Propyl 3,4,5-trihydroxybenzoate

Basic toxicokinetics

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

Reference

Reference 1

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 2

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 3

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 4

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 5

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 6

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 7

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 8

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 9

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

Test material information

Constituent 1

Reference substance name:

Propyl 3,4,5-trihydroxybenzoate

EC Number:

204-498-2

EC Name:

Propyl 3,4,5-trihydroxybenzoate

Cas Number:

121-79-9

Molecular formula:

C10H12O5

IUPAC Name:

propyl 3,4,5-trihydroxybenzoate

Applicant's summary and conclusion

Conclusions:

Several studies on toxicokinetics of Propyl gallate are available for different species including mice, rats, rabbits, dogs, pigs and humans.

Executive summary:

Several studies on toxicokinetics of Propyl gallate are available for different species.

Mice

A mouse study by Vora et al. (1999) compared the toxicokinetics of Propyl gallate when administered in 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 in 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 in a study by Niimura et al. (1986). Several strains were isolated from the faeces of rats, which converted Propyl gallate to Gallic acid and then further decarboxylated to produce Pyrogallol.

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 interspecies 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).