GALLATES (PROPYL, OCTYL AND DODECYL)
First draft prepared by
Dr G.J.A. Speijers and Mrs M.E. van Apeldoorn
National Institute of Public Health and Environmental Protection
Laboratory for Toxicology
Bilthoven, The Netherlands
1. EXPLANATION
Propyl, octyl and dodecyl gallates have been evaluated for
acceptable daily intake at the third, sixth, eighth, tenth, fifteenth,
sixteenth, seventeenth, twentieth, twenty-fourth, and thirtieth
meetings of the Committee (Annex 1, references 3, 6, 8, 13, 26, 30,
32, 41, 53 and 73). At the twenty-fourth meeting a group ADI of 0-0.2
mg/kg bw was established, based on the supposed similarity in the
biotransformation of these compounds. The Committee used a higher
than normal safety factor (250) because of concern for adverse effects
shown in reproduction studies. The gallates were again reviewed by
the Committee at its thirtieth meeting. Due to lack of adequate data,
an ADI was not established for octyl or dodecyl gallate, and more
information on the hydrolysis and the biotransformation (including
lactating animals) of the different gallates was required. For propyl
gallate an ADI of 0-2.5 mg/kg bw was established.
Since the last evaluation, additional data have become available.
These new data included four-week and 90-day toxicity studies in rats
with propyl gallate and in vitro studies on the hydrolysis of the
gallates in different tissues. These data are summarized and
discussed in this monograph, which also includes all data from
previously published monographs. Because this monograph covers the
data on propyl, octyl and dodecyl gallates separately, a modified form
of the general monograph format has been used.
PROPYL GALLATE
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion.
No information available.
2.1.2 Biotransformation
The available evidence indicates that the gallate esters are
hydrolyzed in the body to gallic acid. Most of the gallic acid is
converted into 4-0-methyl gallic acid. Free gallic acid or a
conjugated derivative of 4-0-methyl gallic acid is excreted in the
urine. Conjugation of the 4-0-methyl gallic acid with glucuronic acid
was demonstrated (Booth et al., 1959).
Detailed metabolic pathways for propyl gallate have been
described (Dacre, 1960).
In vitro incubations with propyl, octyl and dodecyl gallate
were performed using homogenates of liver, mucosa of the small
intestine, and contents of caecum/colon as a source of intestinal
microflora. The various homogenates were incubated at 37° C with the
individual gallate esters. At various time points up to 24 hours,
samples were taken and analysed by HPLC in order to determine the
concentration of gallic acid and residual ester. From the time-course
of gallic acid formation, as well as the disappearance of the specific
esters, the rate of hydrolysis of the three esters was calculated.
All test substances were extensively metabolized by the
homogenate of the intestinal mucosa, which was demonstrated by the
appearance of peaks in the chromatograms. Furthermore, the caecum and
colon contents also showed a high metabolic capacity, especially
towards propyl gallate. The amount of gallic acid detected in the
incubations was always much smaller than the total decrease of the
amount of ester. It seems likely that apart from hydrolysis of the
ester bond, other biotransformation routes (oxidation and/or
conjugation) are of major importance for all three gallate esters.
The three homogenates show quantitatively different structure-
activity relationships for the three esters. Homogenates of liver and
of contents of caecum and colon metabolize propyl gallate most
extensively, followed by octyl or dodecyl gallate. Homogenate of the
mucosa of the small intestine shows the highest rates with octyl
gallate, lower rates with dodecyl gallate and propyl gallate. For
this homogenate, the rate of formation of gallic acid is inversely
related to the chain length of the ester (de Bie & van Ommen, 1992).
2.1.3 Effects on enzymes and other biochemical parameters
Propyl gallate inhibited liver mixed function oxidase (MFO) and
demethylase activity when added at concentrations of 50 to 500 µM to
liver microsomal preparations obtained from male Sprague-Dawley rats.
Specifically, the compound inhibited benzpyrene hydroxylase activity
and demethylase activity with ethyl morphine, aminopyrene or
benzphetamine as substrate. No induction of MFO activity was noted
when propyl gallate was injected intraperitoneally at 300 mg/kg bw 24
hours prior to sacrifice and assay. The microsomes from the treated
animals had lower demethylase activity, probably as a result of
inhibitory amounts of the compound attached to the microsomes (Yang
and Strickhart, 1974).
Weanling female Sprague-Dawley rats were fed high polyunsaturated
fat, high saturated fat or low fat diets for one month, with or
without the addition of 0.3% propyl gallate. Propyl gallate caused no
measurable difference in body weights, relative liver weight or liver
microsomal protein values. Liver enzyme activity of aniline
hydroxylase, aminopyrene N-demethylase and cytochrome-C-reductase were
not affected by treatment, nor was the liver concentration of
cytochrome P-450 and microsomal protein. Rats dosed with BHT at 0.3%
of the diet exhibited liver hypertrophy and induction of cytochrome P-
450 microsomal protein and liver enzymes (King and McCay, 1981).
Addition of 25 or 125 µmol of propyl gallate to an MFO assay
system prepared from the tissues of male Sprague-Dawley rats (liver,
kidneys, stomach, colon and small intestine) inhibited the oxidation
of benzo (a)pyrene (Rahimtula et al., 1979).
Addition of 50 µmol of propyl gallate to a rat testis microsomal
preparation in the presence of arachidonate stimulated the formation
of prostaglandins PGF2. Addition of 0.1 mmol vitamin E instead of
propyl gallate did not result in increased production of any of the
prostaglandins. Addition of propyl gallate to similar preparations
from vitamin E-deficient rats resulted in an increase in production of
PGF2 only. In the female rat both dietary lipid and dietary propyl
gallate affect prostaglandin synthesis by mammary gland preparations.
These effects are concentration-dependent effects with stimulation of
synthesis of some prostaglandins at one level of propyl gallate and
inhibition at higher levels. The effect of propyl gallate is also
dependent upon the type of fat in the rat diet. Propyl gallate
stimulates formation of prostglandin PGF2 in mammary gland from rats
fed polyunsaturated fats, but inhibits PGF2 synthesis in rats fed a
saturated fat diet. Stimulation of synthesis of different
prostaglandins may occur in preparations to which propyl gallate was
added exogenously as compared to a dietary source of the compound.
Changes in levels of PGF2 have been correlated with the
susceptibility of rats to mammary tumours induced by 7,12-dimethyl-
benzo (a)anthracene (Carpenter, 1981).
