*

fd Cosmel Toxicol. Vol. 5, pp. 293-308. Pcrgatnon Press 1967. Printed in Great Britain

*

«
.

BIBRA Annual Scientific Meeting*
Scientific Evidence and Common Sense as a Basis for
F ood-Packaging Regulations
J. P. Frawley
Hercules incorporated, Wilmington, Delaware 19899, USA

'

•

*■ a

I am honoured by your invitation to meet with you tonight and to discuss with you some
of the problems associated with assuring the safety of food-packaging materials. However,
I am equally humbled by my own inadequacies to discuss our subject matteras expertly as
it deserves.
Unfortunately for all of us, there is no individual who can be considered an expert on all
aspects of food packaging. Although essentially all of the individual components used in
food packaging originate in a chemical plant, the technology for formulating and converting
these materials into useful containers varies with every substrate, whether it is plastics,
paper or metal. Moreover, the marketing relationship between producer, formulator, con­
verter and the food industry is notably different for each segment of this complex industry.
Consequently, it is a formidable task to become an expert for even one aspect.
Each of you here this evening possesses expert knowledge in one or more aspects which
I wish I had. It is unfortunate that telepathic communication has not reached my level of
intellectual development, so I could benefit from your experience. In fact, the only thought
waves reaching me suggest that many of you should be delivering this lecture rather than I.
Therefore, if you will consider me to be a substitute speaker, you may be a little more tolerant
towards my remarks.
When was the last time you sat down in the solitude of your study and attempted to
write out a geometrical proof that the shortest distance between two points is a straight line?
Most of us would have a difficult time doing it today because, as you recall, it is not sus­
ceptible to proof. It must be accepted. Indeed, some of the most difficult things in life to
prove are the obvious ones.
A number of months ago, I sat down to try to prove something which was obvious to
me—that there are some uses of food-packaging materials which cannot involve any hazard
to health of the consumer of food. I had no preconceived idea of the end point I would
reach, but it seemed like it would be fun. Sometimes now I wish I had resisted the temptation
and invested my time in some other form of recreation.
My main exercise was to try to determine a level of use of any food-packaging component
which could be considered safe regardless of its degree of toxicity. Many of you know the
conclusion I reached; namely, that any component of a food container or coating which is
•Editor’s note: This paper was delivered to the Fifth Annual Scientific Meeting of the British Industrial
Biological Research Association (BIBRA), held in London on 2$ January 1967. The Annual Scientific
Meeting, instituted in 1962, provides an opportunity for members and guests of the Association to receive
an address from an eminent toxicologist on atopic related to BIBRA's field of interest. Previous speakers
have been Professor H. C. Hodge, Dr. A. J. Lehman, Professor L. J. Goldwater and Dr. J. M, Barnes.

293

m

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294

). T. IRAWU:Y

present at
or less is safe beyond any reasonable doulu, and consequently, should not
be subject to government regulations. When 1 first advanced this proposal, it was presented
within the framework of existing legislation in my country, as a mechanism For correcting
some of our mistakes. Tonight, 1 shall cast my remarks in a different vein, since your
country has not yet committed itself to a rcgulatoiy procedure on packaging materials.
I do not pretend to be able to propose the best regulatory procedure for Great Britain.
There are too many aspects of your business and government operations which I do not
understand. However, I can review some of the evolutionary history of our regulatory
procedure and suggest some ways to avoid the mistakes we have made.
According to the title of my lecture, l am scheduled to talk about scientific evidence and
common sense. For no particularly good reason, I am going to reverse this order and
address myseif to the common-sense aspects of food-packaging regulations first.
It has always seemed axiomatic to me that in ail mailers of environmental health, the
degree of hazard should define the degree of control. The amount of attention devoted to
each problem should be in relation to the hazard. To distribute our limited efforts on any
.other basis is a form of gambling with public hcalLh.
Unfortunately, in this decade of doubt, the scientific community lias little control over
the area of its explorations. For the most part, the decision is made by national governments
as to which area of environmental health should receive concerted attention and at least in
the United States, these decisions are not always made on die basis of relative hazard to
health. This certainly has been the case for food-packaging materials and it appears that
many countries arc prepared to follow in our footsteps.
In order to give a certain degree of perspective (which I believe is the foundation of com­
mon sense) in this matter, let us reflect on a few of the sources of environmental exposure
to chemicals. Obviously the overwhelming majority of the chemicals to which we are
exposed are the natural ones which constitute our diet. We tend to overlook these and seem
to be content in assuring society that synthetic chemicals will not cause more disease than
we already have. Reluctantly, I shall dismiss any further conuneuts on these natural products
except to note that it is refreshing to have Dr. L. Golberg and the BIBRA staff occasionally
remind us of our prejudice.
If we restrict ourselves to a consideration of synthetic chemicals contributed to our
environment, certain obvious sources come to mind: drugs, pesticides, food additives, air
pollutants, water pollutants, cosmetics, occupational exposures, household chemicals and
food-packaging. As 1 have already suggested, logically, the amount of time and attention
devoted to each of these areas should be in relation to the hazard to health. Sometimes the
hazard to health is difficult to evaluate until a significant amount of time and money has
been invested. However, after the degree of hazard has been defined, we have the responsi­
bility of accepting the facts and of adjusting our cfTort accordingly.
In recent years, in the United States, we have invested more industry, government and
university time and money on food-packaging materials than on any environmental health
problem other than pesticides and drugs. At the same time we have constructed a complex
and restrictive maze of government controls which is too involved to be understood by the
regulated industries. After 8 yr of effort we have now clearly demonstrated that the return
on our investment has been negligible and that the health hazard is slight in comparison
with other sources of chemical exposure. Consequently, I believe we have a responsibility
to the public of restoring a more equitable balance to our programme. By an equitable
balance, I do not mean that we should ignore all aspects of food packaging, but find some

