SCIENTIFIC BASIS FOR INTER-INDUSTRY PROPOSAL

The fundamental position of the scientific advisors to the
Inter-Industry Committee on Indirect Food Additives is that government
cannot protect the public from every conceivable hazard to health.

Because

of limitation of scientific manpower and the priority of other national
programs potential health hazards must be assigned relative probability
factors and available resources applied to those with highest potential
return in health protection.

The eleven years since enactment of the Food

Additives Amendment and the millions of dollars spent on toxicology of
food packaging materials have established that potential health hazard
from food packaging materials is extemely remote and that a significantly
reduced effort in this area would be in the best interest of public health.
Without exception, all non-government scientists who presented
their views at the National Conference on Indirect Food Additives
(February 13-14, 1968) felt that the current system of regulation of indirect
additives was diverting scientific effort from more important health problems.
A specific proposal to help alleviate this problem was outlined by one of
those scientists, Dr, John P. Frawley, of Hercules Incorporated.

The over­

whelming majority of other scientists speaking at the National Conference
endorsed Dr. Frawley's proposal.

In brief, the derivation of Dr. Frawley's

proposal can be summarized as follows:

a)

An examination of all available chronic toxicity
studies (24S compounds) revealed that except for
heavy metals and compounds developed because of their
toxicity -* as pesticides, all.compounds were safe to

TV1 TUJV'

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£SI 0000061S

Page 2
experimental animals when fed for a lifetime at
40 ppm in the total diet.

Applying unusually

conservative margins of safety, it was concluded
that a dietary level of 0.1 ppm of any chemical
suitable for use in food packaging can be
considered toxicologically insignificant for man.*
b)

Any food packaging component which can be shown by
suitable migration studies to contribute no more
than 0.1 ppm to the diet of man should be considered
non-migratory and exempt from regulatory control.

c)

Based on extensive migration studies using uncoated
paper and actual food packaging conditions, it was
demonstrated that if all food were packaged in the
uncoated paper, use of an additive at a level of
0.05% by weight of the container or its coating
could not contribute more than 0.1 ppm to the diet.

d)

Uncoated paper is the most permeable type of food
packaging material and consequently its components
are most susceptible to migration.

Therefore,

components of other types of containers will migrate
less than those used in paper.
e)

No more than 25% of the human diet is in contact with
any specific food packaging additive.

f)

Therefore, any food packaging component (except heavy
metals and pesticides) used at a level of 0.2% or less
by weight of the container or its food dontact surface

*Because the rat consumes from two to four times the amount of food per kilogram
of body weight as man, this represents approximately a 1000-fold margin of safety.

ASI 00000619 \

can contribute no more than 0.1 ppm to the human
diet and should be exempt from regulatory
control.

All of the major industry representatives endorsed the above proposal
at the time of the National Conference.

The Inter-Industry Committee still

endorses these proposals as being scientifically sound and safe for public
health.
Since the time of the National Conference, additional evidence has
been accumulated which supports the steps in the derivation of the proposal.
These are presented below:

a)

The initial compilation of two-year chronic studies
published by Dr. Frawley (Food ^ Cosmetic Toxicol.
Vol. 5_, 293, 1967) contained 220 compounds.

Since

then it has been extended to 252 compounds.

Table 1

presents the 32 compounds and the "no effect" levels
which have been added since Dr. Frawley's publication.
All additions support Dr. Frawley's conclusion that
any compound suitable for use in food packaging can
be considered toxicologically insignificant at a level
of 0.1 ppm in the diet.
b)

After the National Conference, the National Academy of
Sciences, Food Protection Committee appointed an Ad Hoc
Committee on Toxicological Insignificance.

This

Committee of scientists recommended a number of quantitative
guidelines on insignificance, one of which was that "if a

ASI 00000620

Page 4
chemical has been in commercial production for a
substantial period, e.g. 5 years or more, without
evidence of toxicological hazard incident to its
production or use, if it is not a heavy metal or
a compound of heavy metal, and if it is not
intended for use because of its biological
activity, it is consistent with sound toxicological
judgment to conclude that a level of 0.1 ppm of the
chemical in the diet of man is toxicologically
insignificant".