Effects of propyl gallate on glutathione-S-transferase are
described in discussion of the short-term toxicity study (Speijers et
al., 1993).
2.2 Toxicological studies
2.2.1 Acute toxicity studies
The results of acute toxicity studies with propyl gallate are
summarized in Table 1.
Table 1. Acute toxicity studies - propyl gallate
Animal Route LD50 (mg/kg bw) Reference
Mouse oral 2 - 3 000 Lehman et al., 1951
Rat oral 3 800 Orten et al., 1948
Rat oral 3 600 Lehman et al., 1951
Rat i.p. 380 Orten et al., 1948
2.2.2 Short-term toxicity studies
2.2.2.1 Rats
Levels of propyl gallate of 1.2% and 2.3% in the diet of rats
caused a decreased weight gain, the bitter taste of the gallate
apparently making the diet unpalatable. The high dose level caused
some deaths (about 40%) during the first month; the survivors
continued to eat the diet for 10 - 16 months and showed retarded
growth, but no pathological lesions. The animals that died exhibited
renal damage (Orten et al., 1948).
Weanling rats were fed diets which contained 20% lard and 0, 0.1,
0.2, 0.3, 0.4 and 0.5% propyl gallate for six weeks. There was no
effect on body weight, liver weight, liver weight to body weight
ratio, left adrenal weight, total liver lipid, composition of liver
polyunsaturated fatty acids, liver cholesterol, adrenal cholesterol or
serum sodium (Johnson and Hewgill, 1961).
Propyl gallate was added to the dietary fat of weanling rats at
levels of 0.02% in the fat for 13 weeks. The fat content of the diet
provided 30% of its caloric value. There was a very slight inhibition
of growth. The same rats were then placed on a partial
starvation diet and kept until they died. The survival time of the
animals which had received the propyl gallate was considerably reduced
and the reduction in their total body protein was greater than control
rats (Bukhan, 1962).
Weight gain depression of more than 10% was observed in male rats
receiving diets containing 12 500 or 25 000 and in females receiving
25 000 mg propyl gallate/kg feed. Dirty tails, indicating
gastrointestinal disturbance, were noted in both sexes at 25 000 mg
propyl gallate/kg feed. In the 25 000 mg/kg feed groups, reddish
duodenal mucosa was reported in both sexes, in addition to thickening
of the stomach wall with necrosis and ulceration of the mucosal
surface of the stomach, and moderate to severe granulomatous
inflammatory response in the submucosa and muscular wall of the
stomach. No stomach nor duodenal lesions were noted in either sex at
6 000 or 12 500 mg/kg feed (Abdo et al., 1983).
A 4-week oral toxicity study with propyl gallate was performed in
rats (6 animals/group/sex) at dose levels of 0, 1 000, 5 000 and 25
000 mg/kg feed. Parameters studied comprised growth, food and water
intake, biochemistry, haematology, organ weights and histopathology.
In the high-dose group both females and males gained less weight
than those in the control group. Haemoglobin concentration, packed
cell volume, red blood cell concentration, mean corpuscular volume and
mean corpuscular haemoglobin were lowered in the high-dose group.
Consistent with the anaemia, an increased extramedullary
haematopoiesis and slightly decreased haemosiderosis were noted in the
spleen. In kidneys hyperplastic tubuli in the outer medulla were
detected. In the liver of the animals of the 5 000 and 25 000 mg/kg
feed groups increases in activity of aminopyrine-N-demethylase and
glucuronyl-transferase and glutathione-s-transferase and an increase
in cytochrome P-450 content were detected (Strik et al., 1986).
A toxicity study with propyl gallate in SPF-derived Wistar
RIVM:Tox rats (10 animals/group/sex) was performed in which they were
fed a semisynthetic diet containing 0, 490, 1 910 or 7 455 mg propyl
gallate/kg feed for 13 weeks. Body-weight gain was recorded weekly
and food-intake twice weekly. Other parameters included haematology,
biochemical analyses in urine, serum and liver and complete
histopathological examinations.
Adverse effects of propyl gallate observed in the high-dose group
were effects on the haematopoietic system reflected in the
haematological parameters (Hb, Hct and RBC) and the morphological
changes (extramedullary haematopoiesis) in the spleen. The other
effects of propyl gallate comprised a decreased incidence of
nephrocalcinosis normally seen in female rats on semisynthetic diet,
an increased activity of ethoxy-resorufin-o-deethylase (EROD) in the
high-dose group and an increased activity of the conjugating enzymes
glucuronyl-transferase and glutathion-s-transferase, in the mid and
high-dose groups receiving propyl gallate. The effects on the liver
enzymes suggest that other biotransformation routes additional to
hydrolysis of the gallate seem to be involved. The effects on
nephrocalcinosis and on the conjugating enzymes were not considered
adverse. Therefore the NOAEL was 1 910 mg propyl gallate/kg feed,
equal to 135 mg propyl gallate/kg bw day (Speijers et al., 1993).
2.2.2.2 Guinea-pigs
Propyl gallate fed to guinea-pigs in groups of 20 at a level of
0.02% in the diet for 14 months caused no observed ill effects (Orten
et al., 1948).
2.2.2.3 Dogs
A level of 0.01% propyl gallate in the diet was well tolerated by
a group of seven dogs over a period of 14 months (Orten et al.,
1948).
2.2.2.4 Pigs
Diets containing 0.2% propyl gallate were fed to pigs without
observed ill effect; no anaemia was observed (van Esch, 1955).
2.2.3 Long-term toxicity/carcinogenicity studies
2.2.3.1 Mice
Groups of 50 mice (University Animal Breeding Station closed
strain colony) equally divided by sex were maintained on diets
containing 0, 0.25 or 1.0% n-propyl gallate for a period of 21 months.
Water intake, food consumption and growth of test animals were
comparable to controls. Treated male mice showed a greater percentage
survival than control mice at termination. Haematologic measurements
(haemoglobin, packed cell volume, differential white cell count) were
similar for test and control animals. At autopsy, a comparison of
relative organ/body weight showed a reduction in the relative spleen
weight of males on the 1% diet. No compound-related histopathological
changes were observed (Dacre, 1974).