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295

commotvianM approach to allow us to concern ourselves with potential hazards and not
with predictably safe practices.
It is to this assignment that I applied myself last summer—to try to develop a scientific
basis for a start, and only a start, towards a common-sense approach to food-packaging
regulation. However, before proceeding with the scientific evidence I have collected and the
conclusions I have drawn, I have made two statements which require documentation. First,
that the return on our investment has been negligible and second, that our regulatory
scheme has been too complex to serve its intended purpose.
Following enactment of our law, the major task facing the industry was evaluation of
current industry practices. Many of you are familiar with some of the larger research
programmes undertaken by different segments of the industry, for example, the petroleum
wax studies by the American Petroleum Institute, the can enamel studies by the can pro­
ducers and the rosin product studies by Hercules. Many other programmes which received
less publicity were conducted on regenerated cellulose, polyethylene and other polymers,
paper coatings and wet strength resins, to mention only a few. The net result of this invest­
ment of millions of pounds has been that more than 90% of the prior industry practices
have been confirmed as safe, through a combination of low toxicity and low migration, and
have been endorsed by our Food and Drug Administration (FDA), by inclusion on our
permissive list. This general endorsement of the vast majority of industry practices testifies
to the fact that most uses of packaging materials are inherently safe.
However, before sufficient facts were accumulated to confirm the low degree of hazard
associated with packaging materials, we had committed ourselves to an “omnibus” per­
missive list, containing every conceivable chemical which might even remotely come in
contact with food. We now have 94 separate food-packaging regulations or lists dealing
with different uses of packaging chemicals, from 967 ingredients* for adhesives to 8 ingre­
dients for zinc-silicon dioxide matrix coatings. These regulations contain over 43,000 words,
about 10,000 words more than the regulations for all intentional food additives. In 1966
alone, the 8th yr of the law’s existence, over 200 new uses of packaging chemicals were
approved and published in our Federal Register. Even a superficial examination of these
regulations reveals that the vast majority of these words are devoted to the enumeration of
thousands of chemicals for one or more specific uses under which most cannot migrate to
food at an unsafe level, regardless of their degree of toxicity. Unless you work with these
regulations on a daily basis, are familiar with the multiple cross-references and have
sufficient technical training to understand what chemicals are covered by some of the vague
generic terms, it is almost impossible to determine the approved uses of a given chemical.
We have created a complex maze of regulations, too lengthy and involved to be understood
by most of the regulated industry, with the unanticipated result of a growing apathy towards
correct interpretation.
This type of “omnibus” permissive list came about in the United States at the insistence
of some segments of industry, coupled with a change in interpretation of our laws by the
FDA—a change which revoked the long-established principle of de minimis non curat lex
(the law does not concern itself with trifles) by claiming that the law does not recognize any
level of a chemical as insignificant. This denial of the existence of a toxicologically-insignificant level or biological zero is analagous to a denial of the existence of night, on the
grounds that you cannot prove the absence of light. In all countries outside the United
*967 does oot couot the numerous reaction products cleared for one or more of these chemicals. If these
are counted, the number exceeds 3800.

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J. P, FRAWLEY

States, the term toxicological insignificance has real meaning and significance. I believe it
is a sound scientific-principle which must be preserved and eventually I hope will be restored
in my country. It is this principle which I believe is the very crux of intelligent commonsense regulation of food-packaging materials.
Let us take stock. Experience has taught us that most uses of food-packagiag materials
are safe beyond any reasonable doubt. Experience has also taught, at least in the United
States, that an “omnibus” permissive list not only diverts the energies of our corporations,
government and universities into predictably unprofitable research, but can lead to some,
if not general disregard for the law. This leaves us with the conclusion that some mechanism
should be found for subjecting to a permissive list only those uses of packaging materials
which pose a potential hazard to health; that is, constructing a "non de minimis list’’ or
“relevant” list.
Here is where I invite each and everyone of you to sit down and define those uses which
can be assumed to be safe. As I stated earlier this exercise sounds like fun, but it is just
plain hard work. I am not certain that my solution is the best, but I assure you it is the
result of many hours of reflection and analysis. In its briefest form, I believe that any
chemical suitable for use in food-packaging is safe for man at a level of 0-1 ppm in the total
diet. Extrapolating this dietary concentration to a practical and meaningful guideline for
regulatory purposes, use of a chemical in a container at a level of 0-2 % or less will contribute
less than 0-1 ppm to man’s diet.
On the surface, this may not appeafeto propose a major improvement, but application
of this guideline would permit deletion of 75% of the citations in the United States regula­
tions and I am certain would permit more efficient use of manpower, in establishing
permissive lists in other countries.
I do not ask that you accept this conclusion on faith. So, as briefly as possible, I should
like to review the scientific basis for this conclusion.
First of all, what level of a compound, which is suitable for use in food packaging, but
of unknown toxicity, can be assumed to be safe in the human diet? I know of no better
approach to answering this question than to examine our toxicological experience and
tabulate the experimentally determined safe level for all the compounds which have been
studied. Because 90-day toxicity studies are-generally considered inadequate for calculation
of safe levels and because only a small number of these are published, I decided to review
as many 2-yr chronic toxicity studies as I could find and to tabulate tKe "“no-effect” level
confirmed for each.
I can make no claim that I have found every 2-yr chronic toxicity study which has
been conducted. I can only claim that I have tabulated the "no-elTect” levels from every
chronic study which I could find, without any selection or rejection except irradiated foods.
In total, I was able to locate 2-yr chronic toxicity studies on 220 different substances
(see Appendix), and although this may seem like a modest number, it represents between
4 and 7 million pounds in toxicological research. Last September I had been able to locate
only 143 such studies, but with the co-operation of many of my colleagues in the field of
toxicology, I estimate that I now have collected about 90 % of all such studies which have
been conducted.
Table 1 presents the distribution of “no-effect” levels for all of the 220 compounds.
It is apparent from Table 1 that a small percentage of compounds will be extremely
toxic—having a "no-effect” level in experimental animals below 1 ppm, but that the majority
will exhibit no toxic effect even at 100 ppm. Only 19 of the 220 compounds demonstrated

