Mutagenic properties of allylic and α,β-unsaturated compounds: Consideration of alkylating mechanisms

Eder, Erwin; Henschler, D.; Neudecker, T.

doi:10.3109/00498258209038955

Cited by 155 publications

(76 citation statements)

References 19 publications

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“…a,,B-Unsaturated carbonyl compounds are also used as pesticides or formed as degradation products of pesticides (4,5). Since our group first published structure mutagenicity relationships for these compounds (6)(7)(8), many other studies have confirmed that these compounds are mutagenic (9)(10)(11). Cro- tonaldehyde has been found to induce liver cancer in rats (12), and it should be considered as a potential human carcinogen.…”

mentioning

confidence: 99%

Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity.

Eder

Hoffman

Bastian

et al. 1990

Environ Health Perspect

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,-Unsaturated carbonyl compounds are important not only from a theoretical but also a practical standpoint. These ubiquitous compounds can interact with DNA through various mechanisms. The predominant interaction is the formation of cyclic 1,N2-deoxyguanosine adducts; 7,8-cyclic guanine adducts are also found. We have synthesized and characterized the stereoisomers of adducts formed by about 20 a,ID-unsaturated carbonyl compounds. The different types of adducts and the mutagenic and genotoxic response can be explained by the molecular structures of the agents. Compounds forming saturated cyclic adducts are mutagenic in S. typhimurium strain TA100 and to a lesser extent in TA1535. Substances with a leaving group at the C-3 position form unsaturated conjugated cyclic adducts and are mutagenic only in the His D3052 frameshift strains with an intact excision repair system (no urvA mutation). Metabolic epoxidation of the double bond and other metabolic activation, e.g., activation of the nitrogroups via nitroreductases, were also found to contribute to genotoxic and mutagenic activities. Our results have further elucidated the genotoxic mechanisms of these compounds; however, additional investigations are required for a complete understanding of the genotoxic activity of this class of compounds.

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mentioning

confidence: 99%

Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity.

Eder

Hoffman

Bastian

et al. 1990

Environ Health Perspect

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“…9 The Panel noted that the publication of Eder et al, 1982 is not the correct paper to quote from. It has not been possible for EFSA to identify the correct paper.…”

Section: Subgroup I (Acyclic Sulphides)mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 74, Revision 3 (FGE.74Rev3): Consideration of Simple Aliphatic Sulphides and Thiols evaluated by the JECFA (53rd and 61st meeting) Structurally related to Aliphatic and Alicyclic Mono‐, Di‐, Tri‐, and Polysulphides with or without Additional Oxygenated Functional Groups from Chemical Group 20 evaluated by EFSA in FGE.08Rev5 (2012)

Gontard¹

2014

EFS2

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The substances were evaluated through a stepwise approach that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. For nine substances 12.179, 12.198, 12.212, 12.238, 12.239, 12.255, 12.257 and 12.291] considered in this FGE, the Panel concluded that they would pose "No safety concern at estimated levels of intake as flavouring substances" based on the MSDI approach. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered for the substances evaluated through the Procedure and for all nine substances, the information is adequate. Thus, the Panel concluded that nine substances 12.179, 12.198, 12.212, 12.238, 12.239, 12.255, 12.257 and 12.291] do not give rise to safety concern at their levels of dietary intake, estimated on the basis of the MSDI approach. For 10 candidate substances in FGE.74Rev3 12.013, 12.020, 12.023, 12.045, 12.074, 12.155, 12.169, 12.241 and 12.280] This revision is made due to additional genotoxicity data have been submitted for 4-mercapto-4-methyl-2-pentanone ]. In addition, for seven substances 12.020, 12.045, 12.169, 12.238, 12.239 and 12.291] new data on specifications have been included. Industry also submitted additional information intended to support the derivation of a NOAEL for substances in subgroup VI (tri-and poly-sulphides).The Panel concluded that the 19 substances in the JECFA flavouring group of simple aliphatic sulphides and thiols are structurally related to the group of aliphatic and alicyclic mono-, di-, and polysulphides with or without additional oxygenated functional groups evaluated by EFSA in the Flavouring Group Evaluation 08, Revision 5 (FGE.08Rev5).The results of the additional genotoxicity study on [FL no: 12.169] alleviate the concern for genotoxicity of two substances [FL no: 12.169 and 12.241] and therefore these two substances can be evaluated through the Procedure. For the remaining 17 substances in FGE.74Rev2 the Panel considered already before, that the genotoxicity data available do not preclude evaluating these substances through the Procedure.The Panel agrees with the application of the Procedure as performed by the JECFA for five of the 19 aliphatic sulphides and thiols 12.239, 12.255, 12.257 and 12.291], and concluded, similar the JECFA that these would not a pose safety concern at the current levels of exposure based on the MSDI approach. For three substances 12.198 and 12.212] the Panel reached the same conclusion, but used a NOAEL from a different study as the one used by the JECFA.For diallyl sulphide .088] the JECFA evaluated this substance at step B5 to be of no safety concern as the estimated intake in the USA is 0.4 µg/capita/day, which is below 1.5 µg/day. The Panel does not make use of this threshold of 1.5 µg per person per day. However, the Panel decided that this substance could be allocated to subgroup I, for which a sup...