Abdo and coworkers maintained groups of B6C3F1 mice of each sex
on diets containing 0, 6 000 or 12 000 mg propyl gallate/kg feed for
105 - 107 weeks. Lower body weights compared to controls were
observed throughout most of the duration of the study in both sexes
and both dose groups. At week 104, mean body weights of the male mice
were 6% and 8% lower than controls in the high- and low-dose groups
respectively. In the females, both dose groups had about a 12% lower
body weight than the controls at week 104. Feed consumption in low
and high-dose males was 91 and 100%,
respectively, of that of controls while the corresponding figures for
females were 109 and 106%, respectively. No other compound-related
clinical signs were observed. There was no significant effect of
treatment on survival. The survival rate averaged 80% in males and
75% in females. Tumour incidences of the haematopoietic system and
liver in the treated groups showed significant increases, as shown in
Table 2. Tumours at other sites were not significantly different from
controls.
There was a significant positive trend in the incidence of
histiocytic lymphoma in male mice (8%) relative to controls. The
historical control rate for histiocytic lymphomas was 3.3% (21/640).
There was a significant positive trend in the incidence of all
malignant lymphomas in male mice (1/3/8), and significantly increased
incidence by a direct comparison between high-dose and control (p<
0.028). However the high dose incidence was not statistically
significant when compared to the historical control rate at the
performing laboratory for all malignant lymphomas of
9.4 (60/640). In females the highest incidence was noted in the
control group.
The number of male rats in which hepatic adenomas or carcinomas
occurred showed a significant negative trend. Hepatocellullar
adenomas in female mice occurred with a positive trend (p < 0.022)
and the incidence of adenoma in the high-dose females is significantly
greater than in controls (p < 0.039). However the incidence in the
high-dose group was not different from the historical incidence of
this tumour (94/3127; 3%). Further, the combined incidence of
hepatocellular adenomas or carcinomas was similar in dosed and control
groups (Abdo et al., 1983).
A level of 5% propyl gallate in the diet in a two-year chronic
toxicity study in rats and mice gave rise to patchy hyperplasia in the
proventiculus. At a level of 1%, no difference was noted between test
and control animals (Lehman et al., 1951).
2.2.3.2 Rats
Groups of 10 male and 10 female rats were fed for two years on
diets containing 0, 0.001, 0.01, 0.12, 1.2 or 2.3% propyl gallate.
The groups receiving 1.17 and 2.34% propyl gallate showed stunted
growth and evidence of renal damage. In the other groups, there was
no detectable effect on haemoglobin, erythrocyte or leucocyte levels
in the blood, nor on the histopathological appearance of the organs
examined (Orten et al., 1948).
Table 2: Tumour incidence in treated mice, sites with significant increases
Incidence
Males Females
Group - 50 animals/group C L H C L H
Site Lesion
Haematopoietic Malignant lymphoma:
system
Histiocytic 0 0 4 2 0 0
Mixed 0 1 3 4 1 3
Lymphocytic 1 2 0 2 1 3
Not Otherwise Specified 0 0 1 0 1 0
All 1 3 8 8 3 6
Liver Adenoma 3 4 1 0 2 5
Carcinoma 14 11 9 3 1 0
Both 17 15 10 3 3 5
C: control group, L: low dose, H: high dose.
Abdo and coworkers fed groups of 50 F-344 rats of each sex diets
containing 0, 6 000 or 12 000 mg propyl gallate for 105 - 107 weeks,
as shown in Table 3. Throughout the study, there was a dose-related
depression in body weights at both dose levels and in both sexes.
Mean feed consumption was 94% and 98% of the controls in the low and
high-dose males, while the corresponding values for females were 95
and 115% respectively. In males 78% of the controls, 76% of the low-
dose and 88% of the high-dose group lived to the end of the study. In
females the corresponding values were 78%, 76% and 84% respectively.
No treatment-related clinical signs were observed. There were no
significant differences in survival between the groups. For males the
survival was 78%, 76% and 88%, for control, low, and high-dose groups,
respectively, and the corresponding values for female rats were 78%,
76% and 84%.
As shown in Table 3, in male rats the incidence of three types of
neoplasms was increased in the low-dose treatment compared to the
control group, namely, phaechromocytoma of the adrenal medulla, islet
cell neoplasms of the pancreas and neoplasm of preputial gland origin.
Equal or greater increases were not observed in the high-dose male
groups. The occurrence of these tumours was not considered to be
treatment related. The combined incidence of male rats with
follicular cell adenomas or carcinomas of the thyroid was significant
(p< 0.05) by the trend test, but the high-dose incidence was not
statistically different in any tests in direct comparison with the
control. In the high-dose females there were 3 mammary adenomas while
there were none in the other two groups. The trend test was
statistically significant but the incidence in the high-dose group was
not significantly higher than control. There was an increase in the
incidence of females with endometrial stromal polyps of the uterus
with a marginally significant trend. The high-dose incidence falls
within the overall historical control range (4-36%).
Tumours of the brain (an astrocytoma and a glioma) were found in
two low-dose female rats. None of the high-dose female rats showed
this tumour. The incidence of these tumours in the brain of the low-
dose females was not considered to be related to propyl gallate, since
none of the high-dose females had this tumour (Abdo et al., 1983).
Table 3: Tumour incidence at sites with significant variation in rats fed propyl gallate
Incidence
males females
Group C L H C L H
Total Animals 50 50 50 50 50 50
Site Lesion
Pancreas Islet cell:
Adenomas 0 8 2 0 0 0
Carcinomas 2 1 2
Both 2 9 4
Thyroid Follicular cell:
carcinoma 0 0 2 0 0 0
adenoma 0 0 1 0 0 0
Adrenal Gland Phaeochromocytoma 4 12 8 4 1 3
Preputial gland Adenoma or carcinoma 1 8 0 2 1 3
Mammary gland Adenoma 0 0 0 0 0 3
Mammary gland Fibroadenoma 2 0 1 11 2 5
Table 3 (contd)
Incidence
males females
Group C L H C L H
Uterus Endometrial stromal 6 8 3
polyp
Brain Astrocytoma 0 0 0 0 0 3
Brain Glioma 0 0 0 0 1 0
Haematopoietic Leukaemia or lymphoma 16 8 6 8 5 6
system
C: control, L: low dose, H: high dose
2.2.4 Reproduction studies
Propyl gallate was fed to rats at concentrations of 0.035, 0.2 or
0.5% in the diet for two successive generations. Neither effects on
reproduction performance nor on indices of reproduction were reported.
No abnormalities were observed in the organs or tissues of the rats at
autopsy (van Esch, 1955).