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297

Table 1. Distribution of "no-effect"
levels in 2-yr chronic studies
“No-effect"
level
(ppm)

All
compounds
(220)

<1
<10
<100
<1000
<10,000

5
19
40
101
151

|
I

any toxic effect below 10 ppm. We might conclude that the odds of detecting a toxic effect
at 10 ppm from any “unknown” compound are approximately 1 in 10.
Let us now look at Table 1 a little more closely and examine the nature of these 19
compounds which had a “no-effect” level at 10 ppm or less. Table 2 shows the same in­
formation as Table 1, except two additional columns have been added which subdivide
these 220 compounds into two categories: (l) a “heavy metals and pesticides” category and
(2) an "all other compounds” category. I believe this breakdown is worthy of careful
examination. The most apparent conclusion is that ail 19 of the compounds, which were
toxic below 10 ppm, were pesticides and heavy metal compounds. Equally significant is the
fact that 39 of the 40 compounds, which had “no-effect” levels below 100 ppm in expert-

!
I

mental animals, were also pesticides or heavy metal compounds. The only compound in the
“all other compounds" category which was toxic below 100 ppm was acrylamide.

Table 2. Distribution of "no-effect" levels in 2-yr chronic
studies

“No-effect”
level _
(ppm)

All
compounds
•
(220)- ____

Heavy
metals and
pesticides
(88)

Others
(132)

<1
<10
<100
<1000
<10,000

5
19
40
101
151

5
19
39
72
86

0
0
1
29
65

It is obvious that the degree of toxicity of pesticides and heavy metals (which were used
as pesticides at one time) is quite different from that of other commercial chemicals. This
should represent no surprise because pesticides are synthesized, screened and selected for
their toxicity to one or more forms of life before becoming commercial products. This
contrast is more clearly shown by Fig. 1 which depicts the distribution of “no-effect” lewis
for the two categories of chemicals. It is obvious that the average toxicity of a pesticide is
about 100 times as great as the average for other chemicals.

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J. P. FRAWLEY

Therefore, if we exclude heavy metals and .pesticides from our consideration, experience
has indicated that only a very occasional (fewer than 1 out of 100) commercial compound
will have a “no-effect” level below 100 ppm and that an infinitely small number will exhibit
any toxicity at 10 ppm or less.

Dietary rwj-*<f«ct

ppm

FlO, 1. Histogram showing distribution of “no-effect” levels in 2-yr chronic studies on 220 compounds.
Shaded areas denote pesticides and heavy metals, and blank spaces other chemicals.

Now if we apply the conventional 100-fold margin of safety to these experimentally
determined “no-effect’' levels, all 132 of the non-pesticidal chemicals are safe for man’s
diet at a dietary concentration of 01 ppm or higher. Many of these materials are used at
much higher levels in food, but had we assumed that they were all safe at 0-1 ppm and
permitted their use up to that level without toxicity studies, we would have been correct in
100% of the cases and would not have exposed the public to any health hazard.
For accuracy, I should point out that in the above calculation I have dealt only in orders
of magnitude. If these “no-cffect" levels are subdivided into small groups as 10,30,100 or
300 ppm, it can be concluded that all were safe to animals at 30 ppm. Moreover, 1 did not
take into consideration the larger food consumption per kg of body weight of rats and dogs
versus man. Combined, these additional calculations show that the 0*1 ppm level in the
human diet provides less than 1/1000th the mg/kg/day intake of the most toxic of the 132
compounds. Some may argue that I have been unnecessarily conservative, and perhaps 1
have been.
Now let me consider briefly the other aspect of our problem—migration to food—and
attempt to develop some guidelines which will tell us which uses may contribute more than
0*1 ppm to the diet of man, and which uses cannot.
First of all, it is .obvious to everyone that any major component of a food container must
be assumed to possess the capability of migrating to food at a level in excess of 0*1 ppm,
unless proven otherwise. However, it is equally obvious, that some uses will not contribute
0-1 ppm to the diet. Our problem is to find this dividing line.
Undoubtedly, this dividing line is different for each type of substrate. It will be different
for films than for bottles. It will be different for one polymer than for another. We could
establish a whole series of levels for each food-packaging substrate and its intended use, but
most of these differences are not sufficient to justify complication of regulations.
Therefore, in order to determine the level of addition which would contribute less than
0*1 ppm to the diet with all types of substrates, I selected the substrate which is the most
permeable and susceptible to extraction by food, namely, papei. In addition 1 have selected

