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• •••

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···�

1

1

XO RESPONSIBILITY is assumed by thP Institute 0! Food Technologists for statement� and up1m�ms ��prcsse( i dJ)·th e c ontributorstoitspubiica.uons.
Copyright © 1972 by Institute of Food Technologists. All R1ghts Reserve .

RECENT PROGRESS in theConsideration of Flavoring Ingredients
Under the Food Additives Amendment

5. GRAS Substances
BERNARD L. OSER and RICHARD L. HALL

D RESEARCH in the field of food flavors has been
greatly stimulated by the application of modern ana­
lytical techniques, particularly gas chromatography
and mass spectroscopy, which have permitted the iden­tification of the chemical components of many natural
flavors (1-5). As a consequence, improved artificial
flavoring agents have been and are being developed
which faithfully reproduce the nuances of natural fla­vors and intensify their characteristic properties.
THE EXPERT PANEL

It has been the policy of the Flavor and Extract
Manufacturers Association (FEMA) to urge member
companies to submit to an independent panel of qual­
ified scientists, flavoring substances intended for com­
mercial application, whether or not they are analogs
of natural substances, for appraisal of safety underconditions of proposed use. Results of this expert
panel's GRAS (generally recognized as safe) evalua­·tions have been published in Food Technology (6-9).
The basis for selection of the original panel of tox­
icologists, pharmacologists, and biochemists, has �een
previously described (7). It should be emphasizedthat the members of the panel were affiliated with aca­
demic institutions and organizations having no con­nection with the flavoring industry, either directly or
indirectly. The panel that evaluated the items re­ported herein consisted of: Dr. Anthony M. Ambrose,
Medical College of Virginia; Dr. Frank R. Blood, Van­
derbilt University; Dr. David W. Fassett, Eastman
Kodak Company; Dr. Horace W. Gerarde, Fairleigh
Dickinson University; Dr. Maurice H. Seevers, Uni­
versitv of Michigan; Dr. Howard C. Spencer, Dow
Chem"ical Co.; Dr. Frank M. Strong, University of'Wisconsin; Dr. Lauren A. Woods, Medical College of
Virginia.

WHY PUBLISH GRAS LISTS?

Data concerning the usage levels of flavoring sub­stances,_ and_all available scientific information rele­vant to safety evaluation have been the basis for thedevelopment over a period of several years of lists of
GRAS flavoring substances. The policy of FEMA topublish the GRAS lists has resulted in their receiving
wide recognition. The Federal Food And Drug Ad­
ministration has adopted (with very few deletions) the
first such list of substances in the form of two Food
Additive Regulations ( 10).
It has been the view of the U.S. Food and Drug
Administration, with which there can be no disagree­
ment, that only by publication can the scientific com­munity have the opportunity to comment on, or takeissue with, the opinion of other specialists in the fieldof food safety evaluation. The purpose of the present
report is to present the additions to the list of GRAS
substances made in 1970-71.
CRITERIA FOR JUDGEMENTS

The criteria employed by the Expert Panel in arriv­
ing at judgements of GRAS status have been discussed
in previous publications of GRAS lists (6-9) and in areview on the safety of flavoring substances by Halland Oser ( 11). In essence, these requirements in­clude evidence for the identity and purity of the sub­stance, its chemicai and pharmacoiogicar reiation to
structurally analogous substances, its presence and

THE AUTHORS are respectively Chairman of Food and Drug
Research Laboratories Incorporated, Maurice Ave. at 58th
St., Maspeth, N.Y. 11378; and President of 1FT and Vice­
President of McCormick & Co., 11350 McCormick Rd.,
Hunt Valley, Md.
21030

GRAS substances .

.

Council (12), from which the following quotation isrelevant.

.