This level is the same level

proposed by Dr. Frawleyas the appropriate level of
toxicological insignificance for food packaging
components.
c)

Dr. Frawley's original extrapolation from maximum
quantity migrating to food to maximum concentration
in the container was based on rosin size migration
to food from uncoated paper.

Since that time,

comparable data have been obtained for a plasticizer
migrating from polyvinyl chloride film..

These data

are summarized in Table 2, and confirm the conclusion
that the uncoated paper used in Dr. Frawley's
calculation represents the extreme condition.
d)

In Dr. Frawley's extrapolation to the container,
he made the "assumption" that no more than 25% of
the diet would be in contact with any specific
food packaging component,

* '*■

In an effort to obtain

ASI 00000621

Page S
a more quantitative measure of the maximum dietary
percentage which might be in contact with a specific
substrate type, a survey of food packaging
practices was conducted in four supermarkets.

The

106 food items which compose the basis of the
U. S. Department of Agriculture survey of food
consumption were tabulated with the type or types
of food contact surface.

These data are presented

in Table 3.
The total for each category of container is
presented.

The grand total exceeds 100% because

foods which are commonly packaged in two or more
types of containers are listed under all
appropriate types.

The absolute maximum of the

average diet which may be in contact with a
specific substrate is 45% for all types of plastics
and plastic coatings.

Other categories were 34% for

glass, 32% for paper, 23% for can, 10% for cellophane
and 6% for metal foil.

About 23% of the diet is bulk

packaged or not in sufficient contact to be considered
packaged.
With the unlikelihood that any individual would
consistently choose one type of container over
another for food offered in several types of containers,
and with the improbability of any minor component of

Page 6
food packages being universally used in all of
a container type, Dr. Frawley's estimate of 25%
is reasonable and conservative.*
e)

The proposal to exempt from regulation components
present in containers at 0.2% or less by weight of
the container or its coating has been formally
endorsed by at least 23 other scientists who
addressed letters to the Hearing Clerk expressing
their personal professional conclusions.

Table 4

lists the names of the experts who have officially
stated that this level of use of additions is
generally recognized as safe.

It is apparent that the Food and Drug Administration is reluctant
to establish a level of insignificance in the total diet, or in the food
container.
Because of difficulty of enforcing a level in the total diet, the
Committee agrees with the Food and Drug Administration proposal to establish
a level of toxicological insignificance in the packaged food.

However,

starting with a level of 0.1 ppm in the diet which has been recommended by
the National Acadmey of Sciences as insignificant, and using the conservative
dietary exposure of 25%, an extrapolation to 0.4 ppm in specific foods is
apparent as a level of exemption rather than 0.05 ppm as proposed by the Food

*In other areas of safety evaluation, it is customary to make reasonable
assumptions concerning human exposure. Uses of most pesticide tolerances
would exceed the ADI if the tolerance level was assumed to be present on
100% of the agricultural commodity. Many direct food additives would exceed
th ADI if used at the maximum level in all permitted foods.
In the case of
food packaging, it is even less likely that a single chemical will be used by
all manufacturers of even one type of substrate, much less all types.

,

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ASI 00000623

Page 7
and Drug Administration,

For practical reasons, a level of 0.5 ppm is

proposed by the Inter-Industry Committee, in light of the fact that the
original calculations by Frawley employed a 1000-fold margin of safety.
This additional 10-fold margin of safety beyond the conventional 100-fold
safety factor also allows for any possible exposure to a chemical from other
environmental sources than food.
It is also the firm recommendation of the Inter-Industry Committee
that a level of exemption be established in the food container and its food
contact surface.

Scientifically, this is the most readily enforced point of

addition of a chemical and practically the most useful for industry and
government.

With the restrictions placed on such an exemption as contained

in the preamble of the Food and Drug Administration proposal, the level of
0,2%, as proposed by Dr. Frawley and supported by the scientific community
is eminently justified and supported.

