The Metabolic Fate of Gallic Acid and Related Compounds

Booth, A. N.; Masri, M. S.; Robbins, D. J.; Emerson, Oliver H.; Jones, Francis T.; DeEds, Floyd

doi:10.1016/s0021-9258(18)69715-7

Cited by 116 publications

(19 citation statements)

References 11 publications

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“…Gallic acid, 2methoxypyrogallol and glucuronides of the methoxylated products were minor metabolites (CIR, 2007). This indicates hydrolysis of the ester followed by 4-O-methylation of gallic acid (Booth et al, 1959, as reported in JECFA, 1993.…”

Section: Ratssupporting

confidence: 73%

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Scientific Opinion on the re‐evaluation of propyl gallate (E 310) as a food additive

2014

EFS2

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The Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion reevaluating the safety of propyl gallate (E 310). Propyl gallate is an antioxidant authorised as a food additive in the EU. In 1976, the SCF established a group ADI of 0-0.2 mg/kg bw for three gallates (propyl, octyl, dodecyl). JECFA in its last evaluation in 1996 allocated an ADI only to propyl gallate of 0-1.4 mg/kg bw and did not establish ADIs for octyl and dodecyl gallate. The Panel considered that no substantial new toxicological data have emerged since this last evaluation. The Panel concluded that the 90-day toxicity study in rats was the key study for the evaluation of propyl gallate considering the uncertainties and lack of a NOAEL in the carcinogenicity database on propyl gallate. Based on the NOAEL of 135 mg propyl gallate/kg bw/day of this study and taking account of the Opinion of the Scientific Committee of EFSA on Default values, the Panel concluded that an uncertainty factor of 300 should be applied for extrapolation from a subchronic to chronic data and due to the limitations in the reproductive toxicity database and derived an ADI of 0.5 mg/kg bw/day for propyl gallate.The Panel also concluded that there was no longer a basis for the present group ADI and that propyl, octyl and dodecyl gallates should be evaluated separately and the present group ADI should be withdrawn. The high level of exposure exceeded the ADI in adults and the elderly. However, given the conservatism of the exposure assessment, the Panel concluded that the use of propyl gallate as food additive at the current uses and use levels is not of safety concern.

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Section: Ratssupporting

confidence: 73%

“…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 (Booth et al, 1959, as reported in JECFA, 1993.…”

Section: Ratssupporting

confidence: 62%

Scientific Opinion on the re‐evaluation of propyl gallate (E 310) as a food additive

2014

EFS2

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“…Gallic acid was also found in urine at a higher concentration than in the inferior vena cava, but at lower concentration than 4-O-methyl gallic acid in urine. In contrast to previously published studies (Booth et al, 1959;Scheline, 1966a), this study (Zong et al, 1999) did not detect pyrogallol as a metabolite in blood or urine. The authors attribute this discrepancy to the earlier studies using TLC for determination of metabolites, but without proper determination of structures, and also comment that the time for collecting urine under unstable conditions may have led to the decomposition of gallic acid to pyrogallol (Zong et al, 1999).…”

Section: Subgroup 2 (Hydroxy-and Alkoxy-substituted Benzyl Derivatives)contrasting

confidence: 99%

“…The results indicate that O-methylation and decarboxylation are the reactions involved in the metabolic conversion of gallic acid. The authors stated that this selective O-methylation would prevent the formation of the catechol configurations (Booth et al, 1959). Scheline (1966a) reported that rats that were administered 100 mg/kg bw of gallic acid [FL-no: 08.080] by oral gavage excreted the parent substance and the free and acid-labile conjugates of its 4-O-methyl ether.…”

Section: Subgroup 2 (Hydroxy-and Alkoxy-substituted Benzyl Derivatives)mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 20, Revision 4 (FGE.20Rev4): Benzyl alcohols, benzaldehydes, a related acetal, benzoic acids, and related esters from chemical groups 23 and 30