2.2.5 Special studies on genotoxicity
Propyl gallate was investigated in vitro at concentrations of
0.5, 5.0 and 50 µg/ml employing WI-38 human embryonic lung cells for
anaphase abnormalities. It was also investigated in vivo by the
cytogenetic analysis of metaphase cells from the bone marrow of rats
(Sprague-Dawley C-D strain). The dosages employed were 5.0, 50.0 and
500 mg/kg bw. Propyl gallate was mutagenic in neither assay.
The genotoxic effect of propyl gallate was studied using
Salmonella typhimurium strains TA-1530 and G-46 and Saccharomyces
D-3 in presence or absence of metabolic activation. A 0.25%
concentration was tested. Propyl gallate was non-mutagenic in all
tests.
In a host-mediated assay, propyl gallate was tested at dose
levels equivalent to 5, 50, 500 and 2 000 mg/kg bw in ICR Swiss mice
employing, as indicator organisms, Salmonella G-46 and TA-1530 and
Saccharomyces D-3. Propyl gallate was non-mutagenic under the
conditions of the test.
In a dominant lethal test, Sprague-Dawley CD strain male rats
were dosed at 5, 50 and 500 mg/kg bw. In an acute study, a single
dose was administered with subsequent mating for each of eight weeks.
Propyl gallate did not produce any significant dominant lethality. In
a subacute study, five daily doses were administered (5 x 5, 5 x 50,
5 x 500 and 5 x 5 000 mg/kg bw). Males were subsequently mated for
each of seven weeks. No dominant lethal effects were noted (Weir and
Brusick, 1974).
2.2.6 Special studies of the effect of propyl gallate on the
forestomach
Propyl gallate incorporated into the diet (0.52 and 2%) and fed
to male F-344 rats, for 9 days neither affected the morphological
appearance of the forestomach squamous epithelium nor induced changes
in the (methyl-3H) thymidine labelling index in the fundic region of
the forestomach (Nera et al., 1984).
2.2.7 Special studies on the effect of propyl gallate on toxicity
of chemical agents
2.2.7.1 Teratogenesis
Pregnant New Zealand white rabbits (on gestation day 12) were
injected s.c. with propyl gallate (362 - 900 mg/kg bw) and
hydroxyurea (600 - 750 mg/kg bw). The materials were injected either
simultaneously or mixed over periods of 45 minutes. The extent of
amelioration of the teratogenic effects of hydroxyurea was dependent
on the dose of propyl gallate. There was a significant linear
decrease in both resorptions and specific malformations with
increasing doses of propyl gallate (de Sesso, 1981).
2.2.7.2 Genotoxicity
Propyl gallate inhibited the genotoxicity of benzo( a)pyrene for
Salmonella typhimurium (Strain TA 98), and moderately increased the
mutagenicity of aflatoxin B1 for Salmonella typhimurium TA 100 and
TA 98 (Calle and Sullivan, 1982).
Four-week old random-bred ICR Swiss male mice were fed diets
containing 0, 10, 100, 1 000 or 5 000 mg propyl gallate/kg feed for 3
months. They were exposed to 50 or 125 rad of whole gamma radiation
from a 137Cs source. Thirty hours after irradiation, animals were
scored for micronuclei in polychromatic bone marrow erythrocytes. As
compared to controls not given propyl gallate, the propyl gallate-
treated animals had an increased incidence of micronuclei of about 1.6
- 2-fold. However, there was no dose dependence, 10 mg/kg of propyl
gallate was as effective in producing radio-sensitization as 5 000
mg/kg feed (Kamra and Bhaskar, 1978).
Propyl gallate itself was not mutagenic towards Salmonella
typhimurium strains TA 98 and TA 100 in the presence or absence of
arochlor-induced rat liver homogenates. Treatment of bacteria
(evidently without activation) with propyl gallate and N-acetoxy-AAF
or N-methyl-N-nitrosoguanidine (MNNG) resulted in a reduction of
mutation rate compared to that observed in the presence of N-acetoxy-
AAF or MNNG alone. By contrast, mixtures of propyl gallates and 4-
nitroquinoline oxide (4NQO) or N-hydroxy-AAF showed increased
mutagenicity as compared to that observed with the compounds in the
absence of the propyl gallate. The proceeding studies were all done
using Salmonella strain TA 100, except that the propyl gallate-4NQO
mixture was tested with both Salmonella strains TA 100 and TA 98.
Propyl gallate was more efficient at enhancing mutagenesis for
Salmonella TA 100 than TA 98. A propyl gallate-aflatoxin B1
mixture was also tested using liver activation from arochlor-treated
rats; the addition of propyl gallate substantially reduced the
mutagenic activity of aflatoxin B1 (Rosin and Stich, 1980).
Propyl gallate was not mutagenic to Salmonella strains TA-98 or
TA-100 with or without activation by liver extracts from arochlor-
induced rats. In contrast to the results reported above these workers
observed a small increase in aflatoxin B1 mutagenesis in TA 100 in
the presence of propyl gallate (Shelef and Chin, 1980).
2.2.8 Special studies on the effects of propyl gallate on the
carcinogenic activity of carcinogens
Lung adenomas were induced in strain A mice by chronic treatment
with nitrite in drinking water and morpholine in food. Addition of
gallic acid to the diet resulted in an 86% inhibition of adenoma
induction. Dietary gallic acid reduced or did not affect the
induction of adenomas by mononitrosopiperazine or nitrosomorpholine
given in drinking water, and failed to induce lung adenomas when given
alone (Mirvish et al., 1975).
Weanling (21 day old) female Sprague-Dawley rats were fed with
one of three basal diets: polyunsaturated fat (20% corn oil, HPF);
saturated fat (18% coconut oil and 2% linoleic acid, HSF); or low fat
(2% linoleic acid, LF), with and without 0.3% propyl gallate (PG). At
50 days of age , one half of each group (30 rats/group) received 10 mg
of DMBA in 1 ml corn oil p.o. as a tumour inducer. Both the amount of
fat and the degree of unsaturation were found to affect the extent of
protection against tumorigenesis afforded by PG, with some protection
seen in all three dietary groups. Tumour incidences at 32 weeks of
age were: HPF, 100%; HSF, 63%; LF, 29%; HPF+PG, 77%; HSF+PG, 11%.
Tumours grew most rapidly in the HPF group. Propyl gallate did not
alter the function of the hepatic mixed oxidase system by induction or
inhibition under the dietary conditions used (King and McCay, 1980).
