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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Scientific Opinion on the re-evaluation of propyl gallate (E 310) as a food additive
Author:
European Food Safety Authority (EFSA)
Year:
2014
Bibliographic source:
EFSA Journal 12(4), 3642
Reference Type:
publication
Title:
Influence of dosing vehicles on the preclinical pharmacokinetics of phenolic antioxidants
Author:
Vora J. et al.
Year:
1999
Bibliographic source:
Research Communications in Molecular Pathology Pharmacology, 104, 93-106
Reference Type:
publication
Title:
The metabolic fate of gallic acid and related compounds
Author:
Booth A. N. et al.
Year:
1959
Bibliographic source:
J Biol Chem, 234, 3014-3016
Reference Type:
publication
Title:
Participation of intestinal bacteria in metabolism - metabolism of propyl gallate by the intestinal bacteria in the rat
Author:
Niimura T.
Year:
1986
Bibliographic source:
Journal of the Food Hygienic Society of Japan, 27(2), 163-170
Reference Type:
publication
Title:
Comparative metabolism of BHA, BHT and other phenolic antioxidants and its toxicological relevance
Author:
Conning D. M., Phillips J. C.
Year:
1986
Bibliographic source:
Food and Chemical Toxicology, 24(10-11), 1145-1148
Reference Type:
publication
Title:
Metabolic pathway of phenolic antioxidants
Author:
Dacre J. C.
Year:
1960
Bibliographic source:
Journal of the New Zealand Institute of Chemistry, 24 (1960), p. 161-171
Reference Type:
publication
Title:
Studies on the toxicity of propyl gallate and of antioxidant mixtures containing propyl gallate
Author:
Orten J. M. et al.
Year:
1948
Bibliographic source:
Food Technol. 2:308–316
Reference Type:
review article or handbook
Title:
Food antioxidants: Technological, toxicological Health perspective
Author:
Madhavi D. L. et al.
Year:
1996
Bibliographic source:
New York: Marcel Dekker
Reference Type:
other: Website
Title:
unknown title
Author:
Tullberg
Year:
2004
Bibliographic source:
UK Food Standards Agency. http://www.foodbase.org.uk//admintools/reportdocuments/124-1-200_T01017.pdf (accessed: unknown)

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion

Executive summary:

Several studies on toxicokinetics are available for different species.

Mice

A mouse study by Vora et al. (1999) compared the toxicokinetics of Propyl gallate when administeredin 2 different vehicles: an ethanol:saline solution (2:3, 0.9 % w/v), and a solution of the inclusion complex hydroxypropyl-beta-cyclodextrin (concentration not specified) in saline (0.9 % w/v). No dosing volumes were specified. Harlan Sprague-Dawley mice (4-6 animals/group; 20-30 g bw) were administered 100 mg Propyl gallate/kg bw p.o. and sacrificed in groups at various post-dosing time-points (0-180 minutes) for blood collection and plasma separation. The results suggested that the rate of absorption of Propyl gallate was slower in the ethanol:saline solution. This might be explained by the effects of ethanol on blood flow to the gastrointestinal tract and liver. However, the overall absorption of approximately 5 % was not different between the 2 vehicles. No data on the distribution of Propyl gallate to organs has been identified.

Rats

Adult albino rats were administered 100 mg Propyl gallate per animal by gavage (vehicle not specified) in a study by Booth et al. (1959). The major metabolite detected in urine was 4-O-methyl-gallic acid. Gallic acid, 2- Methoxypyrogallol and glucuronides of the methoxylated products were minor metabolites. This indicates hydrolysis of the ester followed by 4-O-methylation of Gallic acid.

In a study in which rats were given 100 mg Gallic acid per animal either by gavage or by intraperitoneal (i.p.) injection (vehicles not specified) or fed a diet containing 0.5 % (equivalent to 600 mg/kg bw) Gallic acid, urinary excretion of 4-O-methyl gallic acid as well as Gallic acid was reported. In rats given the i.p. injection of Gallic acid, an additional metabolite, suspected to be Pyrogallol, was also detected along with trace levels of 2-O-methyl-pyrogallol.

Metabolism of Propyl gallate by intestinal bacteria in the rat was investigated. Several strains were isolated from the faeces of rats which converted Propyl gallate to Gallic acid which was then decarboxylated to produce pyrogallol in a study by Niimura et al. (1986).

Rabbits

4-O-methyl-gallic acid, and pyrogallol were found in the urine of New Zealand White rabbits (weighing approximately 2 kg) fed 0.5% (equivalent to approximately 150 mg/kg bw/day) Gallic acid in the diet (duration not specified) in a study by Booth et al. (1959).

In rabbits fed 1 g Propyl gallate, the major urinary metabolite was a glucuronide conjugate hypothesised to be 4-O-methyl galloyl-β:D-glucosiduronic acid (72.0 % of the dose administered) and unconjugated phenols: 4-O-methyl gallate, Gallic acid and Pyrogallol (6.7 % of the dose administered) (Dacre, 1960). In rabbits fed Gallic acid for 10 days, most of the dose was excreted in the urine unchanged, although some 4-O-methyl-gallic acid and Pyrogallol were also detected (Conning et al., 1986).

Dogs

No Propyl gallate was detected in the urine of dogs fed 0.0117 % Propyl gallate in the diet for 14 months (Orten et al., 1948).

Pigs

Madhavi (1996) reported that the metabolism of gallic esters in the pig is similar to that in rats.

Rat and human comparison

In a project for the UK Food Standards Agency, Tullberg and colleagues (2004) compared the kinetics of four food additives (BHT, curcumin, propyl gallate and thiabendazole) in vivo in rats and humans and in hepatocytes from human and rat to examine the adequacy of the kinetic uncertainty factors.

The plasma concentration-time curves for Propyl gallate in rats showed rapid absorption and elimination, with significantly higher concentrations in males than in females. The plasma concentrations in humans dosed at the current group ADI (0.5 mg/kg bw) were close to the limit of quantification, whereas more reliable data were obtained at a dose of 10 times the ADI. The kinetics were essentially linear in both rats and humans at the doses studied. The data indicated that the default uncertainty factors for interspecies differences and human variability would be adequate for Propyl gallate. Studies with Octyl gallate and Dodecyl gallate showed the presence of extremely low plasma concentrations, which combined with the low ADI values for these food additives, meant that further in vivo studies were impracticable.

In vitro studies on Propyl gallate using rat and human liver preparations showed that there were minor species differences in the rates of metabolism and in the estimated Vmax and Km values for the BHT, Propyl gallate and TBZ metabolising enzyme systems. The estimated inter-species adjustment factors based on Vmax/Km were 2.4 for Propyl gallate compared with in vivo values of 2.0 for Propyl gallate (at dose-equivalence). The in vitro values do not take into account differences in organ blood flow, and such analyses would require the development of a full PBPK model. Interestingly the Km values for Propyl gallate were considerably higher than the in vivo plasma levels, indicating little likelihood of saturation of metabolism (Tullberg et al, 2004).

Other studies:

Bianchi et al., (1997) described a sensitive HPLC method with electrochemical detection for the measurement of Propyl gallate in mammalian tissues. Tissue specimens of omentum were collected from 50 patients (20 females, mean age 69±4 years and body weight 60±3 kg; 30 males, mean age 59±3 years and body weight 73±3 kg). Forty-two of the 50 omentum samples and 45 plasma samples from a hospital blood bank were analysed for Propyl gallate. Propyl gallate was not detected in the plasma samples but was detected in 30 % (13 out of 42) of the omentum samples.