For many substances that are functionally effective in·food at dietary concentrations above 0.1 ppm, but stillmuch below any reasonable judgment as to their max­level as a naturally occurring constituent of foods, in­tended use levels, and any pertinent metabolic or tox­
icologic data. From the accumulated experience in theevaluation of large numbers of chemically related sub­stances has evolved certain general principles whichhave established the rationale and facilitated the pro­
cess of safety evaluation by the Expert Panel.

imum safe level, as previously defined, there is need toarrive at estimates of toxicologically insignificant levels.
For these substances, it is justifiable to employ accumu­
lated scientific experience and to recognize their struc­tural analogy to other chemicals whose metabolism or
toxicity is known. Reasoning by analogy may be used
to arrive at conclusions of toxicological insignificance.
If a substance meets all the following criteria, it may
be presumed to be toxicologically insignificant at a levelof 1.0 ppm or less in the human diet:

1. The substance in question is of known structure
and purity;
2. It is structurally simple;
3. The structure suggests that the substance will bereadily handled through known metabolic pathways; and4. It is a member of a closely related group of sub­stances, that, without known exception, are or can bepresumed to be low in toxicity.

TOXICOLOGICAL INSIGNIFICANCE

A nationwide survey of the flavor and food indus­
tries conducted in 1960 revealed that of the 1121 sub­stances on the FEMA GRAS list, 859 were estimatedto be used in total amounts not exceeding 1000 lb an­
nually. Moreover, the average maximum use levels infood were below 10 ppm in 399 of these substances.
These criteria of total annual usage and minimal lev­els in foods, together with a safe history of common
use in food, have been regarded by the FEMA panel
as a basis for "toxicological insignificance," in the ab­sence of any specific evidence or reasonable suspicion(based, for example, on chemical structure) to thecontrary.
In this connection, reference may be made to therecent guidelines for evaluating toxicological insignif­
icance published by the Food Protection Committee of
the National Academy of Sciences-National Research

TOTAL PER CAPITA INTAKEOF FLAVORING SUBSTANCES

It is interesting to note in this connection that if aflavoring agent were used at a level of 10 ppm in every
major category of flavored foods, the total per capita
intake of that substance (based on USDA Food Con­. sumption data for aU urbani�atcions) wou!a be 2,336
mg per day. This would be equivalent to 1.3 ppm of
the total diet or 0.0334 mg per kg body weight for a
70 kg adult. On the highly exaggerated assumptionof the daily ingestion of average portions of all classesof flavored foods and the presence of 10 ppm of flavor­
ing substance in each of them, the total daily intake
would reach 11.5 mg or only 0.164 mg per kg bodyweight (Table 1).
Nearly a decade has passed since the original survey···. . . text I continued on p. 42 .

.

.

Table I-TOTAL DAILY PER CAPITA INTAKE OF FLAVORING SUBSTANCES based on the exaggerated assumption of the daily
ingestion of average portions of all classes of flavored foods and the presence of 10 ppm in each of them
Flavored Food Consumptionc

Class of Flavored foodSoft drinks

Flavor Component

Flavor Component"Averageper Householdb

per Capita•

at 10 ppm

Portion"at(lb/wk)(g/day)(mg/day)(g/day)(mg/day)

5.09

100.3

1.00

540

5.40

1.36

26.8

0.268

90

0.90

0.52

10.2

0.102

40
340

0.40
3.40

0.48
3.28

9.5
64.6

0.095
0.646
120

1.20

0.45
0.31
0.38

8.9
6.1
7.5

0.089
0.061
0.075
2.336
1.30
0.0334

20

0.20
11.50
6.40
0.164

10 ppmFrozen milk desserts:
ice cream, ice milk, sherbet
Candy, toppings
Baked goods•
prepared mixes"other" bakery products
Jelly, jam, fruit, gelatin
puddings, ices
popsicles, icings
Condiments
Total intake, mg per day
Total intake, ppm diet •Total intake, mg per kg body weight (70 kg)• Includes
u kes, pies, crackers_. muffins, biscuits, cookies, coffee ake, doughnuts
b 3.29 personse Household
food consumption levels based on 1965-66 survey, U.S. Dept. of Agr icultur e (all urbani.zations)
4 lb pet household per week X 454 g
9 per upit& per day
3.29 persons X 7 days
• 1800 g food per day(estimate bued on USDA Food Consumption sta tistics)

�UK.Vt:Y

Ul- rLAVUK.IN{.;J iNGK.cUitN l

U�Al:lt: U:VtL�

Flavor and Extract Manufacturers Association average maximum use levels (in ppm) on which the expert panel based its judgements that the substances are generally recognized as safe.
Meat,
Baked

Ice Cream,
FEMA No. and Substance

Gelatins

Beverages

Ices, Etc.

Candy

Goods

& Puddings

10.