The induction of epidermal ornithine decarboxylase by 12-0-
tetradecanoylphorbyl-13 acetate in mouse epidemis was inhibited by the
topical application of propyl gallate. Its potency was approximately
10% of that of BHA (Kozumbo, Seed and Kensler, 1983).
Propyl gallate did not modify tumour development of
1,2-dimethylhydrazine-initiated colon carcinogenesis in F344 rats
(Shirai et al., 1985).
The promoting activity of 3 antioxidants, alpha-tocopherol,
propyl gallate and tertiary butylhydroquinone (TBHQ) in urinary
bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)
nitrosamine (BBN) in male Fischer 344 rats was examined. Rats, 6
weeks old, were treated with 0.05% BBN in the drinking water for 4
weeks and then administered 1.50, 0.75 or 0.38% alpha-tocopherol, 1.0%
propyl gallate or 2.0% TBHQ in the diet for 32 weeks. The urinary
bladder of each animal was examined histologically after the 36-week
experimental period. The incidence of papillary or nodular
hyperplasia (PN hyperplasia) of the urinary bladder was
significantly higher in the rats treated with BBN followed by 2.0%
TBHQ than in controls initiated with 0.05% BBN followed by control
diet. This result indicates that TBHQ has weak promoting activity in
urinary bladder carcinogenesis. alpha-tocopherol and propyl gallate
did not demonstrate a promoting effect for urinary bladder lesions
(Tamano et al., 1987).
2.2.9 Special studies on the interactions of propyl gallate
Propyl gallate, gallic acid and nordihydroguaiaretic acid were
all potent inhibitors of the in vitro mouse spleen cell antibody
response as assayed by anti-sheep erythrocyte plaque-forming cell
response. These compounds also suppressed clone formation in vitro
by human WISH or mouse L-cells (Blalock et al., 1981).
Gallic acid was reported to suppress the in vitro thymus-
dependent plaque forming response of mouse C57B1/6 spleen cells to
sheep red blood cells. The compound also suppressed mitogen-induced
DNA synthesis of 6 lymphocytes but had no effect on ß-lymphocyte
function (Archer et al., 1977).
2.2.10 Special studies on sensitization
Gallates have been shown to cause contact dermatitis in bakers
and other workers handling gallates. Patch tests with lauryl gallate
at 0.2% showed a weak positive response in one sensitized individual.
Other individuals have suffered recurring episods of dermatitis,
presumably caused by gallates in food products (Brun, 1970).
2.2.11 Other special studies
Partial protection against liver damage by single oral doses of
2.5 or 0.25 ml/kg of chloroform was provided by i.p. injection of 150
mg/kg bw of propyl gallate (Torrielli and Ugazio, 1975).
2.3 Observations in humans
No information available.
OCTYL GALLATE
2. BIOLOGICAL DATA
2.1 Biochemical aspects
See propyl gallate.
2.2 Toxicological studies
2.2.1 Acute toxicity studies
The results of acute toxicity studies with octyl gallate are
summarized in Table 4.
Table 4. Acute toxicity studies - octyl gallate
Animal Sex Route LD50 mg/kg bw Reference
Rat ? oral 4 700 van Sluis, 1951
Rat ? i.p. 60-80 van Esch, 1955
Rat M oral 2 710 Brun, 1970
Rat F oral 1 960 Brun, 1970
Rat M oral 2 710 Brun, 1970
Rat F oral 2 330 Brun, 1970
2.2.2 Short-term toxicity studies
2.2.2.1 Rats
Groups each of 20 rats (equally divided by sex) were maintained
on diets containing 0, 1 000, 2 500 or 5 000 ppm (0%, 0.1%, 0.25% and
0.5%) octyl gallate for 13 weeks. All groups showed normal weight
gains and food consumption. Haematology and blood chemistry and
urinalyses revealed normal values. A complete gross and
histopathologic examination showed no compound-related effects
(Blackmore and Voelker, 1969a).
2.2.2.2 Dogs
Groups of eight dogs, each equally divided by sex, were fed diets
containing 0, 0.1, or 0.3% n-octyl gallate for 90 days, or 1.0% n-
octyl gallate for four weeks; the 1.0% level was then reduced to 0.65%
for the rest of the study. All groups showed normal weight gain and
food consumption, except the 1.0% group. Haematology and blood
chemistry and urinalyses were normal. A complete gross and
histopathologic examination showed no compound-related effects
(Lindberg et al., 1970).
In another study groups of eight dogs, each equally divided by
sex, were maintained on diets containing 0, 0.1, 0.25 or 0.5% octyl
gallate for 13 weeks. All animals showed normal food consumption and
weight gain. Haematology and urinanalyses were similar for test and
control animals. ASAT activity was slightly elevated in the 0.5%
group. Gross and histopathologic examination of tissues and organs
showed no compound-related effects (Blackmore and Voelker, 1969b).
2.2.2.3 Pigs
Diets containing 0.2% octyl gallate were fed to pigs without
demonstrable ill effect; no anaemia was observed (van Esch and van
Genderen, 1955).
2.2.3 Long-term toxicity/carcinogenicity studies
No information available.
2.2.4 Reproduction studies
2.2.4.1 Rats
Young rats in groups of 12 males and 12 females were fed diets
containing 7% fat and 0.2% octyl gallate. There was no significant
difference between test and control animals over three generations
(van Sluis, 1951).
Octyl gallate was fed to rats at concentrations of 0.035, 0.2 and
0.5% in the diet for two successive generations. No effects on
reproductive performance or other indices of reproduction were
reported. A slight hypochromic anaemia was noticed in the 0.2% group.
No abnormalities were observed in organs or tissues of the rats at
autopsy (van Esch, 1955).