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FOOD-PACKAGING CONTROL

an additive which is very readily extracted from its substrate, namely, rosin size. Tbit
combination of substrate and additive, I believe, represents the most extreme case of
migration and values determined from rosin sized paper should represent a maximum for
any component of any packaging media. Indeed, such data would be excessive for most
uses of packaging components.
In our initial efforts to study the migration of rosin size from paper, we used typical
simulated solvents: various aqueous solutions, hexane, maize (or com) oil, etc. This was
wasted effort because, in water and oil, the extraction was a direct function of time and
temperature and did not plateau until essentially 100% of the rosin size was extracted and
the integrity of the paper sheet was destroyed. Nevertheless a century and a half of experience
has shown paper to be a satisfactory packaging material. Although these studies clearly
demonstrated that rosin sized paper would be an appropriate choice for developing maximum
migration data, they contributed nothing to the evaluation of safety of rosin size which was
our principal motive at that time.
As a consequence of this failure of the simulated solvents test to help define the amount
actually migrating to food, we prepared radioactive samples of rosin size, incorporated
them into typical commercial paper and paperboard at known levels, packaged a yide
variety of food in contact with these paper samples at typical package ratios, stored them at
typical storage temperatures for typical storage times and determined the rosin size content
of each food by counting the radioactivity.
The study was far more extensive than I shall describe, because wc used several types of
paper (greaseproof, waxed, unwaxed, etc.), containing three different levels of-rosin size,
24 different types of food (water, ice-cream, oysters, apricots, green beans, dry breakfast
Table 3. Maximum migration of rosin sixe* from uncoated paper
under typical storage conditions

Food
Milk products
Water
Ice-cream
Vegetables
Green beans
Green beans
Lettuce
Potatoes
Meats
Ground beef
Chicken
Beefsteak
Sausage
Fruits
Apricots
Apples
Grain products
Putted rice
Wheaties
Flour
Doughnuts
Others
Sugar
Butter

Temperature
CF)

Time
(days)

Migration
(P5*m)

34
10

14
2B

59
03

34
72
34
72

7
14
7
20

1-3
4-1
2-4
02

34
34
34
34

3
3
7
5

8-7
7-2
4-9
1244}

72
72

28
28

0-1
1-2

72
34
72
72

14
28
28
3

58
7-0
02
09

72
34

28
14

02
32-8

•4% in paper.

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J. P. FRAWLEY

food) sugar, doughnuts, ground beef, butter, bacon, sausage, to name just a few) and anal'
ysed each sample at several different storage intervals and temperatures. For our purposes,
I have selected only the uncoated and unwaxed paper and only the maximum migration
levels obtained for the 18 commodities packaged in these uncoated papers under typical
commercial storage conditions. Admittedly this gives unrealistically high values for rosin
size which are not typical of industry practice, but for our present purposes, the worst case
must be presented.

K

Table 4. Calculation of maximum migration of rosin size* to
total diet

Commodity group
Milk products
Vegetables
Meats
Fruits
Grain products
Sugar
Butter, oils

Percentage
of
diet
31
20
18
13
10
5
3

Contribution
to total
diet
(ppm)
3-1
10
0-4
20
38-2
6-9
01
0-5
3-5
04
0-2
00
328
0-9
Total ... 9-7

Average
migration
(ppm)
<

•4% in paper.

.#
j

Table 3 shows the maximum migration value for 18 food commodities at various typical
storage times and temperatures when exposed to paper containing an average of 4%
rosin size. It is obvious from some of these values that high levels of migration can occur with
some foods, whereas other foods contain much less rosin size. The data in Table 3 cm be
quickly considered since the individual values are of no great significance, but the composite of these values can be helpful. Table 4 shows the average consumption of these
various commodity groups in the USf, the average migration to that commodity group and
a calculation of the maximum level of rosin size in the average total diet, if 100% of the
diet were packaged in uncoated paper containing 4 % rosin size. Undoubtedly there are
some differences in dietary habits between our countries, but 1 doubt that they would
significantly alter the calculation.
As I mentioned previously, three different sizing levels were used in these studies. Table 5
shows the final dietary calculations for the same foods, under the same conditions for paper
containing 2 or 1 % rosin size. The extrapolation is remarkably good. The last column
shows the migration in ppm expressed on the basis of a unit of 1 % rosin size in the paper
or container. For each per cent addition to the container, man’s diet would contain a
maximum of 2 ppm of the additive, if the entire diet was in contact with that container.
One further calculation is necessary in order to arrive at a realistic determination of the
Table 5, Maximum migration of rosin size to diet
Level of rise
in paper
<%)
4
2
1

r
->■

Migration
(ppm)
9-7
4-4
1-9

Ppm//S
2-4
2-2
1-9

fU.S, Department of Agriculture Dietary Evaluation of Food Used in Households in U.S., 1961.

A.

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[

FOOD-PACKAGING CONTROL

level of addition which will contribute no more than 0-1 ppm to the diet. Obviously, 100%
of man’s diet is not in contact with paper, or any other single type of food container.
There are live major types of food container substrates, glass, metal, paper, plastics and
regenerated cellulose. In addition, there is a significant portion of food which is not packaged
or is packaged in bulk so that most of the individual units are never in contact with the
container. It is impossible to get reliable figures revealing the percentage of the food-packaging market shared by each type. However, it is conservative to assume that no more
than 25% of man’s diet is in contact with any given type of food packagc_or packaging
additive.
Table 6 shows this final calculation of the maximum migration to the diet which would
result from the use of a component at a level of I % in the container (as directly measured
from the rosin size experiments) and the maximum migration from a level in the container
of 0-2 %. Undoubtedly, this calculation is an exaggeration for most uses of packaging com­
ponents which possess greater insolubility or which are used in substrates more resistant to
penetration than paper. Nevertheless, it permits theconservative conclusion that any compon­
ent of an article contacting food which is present in the article itself or its coating at a level of
0*2 % or less by weight will contribute to the diet a level which can be of no possible public health
significance. Consequently, such trivial uses should not be included on lists of components
permitted in food packaging.
Table 6, Calculation of maximum contribution to
the diet
2 ppm/each %
Concn in
package

