f f e c t s o f NTA and t h e Task Forces on t h e Environmental E f f e c t s o f NTA and Non-NTA Detergent Bu i l de rs , r e s p e c t i v e l y , i n o rde r t o ma in ta i n some cons is tency i n approach.

The Task Force on t h e Hea l t h E f f e c t s o f Non-NTA Detergent B u i l d e r s i s charged t o :

A. ( 1 ) determine t he chemicals which a re c u r r e n t l y i n use as de te rgen t b u i 1 ders;

( 2 ) determine those chemicals which a re l i k e l y t o be used i n t h e near f u t u r e ; and

( 3 ) appra ise what i s known and what i s unknown about t h e h e a l t h e f f e c t s o f t h e substances l i s t e d i n 1 and 2.

B. The task, f o r c e w i l l adv ise t h e Science Adv isory Board rega rd ing t h e i r o v e r a l l app ra i sa l o f t h e impact on human h e a l t h o f t h e non-NTA de te rgen t b u i l d e r s and any s p e c i f i c areas which r e q u i r e a d d i t i o n a l research.

C. These tasks a re t o be corr~pleted by January 1, 1979, w i t h an i n t e r i m r e p o r t on May 1, 1978.

MEMBERSHIP, TASK FORCE ON THE HEALTH EFFECTS OF NON-NTA DETERGENT BUILDERS

Dr. James H. Day Head, D i v i s i o n o f A l l e r g y Department o f Med ic ine Queen 's U n i v e r s i t y K ings ton , O n t a r i o K7L 2N6

Dr. G. C. Beck ing Ch ie f , Env i ronmenta l T o x i c o l o g y D i v i s i o n Dept. o f N a t i o n a l H e a l t h and Welfare Env i ronmenta l H e a l t h Centre, Room 118 Ottawa, O n t a r i o KIA OL2

Dr. L a r r y F i s h b e i n A s s i s t a n t t o D i r e c t o r f o r

Env i ronmenta l S u r v e i 1 1 ance N a t i o n a l Center , f o r T o x i c o l o g i c a l

Research J e f f e r s o n , Arkansas 72079

P r o f e s s o r R. O ' B r i e n O f f i c e o f t h e P r o v o s t U n i v e r s i t y o f Rochester Rochester , New York 14627

Dr. A r t h u r S. Kraus (~ffective Dec. 1978) Pro fessor Dept. o f Community H e a l t h - Epidemio logy Queen 's U n i v e r s i t y 25 Union S t r e e t K ings ton , O n t a r i o K7L 2N6

Represen t ing Soap and De te rgen t A s s o c i a t i o n o f Canada M r . F. A l a n Brownr idge Manager P r o f e s s i o n a l and R e g u l a t o r y S e r v i c e s P r o c t e r & Gamble I n c . Hami l ton, O n t a r i o L8N 3L5

Represen t ing Soap and D e t e r g e n t ~ s s o c i a t ion; ~ e w York Dr. W a l t e r L. Sch leve r Government & industry R e l a t i o n s Manager PQ Corp., P.O. Box 258 Research and Devel opment Center L a f a y e t t e H i l l , Penn. 19444

A d j u n c t Members Dr. R. T a r d i f f Board on T o x i c o l o g y and

Env i ronmenta l H e a l t h N a t i o n a l Academy o f Sciences 2101 C o n s t i t u t i o n Avenue Washington, D.C. 20418

Dr. S. I. Shibko Ch ie f , Contaminants and N a t u r a l

T o x i c a n t s E v a l u a t i o n Branch D i v i s i o n o f Tox ico logy , HFF-195 Food and Drug A d m i n i s t r a t i o n Dept. o f H e a l t h and Human S e r v i c e s Washington, D.C. 20204

Dr. Raymond E. Shap i ro Asst . D i r e c t o r f o r T o x i c o l o g y

C o o r d i n a t i o n , NIEHS P.O. Box 12233 Research T r i a n g l e Park, N.C. 27709

FORMER MEMBERS

Dr. Dav id G a y l o r (until Dec., 1978) S t a t i s t i c i a n N a t i o n a l Center f o r T o x i c o l o g i c a l Research J e f f e r s o n , Arkansas 72079

Dr. R.A. Goyer (until Feb., 1979) Former l y : Chairman and P r o f e s s o r Department o f Pa tho logy U n i v e r s i t y o f Western O n t a r i o London, O n t a r i o N6A 5C2

Dr. G. J. Stopps (until Sept., '1978) Department of Preventive Medicine

and Pesticides University of Toronto Toronto, Ontario M5S 1Al

Secretariat Responsibilities Dr. A. E. P. Watson. Research Scientist Great Lakes Regional Office International Joint Commission 100 Ouellette Avenue, 8th Floor Windsor, Ontario N9A 6T3

APPENDIX C

TERMS OF REFERENCE FOR THE SCIENCE ADVISORY BOARD

1. As used herein, "research" includes development, demonstration and research activities, but does not include regular monitoring and surveillance of water quality.. .

2. The functions and responsibilities of the Science Advisory Board relating to research activities in Canada and the United States concerning the quality of the waters of the Great Lakes System shall be as follows:

(a) to review at regular intervals these research activities in order to:

(i ) examine the adequacy and re1 iabi 1 ity of research results, their dissemination, and the effectiveness of their application;

(ii) identify deficiencies in their scope, and inadequacies in their funding and in completing schedules;

(ii i) identify additional research projects that should be undertaken;

(iv) identify specific research programs for which international cooperation will be productive;

(b) to provide advice and consolidations of scientific opinion to the Commission and its boards on particular problems referred to the Advisory Board by the Commission or its boards;

(c) to faci 1 i tate both formal and informal international cooperation and coordination of-research; and

(d) to make recommendations to the Commission.