10.

10.

10.

10.

3,250
2-Acetyl-3-ethyl pyrazine

Meat

Milk.

Chewing

Sauces,Dairyments,

Gum

Soups

Product

Pickleo10.

10.

Cerealo
10.
Cereals
3.0

CondiOther

Category Uoea

2-Acetyl-3-ethyl-1,4-diazine (see 3,250)
3.251
2-Acetylpyridine
3.252,6-Aianine

3.0
10.

.1.253Allyl methyl trisulfide

5.0

3.0

3.0

10•

10.

10.

2.0

2.0

10.

Cereals10.

2.0Allyl trisulfide (see 3,265)
Aminoacetic acid (see 3,287)
Aminoethanoic acid (see 3.287)
Aminoglutaric acid (see 3,285)
a-Aminoisocaproic acid (see 3,297)
2-Amino-3-methylpentanoic acid (see 3,295)
2-Amino-4-methylpentanoic acid (see 3,297)
2-Amino-3-mercaptopropanoic acid (see 3,263)
a-Amino-,6-mercaptopropionic acid (see 3,263)
2-Amino-4-(methylthio)-butanoic acid (see 3,301)
a-Amino--y-(methylthio) -butyric acid (see 3,301)
a-Amino-,6-methylvaleric acid (see 3,295)
2-Aminopropanoic acid (see 3,252).B·Aminopropionic acid see 3,252)a-Angelica lactone (see 3,293)
3,254
Arabinogalactan
3,255
L-Arabinose

85%
450.

1.256
Benzothiazole

450.

•

0.5

Preserves

450.

450.

0.5

0.5

0.5

0.5
3.0

& Spreads
450 .

3,257

Bisl2-furfuryl) disulfide

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.258
Bis12-furfuryl) sulfide

5.0

5.0

5.0

5.0

5.0

5.0

5.0

5.0
0.1

3.259

3.0

Bisl2-methyl-3-furyl) disulfide

0.1

0.1

3.260
Bis (2-methyl-3-furyl) tetrasulfide

0.1

0.1

0.1

0.1

Ce•eals
0.1

0.1

0.1

0.1

Cereals
0.1

100.

Cereals100.

3,261
2-sec-Butylcyclohexanone

25.

25.

150.

100.

1000.

-y-Butyrolactone (see 3,291)
Cinnamic acid. tetrahydrofurfuryl ester(see 3,320)
Cyclohexapyrazine (see 3,321)
3,262
Cyclopentanethiol

0.1

Cyclopentyl mercaptan (see 3,262)
3,263.
L-Cysteine

100.

3.264
4-Decenal

0.5

3.265
Diallyl trisulfide

100.

100.

100.

1.0

0.5

0.5

1.0

1-0

Difurfuryl disulfide (see 3,257)

1.0

Difurfuryl sulfide (see 3,258)
3,266
4,5-Dihydro-3(2H) thiopheoone

1.0

3.267
2,4-Dimethyl-5-acetylthiazole

1.0

1.0

1.0

10.

10.

0.3

4.0

6.0

5.0

1.0

6.0

1.0

_1.0

Cereals
1.0

10.

3.268

3,4-Dimethyl-1,2-cyclopentadione

1.0

Protein Foods

3.5

1.9

3,269

3,5-Dimethyl-1,2-cyclopentadione

2.4

3,270

•piro[2 ,4-Dithia-1-methyl-8-oxabicyclo [3.3.0]
octane-3,3' (I' ·oxa-2' -methyl) cyclopentane]•and spiro[2,4-dithia-6-methyl-7-oxabicyclo[3.3.0 ]octaoe-3,3'- (1' -oxa-2-methyl)
cyclopentane]

0.045

0.25

0.07

0.1

2,3-Dimethyl-1,4-diazine (see 3,271)
2,5-Dimethyl-1,4-diazine (see 3,272)
2,6-Dimethyl-1,4-diazine (see 3,273)
3,271
2,3-Dimethylpyrazine

10.

10.

10.

10.

10.

10.

Protein Foods
0.4
Mayonnaise
2.4

Meat,
Ice Cream,

Baked

Gelatins

Meat

Milk,

Chewing

Sauces,Dairyments.

Other

Gum

Soups

Product

PicklesCategory Uses

Beverages

Ices, Etc.