(%)
10
0-2

Maximum concn
in diet
(ppm)
0-5

01

As most of you know, I submitted this conclusion to the profession and to the industry
in the United States last September. It was worded differently, by describing a level of
0*2% as GRAS*, because of the particular structure of our law. It has received overwhelming
and gratifying support and only a few questions have been raised. Our own Food and Drug
Administration has authorized me to tell you that they are giving it serious consideration,
but could not reach a decision prior to this meeting.
At this point, I can only say that after 6 months, I am even more convinced that the
conclusion is sound and conservative; and, that it offers a common-sense approach to a
reduction in the extensive waste of time and money of both industry and government on
problems which can be of no possible public health significance. From a regulatory point
of view, I believe it offers one mechanism of avoiding preparation and constant modification
of an omnibus permissive list which experience has shown becomes so unwieldy and com­
plicated as to invite disregard. I do not believe that type of situation is in the best interest
of the consumer, industry or government.
Now I have intentionally reserved for my closing remarks a discussion of the few questions
and mental reservations about this proposal which have been raised by groups throughout
the world. Perhaps, some of these points will answer some of the questions you would
like to raise.
•Generally recognized as safe.

• • jr .

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J. P. FRAWLEY

The most frequent comment is a concern that despite our toxicological experience to date,
we cannot assume that the next compound will not be toxic at 0.1 ppm. The same basic
concern has been expressed in another way, by expressing doubt that toxicity data from
2-yr chronic studies represent a valid cross-scciion of chemicals, since some of the more
toxic ones are rejected by short-term toxicity tests.
It is, of course, possible that some chemical may be synthesized at some time in the
future which would be toxic at 0-1 ppm in the diet. However, it is almost impossible for
such a compound to become an intentional component of a food container. For a compound
to be toxic for man at 0-1 ppm presumes that it will be as toxic or more toxic than any
commercial pesticide. For it to be used as a component of a food container presumes that
it must be manufactured, packaged, distributed, and in other ways handled several times
before contacting the food. It is inconceivabie that a compound as toxic as this could pass
through so many hands, in an industry not accustomed to handling highly toxic substances,
without revealing its toxicity through injury to personnel. Once recognized, safe handling
of such a compound would require such extreme industrial hygiene precautions as to be
incompatible with converting operations and food-packaging practices. It seems to me that
in order to produce an unsafe food package, due to incorporation of a toxic ingredient at a
level of 0-2 % or less, it would require a deliberate or intentional act on the part of a manu­
facturer to poison the public, without at the same time poisoning his own workers. No­
amount of legislation or regulation Can protect against such insanity.
It has been suggested by a few of my colleagues that the extreme toxicity of such materials
as aflatoxin rules out an assumption that any chemical is safe at even one part in a thousand
million unless it has been tested. I believe that such an assumption is valid, if we limit our
discussion to certain uses or industries. Again, I believe common sense tells us that it is
inconceivable that anyone could manufacture millions of pounds of aflatoxin, or any
substance of extreme toxicity and distribute it for use as a stabilizer in plastics or wetstrength resins for paper without finding out that it was too toxic for that industry. No
company can afford to lose customers that way.
Accidental contamination with aflatoxin or other extremely toxic substances is another
matter, but this is outside the considerations of a permissive list. Whether a permissive list
contains 200 or 20,000 substances, accidental contamination is no more or less likely.
Quality control, inspection, and personal attention to details in manufacture are all necessary
ingredients to the prevention of contamination of any product.
A few individuals have questioned the validity of my estimate that no more than 25%
of the diet will be in contact with the same packaging substrate or chemical. In rare circum­
stances, of course, some individuals may eat canned foods almost exclusively and some may
eat fresh or unpackaged food almost exclusively. These variations in dietary habits, along
with other intraspecies differences have been taken into consideration as part of the basic
concept of our 100-fold margin of safety. Moreover, as mentioned above, the conservative
calculations used above provide a lQQO-fold margin of safety.
The principal objection to this proposal in the United States has been administrative.
Adoption of this proposal would obviate the need for many of our packaging regulations
and would suggest a complete rewriting of Subpart F. For example, the “general adhesives”
and "defoamer in paper manufacture” regulations would be replaced by a statement of
good manufacturing practice that adhesives should not contact the food (as is already
provided despite the fact that thousands of chemicals are enumerated) and that defoamers
may be used only prior to and during sheet-forming process (as is also already provided).

ASI-PR 0000453

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7

f-

l

i

J03

lOOD-l XCKAGINC, VONTI'OL

I think the time necessary to accomplish .ms l ;sh -vouM f>e time -veil spent ami would be
rapidly recovered in reduced adminisirtuivc cost-..
Let me close with this ceucepL. Your countrx ar e v :.,e ;..ad a limited number of com­
petent specialists in the field of cnvimnmcr.ul iic.hih 1 here arc many problems facing our
society which are competing for their tunc and atieiuion, as well as for financial support.
Included arc community air and water pel muon. mJ ustnai exposures, household chemicals,
pesticides, drugs, cosmetics, food additives, confined civ-iroimicius of space cabins and
submarines and food-packaging. Having some prcfessmmul sesponsibudy in all of these
segments, I am convinced that food packaging cn v-thmes (lie Hast hazard to health of nil
of these. Yet in recent years it has co urn-iiided '
’me •’••J nitention than any other
area other than drugs and pesticides. It r- our ;.■ • ui and pi jfe.'.sional responsibility to
invest our tiute and money in research which is likely to provide the greatest prolcction to
health. I suggest that my proposal is a start toward to; lomlion of a proper balance.