3. The Science Advisory Board on its own authority may seek analyses, assessments and recommendations from other professional, academic, governmental or intergovernmental groups about the problems of Great Lakes water quality research and related research activities.

4. The IJC shall determine the size and composition of the Science Advisory Board. The Commission should appoint members to the Advisory Board from appropriate Federal, State and Provincial Government agencies and from other agencies, organizations and institutions involved in Great Lakes research activities. In making these appointments the Commission should consider individuals from the academic, scientific and industrial communities and the general pub1 ic. Membership should be based primari ly upon an individual's qualifications and potential contribution to the work of the Advisory Board.

5. The Science Advisory Board should work at all times in close cooperation with the Great Lakes Water Quality Board.

75

MEMBERSHIP, SCIENCE ADVISORY BOARD

. .

U n i t e d S t a t e s S e c t i o n

Dr. Donald I. Mount (Chairman) Env i ronmenta l Research L a b o r a t o r y - D u l u t h 6201 Congdon B lvd. Du lu th , Minnesota 55804

Dr. Joseph Kutkuhn, D i r e c t o r U.S. Department o f t h e I n t e r i o r F i s h and W i l d l i f e S e r v i c e Grea t Lakes F i s h e r y L a b o r a t o r y 1451 Green Road Ann Arbor, M i c h i g a n 48105

Dr. Rober t A. R a g o t z k i e Sea Gran t I n s t i t u t e P rogr -m U n i v e r s i t y o f Wisconsin-Madison 1800 U n i v e r s i t y Avenue Madisnn, Wiscons in 53706

M r . D o l l o f f F. B ishop Ch ie f , Technology Dev. Suppor t Branch Wastewater L a b o r a t o r y U.S. EPA 26 West St . C l a i r S t r e e t C i n c i n n a t i , Oh io 45268

Dr. John R. S h e a f f e r P r e s i d e n t S h e a f f e r and Roland, I n c . 130 N o r t h F r a n k l i n Chicago, I l l i n o i s 60606

Dr. Anne Spac ie Department of F o r e s t r y and N a t u r a l

Resources Purdue U n i v e r s i t y West La faye t te , I n d i a n a 47907

Dr. M i t c h e l l R. Zavon Medica l D i r e c t o r Hooker Chemicals 222 Rainbow B lvd . N o r t h P.O. Box 728 . .

N i a g a r a F a l l s , New York 14302

Dr. Lawrence W. L i b b y A s s o c i a t e P r o f e s s o r Department o f A g r i c u l t u r a l Economics M ich igan S t a t e U n i v e r s i t y A g r i c u l t u r e Ha l 1 Eas t Lansing, M ich igan 45824

Canadian Sect i o n

Dr. G. K. Rodgers (Chairman) D i r e c t o r N a t i o n a l Water Research I n s t i t u t e Canada Cen t re f o r I n l a n d Waters P.O. Box 5050 B u r l i n g t o n , O n t a r i o L7R 4A6

M r . Paul D. F o l e y C o o r d i n a t o r , Development & Research Group P o l l u t i o n C o n t r o l Branch O n t a r i o M i n i s t r y o f t h e Env i ronment 135 S t . C l a i r Avenue West Toronto , O n t a r i o M4V 1P5

P r o f e s s o r J. Llamas D i r e c t o r , Water Resources Cen te r F a c u l t y o f Sc ience and Engi n e e r i o g P a v i l l o n P o u l i o t U n i v e r s i t y o f Lava1 Centreau, Room 3717 Ste. Foy, Quebec G1K 7P4

D r . J. R. Va l l en t yne Senior S c i e n t i s t F i s h e r i e s and Mar ine Serv ice O n t a r i o Region Canada Centre f o r I n l a n d Waters P.O. Box 5050 Bu r l i ng ton , O n t a r i o L7R 4A6

D r . James H. Day Head, D i v i s i o n o f A l l e r g y Department o f Medic ine Queen's U n i v e r s i t y K ingston, O n t a r i o K7L 2V7

Dr. J.H. Leach Research S c i e n t i s t Lake E r i e F i s h e r i e s Research S t a t i o n F i s h & W i l d l i f e Research Branch M i n i s t r y o f Na tu ra l Resources R. R. 2 Wheatley, O n t a r i o NOP 2P0

Great Lakes ' ~ i shery Commission M r . Car los M. F e t t e r o l f , J r . Execu t i ve Sec re ta r y Great Lakes F i s h e r y Commission 1451 Green Road Ann Arbor, M ich igan 48105

I n t e r n a t i o n a l A s s o c i a t i o n f o r Great Lakes Research (IAGLR) Dr. R. A. Sweeney Great Lakes Labo ra to r y B i o l o g y Professor S t a t e U n i v e r s i t y Co l lege 1300 Elmwood Avenue Bu f f a l o , New York 14222

S e c r e t a r i a t R e s p o n s i b i l i t i e s Dr. W.R. Drynan Seni o r ~ n g i neer Grea t Lakes Regional O f f i c e I n t e r n a t i o n a l J o i n t Commission 100 Ouel l e t t e Avenue, 8 t h F l oo r , Windsor, O n t a r i o N9A 6T3

International Joint Commission Great Lakes Regional Off ice

100 Ouel lette Avenue Eighth Floor

indsor, Ontario N9A 6T3

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