Publication¹

2012

EFS2

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[FL no: 09.858]. None of the substances were considered to have genotoxic potential. The substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that all the substances do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered. Adequate specifications including complete purity criteria and identity for the materials of commerce have been provided for all 45 candidate substances. Twenty-five flavouring substances in the present group have been reported to occur naturally in a wide range of food items.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake estimates obtained by the MSDI approach.In the absence of more precise information that would enable the Panel to make a more realistic estimate of the intakes of the flavouring substances, the Panel has decided also to perform an estimate of the daily intakes per person using a "modified Theoretical Added Maximum Daily Intake" (mTAMDI) approach based on the normal use levels reported by Industry. In those cases where the mTAMDI approach indicated that the intake of a flavouring substance might exceed its corresponding threshold of concern, the Panel decided not to carry out a formal safety assessment using the Procedure. In these cases the Panel requires more precise data on use and use levels.According to the default MSDI approach, the 41 flavouring substances allocated to structural class I have intakes in Europe from 0.001 to 610 microgram/capita/day, which are below the threshold of concern value for structural class I (1800 microgram/person/day). The four substances in structural class II 05.066, 05.221 and 06.104] have estimated intakes of 0.011, 1.2, 0.61 and 100 microgram/capita/day, respectively. These intakes are below the threshold values of 540 microgram/person/day for structural class II.

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“…When adult albino rats were administered by gavage 100 mg dodecyl gallate/rat, the major metabolite in urine was 4-O-methyl-gallic acid (no further details) (Booth et al, 1959). Gallic acid in smaller amounts was also identified indicating hydrolysis of the ester followed by 4-O-methylation of gallic acid.…”

Section: Animal Studiesmentioning

confidence: 99%

Scientific Opinion on the re‐evaluation of dodecyl gallate (E 312) as a food additive

2015

EFS2

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The EFSA ANS Panel was asked to deliver a scientific opinion re-evaluating dodecyl gallate (E 312) as a food additive. The Panel considered that whilst from theoretical considerations dodecyl gallate could be metabolised to dodecyl alcohol and gallic acid, there were insufficient data to demonstrate the rate and extent of dodecyl gallate metabolism in vivo. Having reviewed the data on the toxicokinetics (rate and extent of metabolism) of propyl, octyl and dodecyl gallate in a previous EFSA evaluation of propyl gallate, the Panel concluded that the available metabolism data on gallates were insufficient to provide a basis for the read-across of systemic toxicity data on propyl, octyl and dodecyl gallate to be valid. The Panel noted the absence of concern for genotoxicity and the lack of increase of tumours in the long-term study. However, owing to the lack of detailed reports on carcinogenicity and chronic toxicity studies with dodecyl gallate and the absence of a basis for read-across for systemic toxicity from propyl gallate data, the Panel could not reach a definitive conclusion on the presence or absence of a carcinogenic potential of dodecyl gallate. The Panel noted that there was no indication for overt toxicity in the available studies; however, owing to the limitations of these studies, the Panel was unable to identify any NOAEL. Overall, the available database was too limited to either establish an ADI or serve as a basis for a margin of safety approach to be applied with confidence. The Panel concluded that although there was unlikely to be a safety concern from the single use for which usage and analytical data were provided, an adequate assessment of the safety of dodecyl gallate as a food additive would require a sufficient toxicological database in line with its current guidance for submission for food additives evaluations. The Panel noted that the available studies on acute toxicity of dodecyl gallate in rats and pigs indicated low acute oral toxicity. There were short-term and subchronic toxicity studies on dodecyl gallate in rats, dogs and pigs, which reported no overt toxic effects of dodecyl gallate. However, the Panel noted that the available studies were poorly reported and was unable to identify a no observed adverse effect level (NOAEL) from these studies.No data on genotoxicity of dodecyl gallate were available. The Panel considered that for the evaluation of the genotoxic hazard of intact dodecyl gallate, read-across from data on propyl gallate and from in silico expert system was scientifically justified. Therefore, based on the available in vitro and in vivo results on propyl gallate, which provide a limited evidence of genotoxicity in some in vitro systems and no evidence in tests in vivo with adequate systemic exposure, the Panel concluded that dodecyl gallate was unlikely to raise concern for genotoxicity.The Panel noted the absence of concern for genotoxicity and the lack of increase of tumours in the long-term study. However, owing to the lack of detailed reports on carcin...

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The Metabolic Fate of Gallic Acid and Related Compounds

Cited by 116 publications

References 11 publications

Scientific Opinion on the re‐evaluation of propyl gallate (E 310) as a food additive

Scientific Opinion on the re‐evaluation of propyl gallate (E 310) as a food additive

Scientific Opinion on Flavouring Group Evaluation 20, Revision 4 (FGE.20Rev4): Benzyl alcohols, benzaldehydes, a related acetal, benzoic acids, and related esters from chemical groups 23 and 30

Scientific Opinion on the re‐evaluation of dodecyl gallate (E 312) as a food additive

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