AITENDIX
No-effect levels established hj 2-yr feeding studies

Compound

No-elTcct
level
(ppm)

Compound

No-cdea
level
(ppm)

40
Acrylamide1
Aldrin1
* 0 5*
1000
Alky) ketene dimer*
4000*
Allcthrin*
Amiben (2,5-DichlorO-3-ammobcnzoic
10,000*
acid)*
5D0
Ammonium suiphamalc*
<500|
Antimony chloride’
50*
Arsonic acid*
2500
f-Ascorbyl pabnitate*
Barium chloride’
2000 k
10*
Benzene hexachtoridc, technical (BIIQ’
a-Benzene hexachloride (a-BHC)’
10*
<10*
0-Benzcne hexachloride (0-DHC)’
'/-Benzene hexachloride (y-BHC)1
50*
<800*
(5-Bcnzene hexachloride (5-BHC)’
Benzoic acid1*
5000
7500
Biurea11
Butoxypolypropylene glycol (moi wt
800)1
640
5000
Butylated hydroxyanisole (BHA)10
Butylated hydroxytoluenc lBHT)1,a'
1000
Dutyi 3,4-dihydro-2,2-dirt)Cthyl-4-oxo-l,
2//-pyran-6-carboxylate (Indaloue)14 40,000
1.3-Butylene glycol14
30,000
2-Cp-ferr-Butylphcnoxy) isopropyl
2'-chloroethyl sulphite (Aramiic)1*
ICO*
fert-Butylphenyl salicylate1
2000
Cadmium chloride1
<i0k
Calcium disodium cLhylenediamtue5000
tetraacetate1'1’
Captan*
1CO0*

Cm barsone (p-Urtidobcnzencanonic
acid)18
1000
Cm boxvnicthvlceiiulose (CMC)11
10.000
,-7-C aiotcnc*0
1000
Cv'cchol”
1250V
Cl'loihenudc (p-Chlorobcnzyl
/'-chlorophenyi sulphide)4
20*
Ck'orbcnsidc, suiphunc derivative4
20*
Ch!ord,i;ic?
25*
biMp-Chlorpkeno\v)mctiiancx
3CO
p-Clilorophenyl p-chlorobcuzene,-ulphonatc1
25*
Chlorpropamide11
1250
Chlorlctiacvciinc34
10,000
Citrus Red No. 2 fC.I. (1956) No. 12,156) “ 500
Copper chromate*
500*
Cime”
50*
Cupric chloride4
500-1Dalaron*
300*
D & C Orange No. 5”
10,000
D be C Orange No. 10’*
10,000
D A. C Red Nc*. 9*’
500
D w C Red No. 10!8
500
D.tC lied No. 2114
10,000
D A C Rfd No. 27”
10,000
BCD HOE)*
10*
DDT’
1*
Help dioactiic acid’
1000
Diuzincn4
0-75*
Dioiiiono*
<500*
1,1 -Dici)ioro-2,2-bis(/7-eUiyIpheny!)etliane
(Pcrthane)4
100*

•Pesticide
•(Heavy metal

T—Tumours at higher levels,

ASI-PR 0000454

I. P. FRAWLEY

304
Appendix (contd)

No-effect
level
(ppm)

Compound

2,4-Dich!oro-6't>-chloroanilino-s5000*
triazine (Dyrene)4
2,4-Dichlorophenoxyethyl sulphate,
200*
sodium salt1
4,4'-Didi loro-'i-trichloromelhyl20*
benzhydrot (Kelthane)4
2500
Dicyandiamide**
O'5*
Dieldrin*
<?,<?-Diethyl 0-3-chloro-4-methyMoxo-2/f-l*bcnzopyran-7-yl
phosphorothioate (Co-Ra!)4
2*
1300
Di(2-ethylhexyl) phthalate1
5000
Di-ff-hexyl azelate”
5000
Di-isobutyl adipate1
30,000
Ddauryi thiodipropionjc acid*1
10,000
Dimethyl carbate14
2,4-Dimethyl-2-methylene-1 ,2,4thiadiazolidine-5-thione*
100*
20,000
Dimethyl phthalate14
3,5-D imethyl tetrahydro-1,3,5,2/f<10*
ihiadiazine-2-thione (Mylone)*1
D,D-Dimethyl-0-(2,4,5*trichlorophenyl)
10*
phosphorothioate (Ronnel)4
600*
3,5-Dinitrobenzamide”
3,5-Dinitro-p-to/uamide1
62*
500*
Diphenyl4’”
100*
Diphenylamine*
2000
3-(2-Diphenylyloxy)-l,2-epoxypropane1
30,000
Distearyi thiodipropionic acid”
125*
Diuron4
Dodecyi benzene sodium sulphonate
2000
(Santomerse no. 3)”
350
Dodecyi galiate14
50*
Dodine4’14
30*
Endosulphan4
5*
EPN4
Epoxidized soybean oil (Paraplex
25,000
G-60)*4
Epoxidized soybean oil (Paraplex
5000
G-62)M
4-Elhoxyphenylurea (Sucrof, dulcin)** <1000
120*
Ethoxyquin4
100
Ethyl acrylate”
Ethyl 4,4'*d!chlorobenzilate4
50*
40,000
2-Ethyl hexanediol-1,314
2-Ethylhexyl diphenyl phosphate
1250
(Santicizer 141)”
5000
Ethyl phthalyl ethyl glycolate*
10,000
Fast Green FCF”
5000
FD & C Blue No. 1«
1000
FD & C Blue No. 241
200*
Fcrbam4
100,000
Glycerol41
250,000
Glycerol monostearate41
5000
Gum guaiac44
500
Gum rosin, pale41
0-5*
Heptachlor epoxide4

'

Compound

No-cffect
level
(ppm)