Groups, each of 10 male and 20 female rats, were maintained on
diets containing 0, 1 000 or 5 000 mg/kg feed octyl gallate. The
animals were bred twice for the first generation, and three times for
the second generation. At the time of weaning of the F1B
litters in the 5 000 mg/kg feed group, the level was reduced to
2 500 mg/kg feed for the second generation. In the second generation,
approximately 24 hours after birth, selected litters were
redistributed to female parents so that control females nursed pups
from test animals, and test animals nursed pups from control and other
test groups. Half of the P2 females bred for the third time (F2c)
were examined by Caesarean section at time of delivery and the number
of implantation sites, corpora lutea and fetuses determined. One half
of the pups from each litter were examined for skeletal abnormalities,
and the other half for visceral abnormalities. The other parameters
measured in this study were appearance, behaviour, growth of pups
during the nursing and weaning process, fertility index, gestation
index, live birth index, and weaning survival index. Autopsies were
carried out on F2b weanling pups, (control pups suckled by control
dams, experimental group pups suckled by respective group dams), as
well as microscopic examination of pituitary, thyroid, liver, spleen,
kidneys, adrenals, stomach, pancreas, small intestine, large intestine
and any unusual lesions of five males and five females from high-dose
and control group. Weanling survival index and body weight at weaning
were considerably reduced in the 5 000 mg/kg feed group of the F1a and
F1b generation. Reduction of these indices was still apparent in the
F2a and F2b generations, when the dietary level was reduced to 2 500
mg/kg feed. At 1 000 mg/kg feed, the indices were similar to control.
Redistribution of F2b pups to females of control groups resulted
in similar growth of all pups to weaning. Allowing pups from high
level group to be nursed by control dams resulted in a marked increase
in survival indices, whereas when control pups were nursed by high
level dams, there was a marked decrease in survival indices.
Examination of P2 parents following the third breeding indicated a
dose-dependent reduction in implantation sites, as well as a reduction
in number of corpora lutea. The fertility index of high level P2
females was depressed at the F2c stage. Skeletal evaluation of F2c
litters showed incomplete skull ossification in some pups in the test
groups, but this was not considered remarkable for the size of the
fetuses. Necropsy of the pups indicated a higher incidence of gross
kidney alterations than that observed in controls. No compound-
related histopathological effects were reported. The NOEL was 1 000
mg/kg feed/day, equal to 17.5 mg/kg bw/day (Olson and Voelker, 1970).
n-Octyl gallate was fed in the diet to groups of eight male and
16 female rats for two successive generations at levels of 0, 0.1 or
0.3% (and 0.6% for one generation). Rats were mated to produce two
litters per generation with the next generation selected from
weanlings of the second litter. A dietary level of 0.1% had no effect
on reproduction performance or the offspring. At 0.3 and 0.6% dietary
octyl gallate, there was no significant effect on the rat fetuses
during pregnancy, but a marked effect was observed on
survival through weaning. In the case of the 0.6% group, return to
normal diet for six weeks, prior to a third breeding, did not result
in increased survival of offspring through weaning (Plank et al.,
1971).
2.2.5 Special studies on sensitization
Repeated insult patch tests with 0.1% n-octyl gallate solution
showed reaction in 13/445, or 2.9%, of tested individuals. Oral
mucosa irritation/ sensitization tests conducted with beer containing
20 mg/kg n-octyl gallate showed that the incidence and severity of
erythema were greater with beer containing n-octyl gallate than with
untreated beer. Oedema was also greater with treated beer (Palazzolo
& Fancher, 1971a,b,c).
DODECYL GALLATE
2. BIOLOGICAL DATA
2.1 Biochemical aspects
See propyl gallate
2.2 Toxicological studies
2.2.1 Acute toxicity studies
The results of acute toxicity studies with dodecyl gallate are
summarized in Table 5.
Table 5. Acute toxicity studies - dodecyl gallate
Animal Sex Route LD50 mg/kg bw Reference
Rat ? oral 6 500 van Sluis, 1951
Rat ? i.p. 100-120 van Esch, 1955
2.2.2 Short-term toxicity studies
2.2.2.1 Rats
Weanling rats were given diets containing 2.5 or 5% dodecyl
gallate. All animals fed the smaller quantity were dead within 10
days, and all animals fed the larger quantity died within seven days
(Allen & De Eds, 1951).
Male Wistar rats were administered dodecyl gallate daily by
gavage, at doses equivalent to 10, 50 or 250 mg/kg bw/dy for 150 days.
In the 250 mg/kg bw/dy group, numerous deaths occurred. Both the 250
and 50 mg/kg bw/dy dose caused changes in serum lipids and enzymes,
reduction in weight of the spleen and pathological changes in the
liver, kidney, and spleen. The 10 mg/kg bw/dy level was considered to
be the NOEL (Mikhailova et al., 1985).
Rats fed for 70 days on a diet containing 7% fat and 0.2% dodecyl
gallate showed no effect on body weight (Tollenaar, 1957).
2.2.2.2 Pigs
Diets containing 0.2% of dodecyl gallate were fed to pigs without
demonstrable ill effect; no anaemia was observed (van Esch and van
Genderen, 1954).
2.2.3 Long-term toxicity/carcinogenicity studies
No information available.
2.2.4 Reproduction studies
2.2.4.1 Rats
Young rats in groups of 12 males and 12 females were fed diets
containing 7% fat and 0.2% dodecyl gallate. There was no significant
difference between test and control animals over three generations
(van Sluis, 1951).
Dodecyl gallate was fed to rats at concentrations of 0.035, 0.2
or 0.5% in the diet, for two successive generations. There was
significant retardation of growth in the 0.5% group. Some litters in
this group were lost in the second generation because they were not
fed sufficiently by the mothers. A slight hypochromic anaemia was
observed in the 0.2% group. No abnormalities were observed in the
organs or tissues at autopsy (van Esch, 1955).
2.2.5 Special studies on sensitization
See propyl gallate.
3. COMMENTS
Although there are similarities in the metabolism of the
different gallates as evidenced by earlier limited data and a newly
available in vitro metabolism study, the Committee concluded that
there was not enough evidence to allocate a group ADI for the gallates
when in vivo pharmacokinetic and metabolic studies were not
available. In addition, a 150-day gavage study with dodecyl gallate
revealed a NOEL that was 10-fold lower than the dietary NOEL for
propyl gallate.
4. EVALUATION
In the 90-day toxicity study in rats at a high-dose level
(7 450 mg/kg feed), changes in haematological parameters (decreased
haemoglobin, haematocrit and red blood cell count), morphological
changes (increased extra medullary haematopoeisis) in the spleen, and
increased activity of hepatic ethoxy-resorufin-O-deethylase were
observed. The Committee allocated an ADI of 0-1.4 mg propyl
gallate/kg bw, which was based on the NOEL in this study of 1 910 mg
propyl gallate/kg feed, equal to 135 mg propyl gallate/kg bw/day to
which a 100-fold safety factor was applied.
The Committee concluded that it was unlikely that either octyl or
dodecyl gallate is carcinogenic or genotoxic. Therefore, the
Committee allocated temporary ADIs to both gallates based on the NOELs
observed in limited toxicological studies.