August 27, 1969

ASI 00000624

TABU: 1
ADDITIONAL NO-EFFECT LEVELS ESTABLISHED BY TWO-YEAR FEEDING STUDIES*

Compound

No-Effe
Level
(^ppm

Acetone peroxides treated flour*
Alkyl (Cg-C^c) tolyl methyl trimethyl ammonium chloride (Hyamine 2389)2
200
1,200
Alkyldimethylbenzyl ammonium chloride (Roccal)5
Alkyldimethylbenzyl ammonium chloride (unspecified)^
< 630
1,000
Arsanilic acid5
1,000
2H-l-Benzopyron-2-one (Coumarin)6
10,000
Butoxy polyethylene polypropylene glycol (UCON 50 HB260)7
4-tert-Butyl-2-chlorophenyl methyl methylphosphoramidate (Ruelene)8
1*
1.000
Butyl stearate®
Chlorine (free in ^0)*^
100
Dibutyl sebacate9
..
62,500
2,6-Dichlorobenzonitrile (Dichlobenil)1
100*
(3-[3,4-Dichlorophenyl]-1-methoxy-l-methylurea) (Linuron)12
125*
3,000b
Diethyl carbonaia*3
Di-isobutyl phenoxy ethoxy ethyl dimethyl benzyl ammonium chloride
(Hyamine 1622)2
200
20,000
3- Ethoxy-4-hydroxybenzaldehyde (Ethyl vanillin)0
20,000
4- Hydroxy-3-methoxybenzaldehyde (Vanillin)
Isosafrole5
< 1,000
3,500
6-Methyl-2H-l-benzopyran-2-one (6-Methylcoumarin)6
< 100T
1.2- Methylenedioxy-4-allylbenzene (Safrole)®
^
1.2- Methylenedioxy-4-propylbenzene (Dihydrosafrole)0
< 1,000
Methyl ethyl cellulose*^
10,000
Monochloroacetaldehyde 2,4-dinitrophenylhydrazone (Olin 1763)15
100*
Nonyl phenoxy polyethylene (9) glycol ether (Tergitol nonionic TP-9)7
2,700
Phenyldimethylurea*®
1,250*
Polyalkylene glycol ether (Tergitol nonionic XD)7
2,700
Polyethylene glycol homolog, containing 90,000 ethoxyl groups
terminated by hydroxyls (Polyox WSR301)7
50.000
Polyethylene polypropylene glycol (UN0C 75 H1400)7
10.000
Polyethylene polypropylene glycol (UN0C 25 H200 5)7
2.000
Sodium arsenate*'
255 (62.5 ppm
As)
Sodium arsenite*7
54 (31.25
ppm As)
Sodium 2-ethyl hexyl sulfate (Tergitol anionic 08)7
6,400

aDiet contained 77% flour treated with 0.045% acetone peroxides comprised of 85 to 95%
2,2 dihydroperoxy propane and 5 to 15% bis-(l,l-hydroperoxy-l,l’-methyl) diethyl
peroxide
*Pesticide
b3000 ppm concentration in drinking water
T-Tumors at higher levels
*Supplemental List to that published in Food 8 Cosmetic Toxicol. Vol. 5, 293-308 (1967)

ASI 00000625

TABLE 1 (CONTINUED)
REFERENCES

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.

Food § Cosmetic Toxicol. Vol. 5, 309 (1967)
Soap 8 Chem. Specialties Vol. 30, 147 (1954)
J. Am. Pharm. Assn., Scientific Edition, Vol. 40, 263 (1951)
J. Am. Pharm. Assn., Scientific Edition, Vol. 37, 29 (1948)
Proc. 12th World's Poultry Congr., Sidney, Australia, 234 (1962)
Food 6 Cosmetic Toxicol. Vol. 5, 141 (1967)
Mellon Institute, Pittsburgh, Pa., Unpublished Data
Food 6 Cosmetic Toxicol. Vol. 6, 185 (1968)
AMA Arch. Ind. Hyg. 5 Occup. Med. Vol. 7, 310 (1953)
Food 6 Cosmetic Toxicol. Vol. 6, 147 (1968)
Food 8 Cosmetic Toxicol. Vol. 6, 261 (1968)
Food 8 Cosmetic Toxicol. Vol. 6# 171 (1968)
Arch. Tox. Vol. 22, 98 (1966)
Food 8 Cosmetic Toxicol. Vol. 6, 449 (1968)
Toxicol. 8 Appl. Pharmacol. Vol. 8, 472 (1966)
Allied Chemical Corporation, Unpublished Data
Toxicol. 8 Appl. Pharmacol. Vol. 10, 132 (1967)