2-Heptadecyl glyo*alklmc acetate
(Glyodinj4
210*
n-Heptyl-p-hydroxybenzoate44
1500
l-[5-(3a,4,5,6,7,7a-Hexahydro-4,7methanoindanyl)]-3,3-dimethylurea
(Herban)1
500*
Hydroxyethylcellulose4’
10,000
Hydroxypropylmethylcellulose1
50,000
Hydroquinone11
10,000r
tMsoascorbic acid11
10,000
a'-Isoascorbyl palmitate*1
2500
isopropyl A'-(3 chlorophenyl) carbamate
2000*
(CIPC)*1
4,4'-lsopropylidene bis(2-Isopropyl>
phenol)1
1000
Light Green SF Yellowish”
10,000
Malathion4
100*
Maleic hydrazide1
20.000*
A 25*
Maneb4
Melamine-formaldehyde resin
(Parez 607)«
50,000
Mercaptobenzothiazole4
120*
Mercury acetate’
2-5*
Methoxychlor1’41
200*
0-Methyl-C>-(4-rerr-butyl-2-chloropheny[)
methylphosphoroamidothioate
(Ruciene)1’”
30*
0-Methyl-0-(2,4-dichlorophwiyl)
isopropyiphosphoramidothioate1
10*
20,000
Methyl p-hydroxybenzoate41
100
Methyl methacrylate11
Methyl naphthaleneacetic add*
2500*
Methylpolysiloxane1
3000
10,000
Methyl salicylate4*
250*
Monuron4
1-Naphthyl-iV-methyi carbamate1
200*
o-Naphthylthiourea”
50*
Nicotine*
62
Nordihydroguaiarttic acid”
2500
100,000
Nylon (Zytel)*4
500
Octadecylamine”
Octyl galiate11
350
p-fe/7-OctyIphenoxy-polyethoxy
ethanols (Triton X-405)4*
14,000
l*
Parathion4
50,000
Petrolatum4’
Petroleum wax no. 241
100,000
Petroleum wax no. 8“
100,000
100,000
Petroleum wax no. 12**
100,000
Petroleum wax no. 15‘*
Petroleum wax no. 20**
100,000
Phenacetin4*
630
Phenol*1
10,000
Phenyl mercuric acetate*
0-1*
o-Phenylphenol"
2000*
500
Pimaricin41
Piperonyl butoxide*
700*

"------ -•••

▼

ASI-PR 0000455

i
t
FOOD-PACKAGING CONTROL

305

Appendix (comd)
No-c fleet
level
(ppm)

Compound

10,000
Polyacrylamide (Separan AP30)**
10.000
Polyacrylamide (Separan NPIO)*1
Polyethylene glycol (mol wt 200)1
40,000
20,000
Polyethylene glycol (mol wt 400)'
2000
Polyethylene glycol (mol wt 1500)1
Polyethylene glycol (mol wt 1540)1
40,000
Polyethylene glycol (mol wt 4000)*
40,000
2000
Polymerized turpentine resin1
Polyoxyethylene(20)sorbitan
monolaurate (Tween 20)'*
50,000
Polyoxycthylene(20)sorbitan
monoolcate (Tween 80)4*
50,000
Poiyoxyethylene(20)sorbitan
monopaimitate (Tween 40)**
50,000
Polyoxycthylene(20) sOrbitan
monosteatatc (Tween 60)*4
50,000
Polyoxyethylcnc(20)sorbitan
tristearatc (Tween 65)**
50,000
Polyoxyethylene(8)stearatc (Myrj 4S)*4 20,000
Polyoxyethylene(40)slearate (Myrj 52)** 50,000
5000
Ponceau 3R (C-I- (1956) No. 16,155)**
Ponceau SX (C.I. (1956) No. 14,700)*' 50,000
Potassium bromate**
627
l -/t-Propoxy-2-amino-4-nitrobenzene
(P4000),T
<1000
Propyl gallate*1
10,000
20,000
Propyl /j-hydroxybcnzOate"
Pyrethrum1
1000*
Rosin, disproportionated**
500
Rosin, fully dimerized1*
500
Rosin, partially dimerized1*
500
Rotenone7
2*
Saccharin*7
10,000
Selenium7
<3*
Sodium alginate*7
50,000
Sodium alkylbenzenesulphonatc'*
5000
Sodium bisulphite*7
500
Sodium chromate77
300*
Sodium cyclamate*7
10,000
Sodium 2,2-dichloropropionate1
300
Sodium dioctyl sulphosuccinate71
5000
Sodium hexametaphosphate**
5000
Sodium lauryl glycerylsulphonate7'
5000

*

*

*

,

!

Compound

No-effect
level
(ppm)

Sodium lauryl sulphate71
10.000
Sodium lauryl trioxyethylene
sulphonate7*
■ 5000
Sodium monofluoracetate7
<5*
Sodium nitrate7*
10,000
Sodium /9-suIphopropionamide1
10,000
Sodium tripoiyphosphatc**
5000
Sorbic acid19
50,000
Sorbitan monopaimitate (Span 40)**
50,000
Sorbitan monostearate (Span 60)**
50,000
Sorbitan tristearate (Span 65)**
30,000
Sulphenone (p-chlorophenyl phenyl
sulphone)*
100*
Tall oil rosin, paie4*
2000
Tartar emetic (Potassium antimony!
tartrate)4
<500)
Tartaric acid74
12,000
Tartrazme’4
I0.0Q0
Terpene polychlorinates (Strobane)*
50*
Tetradifon*
300*
Thiodipropionic acid11
30,000
Thiourea7*
500*
Thiram*
200*
Toxaphene7
25*
2,4,5-Trichlorophenoxyethyl sulphate,
sodium salt1
200
Tri(polynonylphenyl) phosphite
(Poiygard)77
3300
—Tylosin7*
10,000
Vinyl chloride-vinylacetate
copolymer7*
120,000
VinyiideQe chloride-vinyl chloride
copolymer1
50,000
Wood rosin, dark41
500
Wood rosin, fully hydrogenated4*
500
Wood rosin, hydrocarbon insoluble
residue1*
500
Wood rosin, pale4*
2000
Wood rosin, partially hydrogenated4*
2000
Yellow AB**
500
Yellow OB"
500
Zineb4
500*
Ziram*
250*