With octyl gallate, a slight hypochromic anaemia was observed at
100 mg/kg bw/day in a study in rats in which the substance was
administered for two generations. A temporary ADI of 0-0.1 mg octyl
gallate/kg bw was allocated based on a NOEL of 17.5 mg/kg bw/day in a
reproduction study with rats, to which a safety factor of 200 was
applied.
With dodecyl gallate, a reduction of spleen weight and
pathological changes in the liver, kidney and spleen were observed in
a 150-day gavage study with rats, with a NOEL of 10 mg/kg bw/day. A
temporary ADI of 0-0.05 mg/kg bw was allocated based on this study,
using a 200-fold safety factor.
The Committee concluded that additional information on the
pharmacokinetic and metabolic behaviour of the different gallates may
help to explain the differences in toxicological potency of the
different gallates and required data from such studies by 1996. If
these studies do not satisfactorily resolve the issue with respect to
similarity of octyl and dodecyl gallate to propyl gallate, further
toxicological studies (including long-term toxicity/carcinogenicity
studies and genotoxicity studies) on octyl and dodecyl gallate might
be required.
5. REFERENCES
ABDO, K.M., HUFF, J.E., HASEMAN, J.K., DIETER, M.P., BOORMAN, G.A.,
HILDEBRANDT, P., PREJEAN, J.D. & FARNELL, D.R. (1983), Carcinogenesis
bioassay of propyl gallate in F-344 rats and B6C3F1 mice, J. Am.
College Toxicol., 3(6), 425-33
ALLEN, C.S. & de EDS, F.D. (1951), The chronic toxicity of lauryl
gallate, J. Amer. Oil Chem. Soc., 28, 304
ARCHER, D., BUKOVIC-WESS, J. & SMITH, B. (1977), Suppression of
macrophage-dependent T-lymphocyte function by gallic acid, a food
additive, Proc. Soc. Exp. Bio. Med., 156, 465-9
de BIE, A.Th.H.J, and van OMMEN, B., (1992) Study on the in vitro
biotransformation of propyl, octyl, and dodecyl gallate. TNO-report
V92.101, TNO Toxicology and Nutrition Institute, Zeist, The
Netherlands
BLACKMORE, R.H. & VOELKER, R.W. (1969a), 13-week dietary
administration, Rats, Octyl gallate, Final report (Project No.
458-115), unpublished report from Hazleton Labs., Inc., Falls Church,
VA, USA, F. & M. Schaefer Brewing Co., Brooklyn, N.Y., USA
BLACKMORE, R.H. & VOELKER, R.W. (1969b), 13-week dietary feedings,
Dogs, Octyl gallate, Final report (Project No. 458-117), Unpublished
report from Hazleton Labs., Inc., Falls Church, Va., F. & M. Schaefer
Brewing Co., Brooklyn, N.Y., USA
BLALOCK, J.E., ARCHER, D.L., & JOHNSON, H.M (1981) Anticellular and
immunosuppressive activities of foodborne phenolic compounds (41185),
Proc. Soc. Exp. Bio. Med., 167, 391-3
BOOTH, A.N., MASRI, M.S., ROBBINS, D.J., EMERSON, O.H., JONES, F.T. &
de EDS, F. (1959), The metabolic fate of gallic acid and related
compounds, J. Biol. Chem., 234, 3014-6
BRUN, R. (1970), Contact eczema due to an antioxidant of margarine
(gallate) and change of occupation, Dermatologica, 140, 390-394
BUKHAN, N.D. (1962), The effect of propyl gallate antioxidant on the
nutritional value of fats (In Russian), Vopr. Pitan., 21, 68
CALLE, L.M. & SULLIVAN, P.D. (1982), Screening of antioxidants and
other compounds for antimutagenic properties towards benzo[ a]
pyrene-induced mutagenicity in strain TA98 of Salmonella
typhimurium, Mutat. Res., 101, 99-114
CARPENTER, M. (1981), Antioxidant effects on the prostaglandin
endoperoxide synthetase product profile, Fed. Proc., 40, 189-194
DACRE, J.C. (1960), Metabolic pathways of phenolic antioxidants,
J. N.A. Inst. Chem., 24, 161-171
DACRE, J.C. (1974), Long-term toxicity study of n-propyl gallate in
mice, Fd. Cosmet. Toxicol., 12, 125-9
van ESCH, G.J. (1955), The toxicity of the antioxidants propyl-,
octyl- and dodecyl gallate, Voeding, 16, 683-686
van ESCH, G.J. & van GENDEREN, H. (1954), Netherlands Institute of
Public Health, Report No. 481
van ESCH, G.J. & van GENDEREN, H. (1954), Netherlands Institute of
Public Health, Report No. 2, 49-52
JOHNSON, A.R. & HEWGILL, F.R. (1961), The effect of the antioxidants,
butylated hydroxy anisole, butylated hydroxytoluene and propyl gallate
on growth, liver and serum lipids and serum sodium levels of the rat,
Aust. J. Exp. Biol. Med. Sci., 39, 353-360
KAMRA, O. & BHASKAR, G. (1978), Radiosensitization of mouse
bone-marrow cells by a commonly used food additive, propyl gallate,
Mutation Res., 53, 207
KING, M., MCCAY, P. (1980), DMBA-induced mammary tumour incidence:
Effect of propyl gallate supplementation in purified diets containing
different types and amounts of fat, Proc. Amer. Soc. Cancer Res.,
21, 113
KING, M., MCCAY, P. (1981), Studies on liver microsomes of female rats
fed purified diets varying in fat content with and without propyl
gallate, Fd. Cosmet. Toxicol., 19, 13-17
KOZUMBO, W.J., SEED, J.L. & KENSLER, T.W. (1983), Inhibition by 2(3)-
tert-butyl-4-hydroxyanisole and other antioxidants of epidermal
ornithine decarboxylase activity induced by 12-0-
tetradecanoylphorbolacetate, Cancer Res., 43, 2555-2559
LEHMAN, A.J., FITZHUGH, O.G., NELSON, A.A. & WOODARD, G. (1951), The
pharmacological evaluation of antioxidants, Advanc. Food Res., 3,
197-208
LINDBERG, D.C., KEPLINGER, M.L. & FANCHER, O.E. (1970) Ninety-day
subacute oral toxicity study with Cold-Pro, GA-8 in Beagle dogs (IBT
No. C8472), Unpublished report from Industrial Bio-Test Labs., Inc.,
Northbrook, Ill., USA, submitted to the World Health Organization by
Nutrico, Inc., Milwaukee, Wisconsin, USA
MIKHAILOVA, Z. et al. (1985) Toxicological studies of the long term
effects of the antioxidant dodecyl gallate on albino rats, Vopr.