Candy

Goods

& Puddings

2.5-Dimethylpyra:cine

10.

10.

10.

10.

10.

10.

10.

3.273
2,6-Dimethylpyrazine

10.

10.

10.

10.

10.

10.

10.

10.

10.

10.

6.0

20.

FEMA No. and SubstanceCondi-.1.272

Cereals
10.
Cereals

10.

3,274

4,5-Dimethylthiazole

20.

3,275

Dimethyl trisulfide

1.0

1.0

1.0

3.276
Dipropyl trisulfide

1.0

1.0

1.0

3.277

Disodium succinate

60.

Cereals

60.

60.

60.

60.

3,3'-Dithio-bis(2·methylfuran) (see 3,259)
2.2'-Dithiodithiophene (see 3,323)
2-Ethyl-1,4-diazine (see 3,281)
Ethyl 2,4-diketocaproate (see 3,278)
3.278
Ethyl 2,4-dioxohexanoate

Hard Candy
20.

15.

120.

120.

10.

Syrups60.
Jellies30.
3.279
Ethyl 2-mercaptopropionato

Mint Oils
0.1

0.1

1.2

10.

1.5

Jellied Produclo
0.2
Other
0.01
3.280
2-Ethyl- (3,5 and 6) -methoxypyrazine (85%)
plus 2-Methyl-(3,5 and 6)-methoxypyrazine
U3%l

5.0

5.0

5.0

5.0

5.0

Ethyl propyl ketone (see 3,290)
3.281
2-Ethylpyrazine
3.282
Ethyl thioacetate

10.

10.

10.

1.0

1.0

1. 0

5.0

5.0

10.

2.0

2.0

2.0

10.
1.0

10.
1.0

1.0

Furfuryl disulfide (see 3,257)

5.0

5.0

Cereals
5.0

10.

10.

Cereals
10.

1.0

1.0

1.0

Cereals
1 .0

Furfuryl isovalerate (see 3,283)
3.283
Furfuryl 2-methylbutanoate

5.0

Furfuryl sulfide (see 3,258)
3.284

N -Fu rfurylpyrrole

2.0

1-(2-Furfuryl)pyrrole (see 3,284)
3.285
L-Glutamic acid
3,286
Glyceryl tripropanoate
3.287
Glycine

Cereals
2.0

2.0

2.0

Cereals
400.

400.

400.

20.

50.

Desserts
20.

150.

150.

Preserves,
Spreads
150.

1.0

15.0

150.

400.

400.

150.

.roo.

150.

Glycocoll (see 3,287)
3.288
2-Heptanol

0.5

0.5

5.0

Dips, Spreads
12.
Salad Dressing

10.

80.

.1.2894-Heptenal (cis and trans)

1.0

1.0

1.0

1.0

Cereals
1.0

1.0

3.290

3-Hexanone

20.

20.

20.

20.

20.

Cereals

20.

20.

3.291

4-Hydroxybutanoic acid lactone

10.

10.

10.

20.

0.3

0.3

5.0

10.

0.2

2.0

4.0

5.0

5.0

10.

Cereals

20.

10.

3.292

3- (Hydroxymethyl) -2-octanone

10.

3.293

4-Hydroxy-3-pentenoic acid lactone
3.294
5-Hydroxyundecanoic acid lactone

2.0

3.295
D.L-Isoleucine

50.

3.296
Isopropenylpyrazine

10.

2.0

25.
50.

10.

10.

!0.

2.0

0.2

Cereals
2.0

1.0

10.

Cereals
5.0

50.

50.

10.

10.

50.

50.

50.

Cereals50.
Cereals10.

2-lsopropenyl-1,4-diazine (see 3,296)
Larch gum (see 3.254)
3.297
L-Leucine

50.

3.298
3-!\1ercapto-2-butanone

0.2

3.299
2-!\1ercaptomethylpyrazine

2·!\1ercaptonaphthalene (see 3 ,31 4)

60.
0.2

0.2
10.

0.2
10.

50.

Cereals50.
Cereals
0.2

0.2
10.

:\!�at,Ice Cream,
FEMA No. and SubstanceBeverages

Ices, Etc.