ASI 00000626

TABLE 2
MAXIMUM MIGRATION OF ROSIN SIZE1 AND 2-ETHYLHEXYL
DIPHENYL PHOSPHATE2 3TO
4 TOTAL DIET _____

Commodity Group

z

Approx.
1 of
Diet

Average Mijjration
(ppm)
Rosin Size^ Santicizer 1415

Contribution to Total Diet
IP£m-i
Santi (ter 141
Rosin Size

*
Aqueous 8 Wet
Foods

43

3.1

Fats, Oils

3

32.8

Dry Foods

39

2.1

M at, Poultry
8 Fish

15

36.2

2.2
120

1.
2.
3.
4.
5.

2.1 ppm/%

Santicizer 141

0.5 ppm/%

0.9

1.0

3.6

0.8

60
TOTAL

Rosin Size

1.3

5.4

9.0

8.5

13.5

Rosin Size - 4% in paper
2-Ethylhexyl Diphenyl Phosphate - Santicizer 141 - 28% in PVC Film
Commodity Groups Taken From Table 3 and Consolidated
Food 8 Cosmetic Toxicol. Vol. 5, 293 (1967) and TAPPI Vol. 48, 433 (196S)
AMA Arch, Ind. Hyg. 8 Occup. Med, Vol. 8, 281 (1953)

b 'nv

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ASI 00000627 ;

&

3

ASI 00000628

TABLE

AVERAGE QUANTITY OF FOOD USED IN AMERICAN HOMES1 AND TYPE OF PACKAGING SURFACE CONTACTING FOOD2

FOOD CONTACT SURFACE3
Food Group and Major Items

Quantity
Percent
None
Glass
Can
Plastic
per Week
of Diet
or Plastic
(lbs)Coating

Milk, Cream, Cheese, etc.
Fresh fluid milk
Evaporated milk
Non-fat dry milk
Cream
Frozen milk dessert
Cottage cheese
Other cheese

19.13
0.62
0.13
0.32
1.68
0.48
0.68

18.8
0.6
0.1
0.3
1.6
0.5
0.7

'ats, Oils
Butter
Margarine
Lard
Vegetable shortening
Salad, cooking oil
Salad dressing

0.42
0.80
0.26
, 0.34
' 0.36
0.53

0.4
0.8
0.3
0.3
0.4
0.5

'lour. Cereal
Flour
Prepared flour mix
Breakfast cereal
Rice
Commeal, grits
Macaroni, other pastas
Other cereal, pastas

>
1.56
0.48
1.06
0.44
0.61
0.42
0.11

1.6
0.5
1.0
0.4
0.6
0.4
0.1

lakery Products
Bread
Crackers
Rolls
Cake
Pie

4.36
0.51
0.34
0.47
0.33

4.3
0.5
0.3
0.5
0.3

Paper

Foil

Cellophane

X

X

X

X
X
X
X

X
X
X

X

X

X
X

X
X
X

X
X
X

X
X
X

X
X

X
X

X
X
X
X
X
X
X

X
X
X
X

X
v

A

X
X
X
X

X
X

00000629

FOOD CONTACT SURFACE3
Quantity
per week
civs)'

Percent
of Diet

Bakery Products (Cont'd)
Cookies
Coffee Cake
Doughnuts § other

0.89
0.31
0.44

0.9
0.3
0.4

X

Beef
Beef steaks
Beef roasts
Ground beef
Other beef

2.23
1.42
1.34
0.43

Food Group and Major Items

Paper

Foil

Cellophane

X

X

X

X
X
X

2.2
1.4
1.3
0.4

X
X
X
X

X
X
X
X

1.25
0.34
‘ 0.79
0.80
0.42

1.2
0.3
0.8
0.8
0.4

X
X

X
X

X
X

X
X

Variety Meats
Veal
Lamb
Liver, brains, tongue, etc.
Frankfurters
Other lunch meats