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'

-

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Asr™ PR 0000456

■ •

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ASI-PR 0000457

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307

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58. Shubik, P., Saffiotti, U., Lijinsky, W., Pietra,
G., Rappaport, H., Toth, B., Raha, C. R.,
Tomatis, L., Feldman, R. A Ramahi, H.
(1962). Studies on the toxicity of petroleum
waxes. Toxic, appl. Pharmac. (Supp.) 4, 49.
59. Woodard, G., Post, K. F., Cockrell. K. O. A
Cronin, M.T.I.(l965).Phenacetin: Long-term
studies in rats and dogs. Toxic, appl. Pharmac,
7, 503.
60. Hodge, H. C., Maynard, E., Blanchet, H. J.,
Jr., Spencer, H. C. A Rowe, V. K. (1952),
Toxicological studies of ortho-phenylphenol
in (Dowicide 1). J. Pharmac. exp. Ther. 104,
202!
61. Levinskas, G. J., Ribelin, W. E. A Shaffer,
C. B. (1966). Acute and chronic toxicity of
pimaricin. Toxic, appl. Pharmac. 8, 97.
62. McCollister, D. D., Hake, C. L,, Sadck, S, E,
A Rowe, V. K. (1965). Toxicologic investiga­
tions of polyacrylamides. Toxic, appl. Pharmac.
7,639.
63. Joint FAO/WHO Expert Committee on Food
Additives—Seventh Report (1964). Specifica­
tions for the Identity and Purity of Food
Additives and Their Toxicological Evaluation:
Emulsifiers, Stabilizers, Bleaching and Matur­
ing Agents. Tech. Rep. Ser. Wld Hlth Org,
281.
64. Fitzhugh, O. G-, Bourke, Anne R., Nelson,
AAA Frawley, J. P. (1959). Chronic oral
toxicities of four stearic acid emulsifiers. Toxie.
appl. Pharmac. 1, 315,
65. Hansen, W, H., Davis, K. J., Fitzhugh, O. G.
A Nelson, A. A. (1963). Chronic oral toxicity
of Ponceau 3R. Toxie. appl. Pharmac. S, 105.
66. Davis, K. J., Nelson, A. A, Zwickey, R. E.,
Hansen, W. H. A Fitzhugh, O. G. (1966).
Chronic toxicity of Ponceau SX to rats, mice
and dogs. Toxic, appl. Pharmac. 8, 306.
67. NUson, H. A Wagner, J. E. (1951). Feeding
tests with some algin products. Proc. Soc. exp.
Biol. Med. 76, 630.
68. Tusing, T. W., Paynter, O. E. A Opdyke, D. L.
(I960). The chronic toxicity of sodium aikylbenzenesulfonate by food and water admini­
stration to rats. Toxic, appl. Pharmac. 2*
464.

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69. Fitzhugh, O. G.. Knudscn, L. S. & Nelson.
A. A. (1946). Chronic toxicity of suilitcs. J.
Pharmae. tXP- Ther. 86, 37,
70. Food and Drug Administration (Unpublished
data).
71. Fitzhugh, 0. G. <Sc Nelson, A, A. (1943),
Chronic oral toxicitics of surface-active agents,
J. Am. pharm. Ass. Sci. Ed. 37, 29.
72. Tusing, T. W,, Paynter, O. E., Opdyke, D. L.
&. Synder, F. H. (1962). Toxicologic studies
on sodium lauryl glyceryl ether sulfonate and
sodium lauryl trioxyethylene sulfate. Toxic,
appl. Pharmae. 4, 402.
73. Lehman, A. J. 0958). Nitrates and nitrites m
meat products. Q. Hull. Ass. Fd Drug Off.
U.S. 22, 136.
74. Fitzhugh, O. G. & Nelson, A. A. (1947), The
comparative chronic toxicitics of fumanc,
tartaric, oxalic and maleic acids. J. Am.
pharm. Ass. Sci. Ed. 36, 217.
75. Davis, K. J., Fitzhugh, O. G. & Nelson, A. A.

0 964). Chronic rat and dog toxicity studies
on tartrazme. Toxic, appl. Pharmae. 6, 621,
76. Fitznugh, O. G. & Nelson, A. A. (1948). Liver
tumours in rats led thiourea or thioacetamide,
Science. ,V, Y. J08, 626.
77. Carson. 5., Oser, ii. L. Sc Oscr, Mctu (1964).
Toxicologic studies with the antioxidant
Polygard. Toxic, appl. Pharmae. G, 342.
78. Anderson, R, C,, Worth, Ft. M., Small, R, M.
& Flams, P. N. (1965). Toxicological studies
on Tylosin: fts safety as a food additive.
Toxic, appl. Pharmae. 7, -178.
79. Smyth, II. F.. Jr. & Weil, C. S. (1966). Chronic
Oral toxicity to rats of a vinyl chloride-vinyl
acetate copolymer. Toxic, appl. Pharmae. 9,
501.
80. Hansen, W. If., Nelson, A, A, & Fitzhugh
O. G. (1963). Chronic toxicity of Yellow AB
(i-phcnyiazo-2-naphthyUmme) and Yellow
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