3,.1003- Men.·apto-2:..-p-entanone

Candy

o.z--

0.2

Meat

Milk,

Baked

Gelatins

Chewing

Sauces.

Dairyments.

Other

Goods

& Puddings

Gum

Soups

Product

PicklesCategory Uses

0.2

0.2

0.2

50.

50.

50.

Condi-

Cereals
0.2

2- Mercaptopropionic acid, ethyl ester (see 3,279)
Methanethiol n-butyrate (see 3,310)
3 . .'101

D,L·Methionine

50.

50.

10.

10.

0.8

0.8

0.8

Cereals
0.8

1.2

1.2

1.2

1.2

Cereals
1.2

9. 0

6.0

10.

10.

0.8

0.8

1.2
0.6

10.

10.

50.

Cereals10.

3.302

Methoxypyrazine

Cereals

10.

2-Methoxy-1,4-diazine (see 3,302)
Methyl allyl trisulfide (see 3,253)
Methyl n-amyl carbinol (see 3,288)
3. .'J0.1

2-Methyl-1-butanethiol
3 ..104

3- Methyl-2-butanethiol.'1 . .'105

1-Methyl-2,3-cyclohexadione

0.2

2- Methyl-1,4-cliazine (see 3,309)
0.045

0.25

1.0

0.15

Protein Foods
0.5

0.1

0.4

1.2

2.5

Protein Food•
0.1

10.

10.

10.

10.

0.0005

0.05

0.5

7.0

3.0

3.0

3.0

5.0

3. .'J06

5H-5-Methyl-6,7 -dihydrocyclopenta [b] pyrazine
5- Methyl-2t3H) -furanone (see 3,293).1..1073-(5-Methyl-2-furyl) butanal

3-(5- Methyl-2-furyl)butyraldehyde (see 3,307)
2-Methyl-3-furyl disulfide (see 3,259)
2-Methyl-3-furyl tetrasulfide (see 3,260)
Methyl n-heptyl carbinol (see 3,315)
3-Methylmercaptopropyl isothiocyanate(see 3,312)
Methyl n-propyl carbinol (see 3,316)
2- (1- Methylpropyl)-cyclohexanone (see 3,261)
3. .'1 08

Methyl propyl trisulfide

2.0

2.0

2.0

Cereals10.

.1.3092-Methylpyrazine
Methyl 2-pyridyl ketone (see 3,251)

10.

10.

10.

3.310

Methyl thiobutyrate

Protein Foods
5.0

0.06

3.311

Methyl thiofuroate

3.0

3.0

Frozen Pie
4.0.'1.312

4. 0

3-Methylthiopropyl isothiocyanate
Methyl tri•ulfide (see 3,275)
2-(1-Methylvinyi)pyrazine (see 3,296)
3..1/34-Methyl-5-vinylthiazole

2. 0.1..114

2.0

2-Naphthalenthiol
2-Naphthyl mercaptan (see 3,314)

8.0

8. 0

6. 0

Cereal•
0.5

0.5

0.5

3.315

2-Nonanol
Pectin sugar (see 3,255)

80.

15.

3.316

2-Pentanol

2.0

2.0

2.0

2.0

2. 0

3.317

2-Pentyl furan

3. 0

3. 0

3.0

3. 0

3. 0

1.0

1.0

1.0

1.0

1.0

50.

50.

50.

3.318

3-Phenyl-4-pentenal
3 ..119

L- Proline
Propionic acid, triglyceride (see 3,286)
Propyl methyl trisulfide (see 3,308)
Propyl trisulfide (see 3,276)
Pyrazinemethanethiol (see 3,299)
2-Pyrrolidinecarboxylic acid (see-3,319)
Sodium •uccinate (see 3,277)
Succinic acid, disodium salt (see 3,277)

50.

50.

Dips, Spreads
12.
Cereals
2.0
Cereals
3.0
Cereals
1.0
Cereal•

50.

3.320

Tetrahydrofurfuryl cinnamate.1.•121

5,6, 7 ,8-Tetrahydroquinoxaline
3-Tetrahydrothiophenone (see 3,266)
3,3' -Tetrathio-bis (2-methylfuran) (see 3,260)
3,322

Thiamine hydrochloride

20.

20.

20.
5.0

5.0

5.0

50.

50.

