Studies on the absorption, distribution and excretion of citral in the rat and mouse

Phillips, John C.; Kingsnorth, J.; Gangolli, S.D.; Gaunt, I.F.

doi:10.1016/s0015-6264(76)80003-x

Cited by 32 publications

(10 citation statements)

References 6 publications

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“…Production of 14 CO 2 essentially ceased 12 hours after treatment and the amount of 14 C found in any tissue was very small (< 2 %). This excretion profile did not change much with increasing oral dose, although both in this study and that of Phillips et al (Phillips et al, 1976) oxidation to CO 2 was somewhat greater at the lowest dose.…”

Section: Iii2 Absorption Distribution and Eliminationcontrasting

confidence: 49%

“…In both species, the radiolabel was excreted rapidly, with most being excreted within 24 hours, predominantly in the urine, but also in exhaled air (as 14 CO 2 ) and faeces. Excretion was essentially complete by 96 hours in rats and by 120 hours in mice (Phillips et al, 1976), as cited by JECFA (JECFA, 2004b).…”

Section: Iii2 Absorption Distribution and Eliminationmentioning

confidence: 72%

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Scientific Opinion on Flavouring Group Evaluation 06, Revision 4 (FGE.06Rev4): Straight‐ and branched‐chain aliphatic unsaturated primary alcohols, aldehydes, carboxylic acids and esters from chemical groups 1, 3 and 4

Beltoft

Binderup

Frandsen

et al. 2013

EFS2

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 56 flavouring substances in the Flavouring Group Evaluation 6, Revision 4, using the Procedure in Commission Regulation (EC) No 1565/2000. This revision is made due to the inclusion of six additional flavouring substances, (-)-3,7-dimethyl-6-octen-1-ol .229], dec-4(cis)-enal .137], neral .170], trans-3,7-dimethylocta-2,6-dienal (geranial) .188], trans-3-hexenyl formate .562] and cis-3-hexenyl 2-methylbutanoate ]. 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 the 56 substances 02.138, 02.152, 02.170, 02.175, 02.176, 02.195, 02.201, 02.222, 02.229, 02.234, 05.061, 05.082, 05.137, 05.143, 05.170, 05.174, 05.188, 05.203, 05.217, 05.218, 05.220, 05.226, 08.074, 08.100, 08.102, 09.341, 09.368, 09.377, 09.562, 09.567, 09.569, 09.572, 09.575, 09.612, 09.638, 09.640, 09.643, 09.672, 09.673, 09.674, 09.831, 09.838, 09.854, 09.855, 09.871, 09.872, 09.884, 09.885, 09.897, 09.898, 09.928, 09.937, 09.938, 09.939 and 09.950] do not give rise to safety concern 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 56 Forty-one of the 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 subs...

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Section: Iii2 Absorption Distribution and Eliminationcontrasting

confidence: 49%

Section: Iii2 Absorption Distribution and Eliminationmentioning

confidence: 72%

Scientific Opinion on Flavouring Group Evaluation 06, Revision 4 (FGE.06Rev4): Straight‐ and branched‐chain aliphatic unsaturated primary alcohols, aldehydes, carboxylic acids and esters from chemical groups 1, 3 and 4

Beltoft

Binderup

Frandsen

et al. 2013

EFS2

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“…Due to the volatile nature of citral and geraniol (2), the amounts of the compounds reaching the systemic circulation are likely to have been considerably less than was actually applied. Citral and geraniol (2) are reported to be metabolised invivo to yield metabolites including hildebrandt acid and dihydrohildebrandt acid, and are also reported to be rapidly excreted (Phillips et al 1976 ;Chadha & Madyastha 1984 ;Ishida et al 1989); this could explain the apparent lack of estrogenic activity observed in-vivo. Citral has previously been reported to induce local hyperkeratosis following repeated application to the same area of skin (Engelstein et al 1996), raising the possibility that this response could interfere with transdermal absorption, and geraniol (2) was not absorbed through the intact skin of the mouse after 2 h (Meyer & Meyer 1959); these occurrences may have reduced systemic concentrations of the monoterpenes.…”

Section: Discussionmentioning

confidence: 99%

Assessment of estrogenic activity in some common essential oil constituents

Howes

Houghton

Barlow

et al. 2002

Journal of Pharmacy and Pharmacology

108

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Estrogenic responses have not only been associated with endocrine function, but also with cognitive function. Several studies have indicated that estrogen replacement therapy has favourable effects on cognition, and may have potential in the prevention and treatment of Alzheimer's disease. Thus, ligands for the estrogen receptor, that have a better efficacy and adverse-effect profile than drugs currently available, require investigation. This study was undertaken to investigate the potential estrogenic activity of a number of essential oil constituents. Initially, estrogenic activity was determined by a sensitive and specific bioassay using recombinant yeast cells expressing the human estrogen receptor. At high concentrations, estrogenic activity was detected for citral (geranial and neral), geraniol, nerol and trans-anethole, while eugenol showed anti-estrogenic activity. Molecular graphics studies were undertaken to identify the possible mechanisms for the interaction of geranial, neral, geraniol, nerol and eugenol with the ligand-binding domain of the estrogen alpha-receptor, using the computer program HyperChem. Citral, geraniol, nerol and eugenol were also able to displace [(3)H]17beta-estradiol from isolated alpha- and beta-human estrogen receptors, but none of these compounds showed estrogenic or anti-estrogenic activity in the estrogen-responsive human cell line Ishikawa Var I at levels below their cytotoxic concentrations, and none showed activity in a yeast screen for androgenic and anti-androgenic activity. The potential in-vivo estrogenic effects of citral and geraniol were examined in ovariectomized mice, but neither compound showed any ability to stimulate the characteristic estrogenic responses of uterine hypertrophy or acute increase in uterine vascular permeability. These results show that very high concentrations of some commonly used essential oil constituents appear to have the potential to interact with estrogen receptors, although the biological significance of this is uncertain.

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“…In general, esters are hydrolyzed to their corresponding alcohol and carboxylic acid. It is expected that the tertiary aromatic alcohols will undergo direct conjugation of the hydroxyl group with glucuronic acid (Williams ), while the tertiary terpenoid alcohols formed as a result of hydrolysis are rapidly absorbed and converted to the glucuronic acid conjugates which are excreted in the urine, or are further oxidized to CO 2 that is subsequently expired (Phillips and others ; Diliberto and others ).…”

Section: Absorption Distribution Metabolism and Eliminationmentioning

confidence: 99%

GRASr2 Evaluation of Aliphatic Acyclic and Alicyclic Terpenoid Tertiary Alcohols and Structurally Related Substances Used as Flavoring Ingredients

Marnett

Cohen

Fukushima³

et al. 2014

Journal of Food Science

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This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panel's 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.

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Studies on the absorption, distribution and excretion of citral in the rat and mouse

Cited by 32 publications

References 6 publications

Scientific Opinion on Flavouring Group Evaluation 06, Revision 4 (FGE.06Rev4): Straight‐ and branched‐chain aliphatic unsaturated primary alcohols, aldehydes, carboxylic acids and esters from chemical groups 1, 3 and 4

Scientific Opinion on Flavouring Group Evaluation 06, Revision 4 (FGE.06Rev4): Straight‐ and branched‐chain aliphatic unsaturated primary alcohols, aldehydes, carboxylic acids and esters from chemical groups 1, 3 and 4

Assessment of estrogenic activity in some common essential oil constituents

GRASr2 Evaluation of Aliphatic Acyclic and Alicyclic Terpenoid Tertiary Alcohols and Structurally Related Substances Used as Flavoring Ingredients

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