Pitan., No. 2, 49-52
MIRVISH, S., CARDESS, A., WALLCAVE, L. & SHUBIK, P. (1975), Induction
of lung adenomas by amines or ureas plus nitrite and by n-nitroso
compounds: Effect of ascorbate, gallic acid, thiocyanate and caffeine,
J. Nat. Cancer Inst., 55(3), 633-636
NERA, E.A., LOK, E., IVERSON, F., ORMSBY, E., KARPINSKY, K.F. &
CLAYSON, D.B. (1984), Short-term pathological and proliferative
effects of BHA and other phenolic antioxidants in the forestomach of
Fischer 344 rats, Toxicol., 32, 197-205
OLSON, W.A. & VOELKER, R.W. (1970) Modified two-generation
reproduction study - Rats, Octyl Gallate, Final report (Project
458-116), Unpublished report from Hazleton Labs., Inc., Falls Church,
Va., USA, submitted to the World Health Organization by F. & M.
Schaefer Brewing Co., Brooklyn, N.Y., USA
ORTEN, J.M., KUYPER, A.C. & SMITH, A.H. (1948), Studies on the
toxicity of propyl gallate, Food Techn., 2, 308-316
PALAZZOLO, R.J. & FANCHER, O.E. (1971a) Human repeated insult patch
test with n-octyl gallate (IBT No. F9309), Unpublished report from
Industrial Bio-Test Labs., Inc., Northbrook, Ill., USA, submitted to
the World Health Organization by Nutrico, Inc., Milwaukee, Wisconsin,
USA
PALAZZOLO, R.J. & FANCHER, O.E. (1971c) Oral mucosa
irritation/sensitization test with treated beer (IBT No. F9655),
Unpublished report from Industrial Bio-Test Labs., Inc., Northbrook,
Ill., USA, submitted to the World Health Organization by Nutrico,
Inc., Milwaukee, Wisconsin, USA
PALAZZOLO, R.J. & FANCHER, O.E. (1971b) Oral mucosa
irritation/sensitization test with treated beer (IBT No. F9310),
Unpublished report from Industrial Bio-Test Labs., Inc., Northbrook,
Ill., USA, submitted to the World Health Organization by Nutrico,
Inc., Milwaukee, Wisconsin, USA
PLANK, J.B., WRIGHT, P.L., KEPLINGER, M.L. & FANCHER, O.E. (1971)
Three generation reproduction study with Cold-Pro, GA-8 in albino rats
(IBT No. P84), Unpublished report from Industrial Bio-Test Labs.,
Inc., Northbrook, Ill., USA, submitted to the World Health
Organization by Nutrico, Inc., Milwaukee, Wisconsin, USA
RAHIMTULA, A., ZACHARIAH, P. & O'BRIEN, P. (1979), Differential
effects of antioxidants, steroids and other compounds on
Benzo(A)Pyrene 3-hydroxylase activity in various tissues of rats,
Br. J. Cancer, 40, 105-112
ROSIN, M. & STICH, H. (1980), Enhancing and inhibiting effects of
propyl gallate on carcinogen-induced mutagenesis, J. Environmental
Path. Toxicol., 4, 159-167
de SESSO, J.M. (1981), Amelioration of teratogenesis, I. Modification
of hydroxyurea-induced teratogenesis by the antioxidant propyl
gallate, Teratol., 24, 19-35
SHELEF, L. & CHIN, B. (1980), Effect of phenolic anti-oxidants on the
mutagenicity of aflatoxin B1, Applied Environ. Microbiol., 40,
1039-1043
SHIRAI, T., IKAWA, E., HIROSE, M., et al (1985). Modification by
five antioxidants of 1,2-dimethylhydrazine-initiated colon
carcinogenesis in F344 rats, Carcinogenesis 6:4, 637-9.
van SLUIS, K.J.H (1951), The higher alkyl gallates as antioxidants,
Food Manuf., 26, 99-101
SPEIJERS, G.J.A, JANSSEN, G.B., WALLBRINK-de DRIEU, Y., van LEEUWEN,
F.X.R, van LOENEN, H.A., KRAJNC-FRANKEN, M.A.M., VAESSEN, H.A.M.G &
WESTER, P.W (1993) Subchronic toxicity of propyl-gallate, RIVM Report
No. 618311002 (Draft) Rijksinstituut voor Volksgezondheid en
Milieuhygiëne, Bilthoven, The Netherlands
STRIK, J.J.T.W.A. DANSE, L.H.J.C, HELLEMAN, P.W., van LEEUWEN, F.X.R,
SPEIJERS, G.J.A, & VAESSEN, H.A.M.G (1986). Subacute toxicity of
propyl gallate Report No. 618311 001 Rijksinstituut voor
Volksgezondheid en Milieuhygiëne, Bilthoven, The Netherlands
TAMANO, S., FUKUSHIMA, S., SHIRAI, T., HIROSE, M & ITO, N. (1987).
Modification by O-tocopherol, propyl gallate and tertiary
butylhydroquinone of urinary bladder carcinogenesis in Fischer 344
rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Cancer
Letters, 35, 39 - 46.
TOLLENAAR, F.D. (1957) (Pub. 1963) Prevention of rancidity in edible
oils and fats with special reference to the use of antioxidants,
9th Proc. Pacific Sci. Congr., Bangkok, Thailand, 5, 92-103
TORRIELLI, M. & UGAZIO, G. (1975), Biochemical aspects of the
protective action of propyl gallate on liver injury in rats poisoned
with carbon tetrachloride, Toxicol. Appl. Pharmacol., 34, 151-169
WEIR, R.J. & BRUSICK, D. (1974), Mutagenic evaluation of Compound FDA
71-39, Propyl Gallate, Unpublished report from Litton Bionetics, Inc.,
Kensington, MD, USA, submitted to the World Health Organization by the
US Food and Drug Administration
YANG, C. & STRICKHART, F. (1974), Inhibition of hepatic mixed function
oxidase activity by propyl gallate, Biochem. Pharmacol., 23, 3129-35.