0.16
0.18
0.26
0.56
0.86

0.2
0.2
0.3
0.5
0.8

X
X
X
X
X

X
X
X
X
X

Poultry
Chicken
Other poultry

2.62
0.19

2.6
0.2

X
X

X
X

Fish
Fresh fish
Frozen fish
Canned fish
Shellfish

0.64
0.13
0.28
0.15

0.6
0.1
0.3
0.1

Pork
Pork chops, hams, loins
Sausage
Smoked hams
Bacon
Other pork

None

Glass

Can

X
X

Plastic
or Plastic
Coating

Y
X

X

AST

Page 2

FOOD CONTACT SURFACE5
Quantity
per Week
(lbs)

Percent
of Diet

None

Eggs
Fresh eggs

2.69

2.6

X

Sugar and Sweets
Sugar
Sirups, molasses, etc.
Jelly § jam
Candy

2.33
0.40
0.45
0.52

2.3
0.4
0.4
0.5

Potatoes
Fresh potatoes
Canned potatoes
Frozen potatoes
Chips, sticks
Other

4.82
0.10
0.17
0.22
0.06

4.7
0.1
0.2
0.2
0.1

X

Fresh Vegetables'*
Dark green leafy
Carrots, pumpkin, squash
Tomatoes
Cabbage
Lettuce
Com
Onions
Beans
Celery
Cucumbers
Other

•
0.35
0.56
1.09
0.65
1.30
0.51
0.82
0.46
0.33
0.30
0.96

0.3
0.5
1.1
0.6
1.3
0.5
0.8
0.5
0.3
0.3
0.9

X
X
X
X
X
X
X
X
X
X
X

Fresh Fruits^
Citrus
Cantaloupe
Apples
Bananas
Melons

2.51
0.37
1.38
1.45
1.28

2.5
0.4
1.4
1.4
1 3

X X X X X

Food Group and Major Items

Glass

Can

X
X

X

Plastic
Paper
Foil
Cellophane
or Plastic
Coating_____________________________________

X

XXX

X

X
X

X
X

X
X
X

X
X

w

AS! 00000630

Page 3

Page 4
FOOD CONTACT SURFACE3
Quantity
per Week
(lbs)

Percent
of Diet

0.24
0.51
0.45

0.2
0.5
0.5

Canned Vegetables § Fruits
Vegetables
Fruits

2.93
1.59

2.9
1.6

Frozen Vegetables § Fruits
V getables
Fruits

0.62
0.05

0.6
0.1

Food Group and Major Items

4

Glass

Can

Plastic
Paper
Foil
Cellophane
or Plastic
_________________________ Coating____________________________________

(Cont * d)

XXX

Fresh Fruits
Peacnes
Berries
Other

None

X
X

X
X

X

X
X

-

0.54
1.41
0.42
0.46

0.5
1.4
0.4
0.5

Dried Vegetables § Fruits
Vegetables
Fruit

0.37
0.10

0.4
0.1

Beverages
Coffee
Tea § cocoa
Cola
Fmit
Ginger ale, seltzer § diet
Fruit ade 5 punch
Beer $ ale
Whisky, gin, rum, brandy
Wine

0.74
0.19
3.06
0.91
1.12
1.02
1.94
0.18
0.12

0.7
0.2
3.0
0.9
1.1
1.0
1.9
0.2
0.1

X
X
XX

XX

X
X

X

.'J

>------a t- i

-.■ ---

1

Juices
Canned vegetables
Canned fruit
Frozen fruit
Fresh fruit

X
X
X
X
X
X
X
X
X

X
X
X
X
X
X
X

X
X

X

ASI 00000631

f

Page 5

Food Group and Major Items

Quantity
per week
(lbs)