.1.3230.15

2-Thienyl disulfide
Thioacetic acid, ethyl ester (see 3,282)
Thiobutyric acid, methyl ester (see 3,310)
Thiofuroic acid, methyl ester (see 3,311)
2-Thionaphthol (see 3,314)
3-Thiophenone (see 3,266)

2.0

2.0

50.
0.1 5

1.0

50.

2.0

50.
0.15

3,324

30.

3,5,5-Trimethyl-1-hexanol

30.

3,325

2,4,5-Trimethylthiazol ..
Tripropionin (see 3,2&>)..1-Unclecalactone (see 3,294)/J· Vinylhydrocinnamaldehyde (see 3,318)
Vitamin B, (see 3,322)

2.0

2.0

6.0

6.0

Cereal•2.0

Cerealo50.

Cereals
0.15

text

I cont. from p. 36
GRAS Substances

.

.

.

.

of usage of flavoring substances by the food industry
was conducted by the Flavor and Extract Manufac­
turers Association. The accumulated data from thissurvey were considered in relation to certain arbitrary
daily consumption levels of the various categories offlavored food in arriving at the FEMA lists of GRAS
flavoring substances published in 1960 and 1965.
GRAS LIST REVIEWS& POSSIBLE REVISIONS

Recognizing that the patterns of use of flavoring
substances may change in both kind and degree, the
FEMA undertook to repeat and extend the survey.
It is currently underway (1972), concomitantly withthe survey of GRAS food substances by the National
Academy of Sciences-National Research Council un­
der contract with the Food and Drug Administration.
Data from both of these surveys will be computer­
ized and analyzed for the purpose of reviewing andpossibly revising the status of substances listed therein.
In this connection it should be recognized that the
FEMA survey will cover all adjuncts and flavoring
ingredients used in foods, including those originaily
published in the FEMA GRAS list which were subse­
quently incorporated by the Food and Drug Adminis­
tration into Food Additive Regulations for natural andsynthetic flavoring substances ( 10).
REFERENCES(1) Hornstein, I. and Teranishi, R. 1967. The chemistry of flavor.
Chern. and Eng. News. 45: 92.
1970. Constituents of citrus oils. Deutsch. Lebensm.
Rundschau 66: 290.
(3) Macleod, A.J. 1970. Flavor volatiles from some cooked vegetables.
J. Food Sci. 35: 734.
(4) Johnson, A.E., Nursten, H.E., and Williams, A.A. 1971. Fruitaromas. A survey of component identification. Part 2. Chem.
and Indy. 556-565.
(5) Downey, W.J. and Eiserle, R.J. 1971. Critical Reviews in Food
(2) Ziegler, V.E.

Technology. A Review ol the Literature Concerned with Flavor
Research as it Applies to the Problem of the Flavor Industry.
July 159.
(6) Hall, R.L. 1960. Recent progress in the consideration of flavoring
ingredients under the Food Additives Amendment. Food Techno!.
14: 1.
(7) Hall, R.L. and Oser, B.L. 1961. Recent progress in the consider­ation of flavoring ingredients under the Food Additives Amend­
ment. 2. Food Techno!. 15: 1.
(8) Hall, R.L. and Oser, B.L. 1965. Recent progress in the consid­
eration of flavoring ingredients under the Food Additives Amend­
ment. 3. GRAS Sl!bstances. Food Techno!. 19: 151.
(9) Hall, R.L. and Oser, B.L. 1970. Recent progress in the consider­ation of flavoring ingredients under the Food Additives Amend­
ment. 4. GRAS substances. Food Techno!. 24: 25.
(10) Code of Federal Regulations Title 21. Part 121. Sections 1163 and1164. Superintendent of Documents. Washington, D.C. 20402.
(11) Hall, R.L. and Oser, B.L.
1968. The safety of flavoring sub­stances. Residue Reviews 24: 1.
(12) Evaluating the Safety ol Food Chemicals. 1970. Appendix: Guide­lines for estimating toxicologically insignificant levels of chemicals
in food. National Academy of Sciences. Washington, D.C.
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The authors acknowledge the valuable technical assistance of Dr.
Richard A. Ford, Assistant Prolessor ol Chemistry, Catholic University,
Washington, D. C. in reviewing the chemical data presented in thisreport and that of Mona Oser in preparation of !he manuscript.