Percent
of Diet

Soups § Other Mixtures
Soups, sauces, gravy
Puddings, popsicles, etc.
Baby foods

0.92
0.85
0.17

0.9
0.8
0.2

Nuts § Condiments
Shelled nuts
Unshelled nuts
P anut butter
Catsup § sauces
Pickles, olives, relish
Salt
Vinegar § other

0.09
0.03
0.30
0.38
0.49
0.29
0.23

0.1
0.1
0.3
0.4
0.5
0.3
0.2

None

Glass

Can

X
X

X
X
X

X

X

X
X
X

X
X

Plastic
or Plastic
Coating

Paper

Foil

Cellophane

X
X
X

X

X

X

X

6%

10%

X
X
X
X

x
.

TOTAL

101.77

23%

34%

23%

45%

32%

FOOTNOTES
Average Quantity of Food Used in American Homes derived from "Food Consumption of Households in the United State
Spring 1965" U. S. Department of Agriculture HFCS- 1965-1966 Report No. 1.

2.

Packaging Surfaces Contacting Food based on 1969 practices observed in survey of supermarkets:
Hearns, Penn Fruit.

3.

Many foodsare occasionally packaged in every type of food contact surface. For example, sugar flavored wt’~
cinnamon is sometimes packaged in glass. Because of the insignificance of these uses, only the more cor.,
container surfaces have been listed.4

4.

For fresh fruits and fresh vegetables, some items, as onions or lettuce are sometimes packaged in plast':
paper and all are carried home in paper bags. Because of the small surface or short durat5^ these have been listed under "None"—meaning not in contact with any pa igi:ig jurf.; :*•,

1

1.

Food Fair, Acme,

AS

I 00000632
i

TABLE 4
EXPERTS WHO ADDRESSED LETTERS TO THE HEARING CLERK
DECLARING COMPONENTS OF FOOD PACKAGING USED AT A LEVEL
OF 0.2% OR LESS AS GENERALLY RECOGNIZED AS SAFE

A. M, Ambrose, Ph.D,

Professor of Pharmacology
Medical College of Virginia

Frank R. Blood, Ph.D.

Director, Division of Toxicology §
Professor of Biochemistry
Vanderbilt University Hospital

Joseph C. Calandra, Ph.D., M. D.

President
Industrial Bio-Test Laboratories, Inc

Sal M. Cannavo

Senior Research Chemist
L. A, Dreyfus Company

Charles P. Carpenter, Ph.D.

Administrative Fellow
Mellon Institute

Steven Carson, Ph.D.

Vice-President
Food and Drug Research Laboratories, Inc.

William B. Deichmann, Ph.D.

Professor of Pharmacology
University of Miami

Daniel M. Dent

For the Scientific Staff
The Borden Company

David W. Fassett, M. D.

Director, Laboratory of Industrial Medicine
Eastman Kodak Company
f

Leon Golberg, D.Sc., Ph.D.

Research Professor of Pathology
Albany Medical School

Richard L. Hall, Ph.D.

Director of Research and Development
McCormick § Company, Inc.

William H. Hunt, Ph.D.

Toxicologist
Monsanto Company

Jo}in H. Kay, Ph.D.

Director
Lifestream Laboratories, Inc.

R. Emmet Kelly, M. D.

Medical Director
Monsanto Company

M. L. Keplinger, Ph.D.

Toxicologist
University of Miami

Donald D. McCollister

Manager, Plant Science and Animal Health
Registrations
The Dow Chemical Company

.
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ASI Q0000633

Page 2
Bernard L, Oser, Ph.

President
Food and Drug Research Laboratories,

ic.

James L. Ritchie

President
American Paper Institute

Henry F. Smyth, Jr., Ph.D,

Advisory Fellow
Mellon Institute

Andrew A. B. Swan, M,

Director, Industrial Hygiene Research Labs.
Imperial Chemical Industries Limited

Joseph F. Treon, Ph.I
‘

Manager, Toxicology Division
Atlas Chemical Industries

Carrol S. Weil

Senior Fellow
Mellon Institute

Geoffrey Woodard, Ph. D.

President
Woodard Research Corporation

■y;

ASI 00000634