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“…The supporting substances are listed in brackets. (Smyth et al, 1970) Rat NR 8930 (Smyth et al, 1969b) Rat NR 9750 (FDA, 1975a) Rat NR 6800 (Kimura et al, 1971a) Rat NR 3465 (Kohli et al, 1967) Mouse M 5250 (Tanii et al, 1986) Rabbit NR 5300 (Krasavage et al, 1982) (Isopropyl alcohol [02.079]) Rat NR 5840 (Smyth & Carpenter, 1948) Rat NR 5280 (Lehman & Chase, 1944) Rat NR 5300 (Kimura et al, 1971a) Rat NR 5330 (FDA, 1975a) Mouse NR 5070 (FDA, 1975a) Rabbit NR 5040 (Lehman & Chase, 1944) Rabbit NR 7990 (Munch, 1972) Dog NR 4830 (Lehman & Chase, 1944) (2-Butanone [07.053]) Rat M 5490 (Smyth et al, 1962) Rat NR 2730 (Kimura et al, 1971a) Rat NR 3980 (Union Carbide Corp., 1956) Rat F 5525 (Pozzani et al, 1959) Mouse M 3137 (Zakhari et al, 1977) Mouse M 4050 (Tanii et al, 1986) (2-Pentanone [07.054]) Rat M 3730 (Smyth et al, 1962) The EFSA Journal (2009) 1020, 53-70 (Tanii et al, 1986) (2-Pentanol [02.088]) Rabbit NR 2820 (Munch, 1972) Pentan-3-one [07.084] Rat NR 2900 (BASF, 1969) Rat NR 2140 (Panson & Winek, 1980) Rat NR 2140 (Eder et al, 1982a) Rat NR 2140 (Kennedy & Graepel, 1991) Rat NR 3100 (Ibatullina & Larionova, 1997) Pentan-3-ol [02.077] Rat NR 1870 (Eder et al, 1982a) ( (Schafer & Bowles, 1985) Mouse M 5460 (Tanii et al, 1986) Methyl-3-butan-2-one [07.178] Mouse M 2572 (Tanii et al, 1986) Rat NR 148 (Kennedy & Graepel, 1991) (4-Methyl-2-pentanone [07.017]) Rat NR 2080 (Smyth et al, 1951a) Mouse M 2670 (Tanii et al, 1986)...…”

Section: Annex Iv: Toxicitymentioning

confidence: 99%

Flavouring Group Evaluation 7, Revision 2 (FGE.07Rev2) : Saturated and unsaturated aliphatic secondary alcohols, ketones and esters of secondary alcohols and saturated linear or branched-chain carboxylic acids from chemical group 5

2009

EFSA Journal

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The present Flavouring Group Evaluation (FGE) deals with 43 saturated and unsaturated aliphatic secondary alcohols, ketones and esters with a secondary alcohol moiety.Twenty-two of the 43 candidate substances possess a chiral centre and two of the candidate substances possess two chiral centres. For six of these substances the stereoisomeric composition has not been specified.Due to the presence and the position of double bonds, six of the substances can exist as geometrical isomers. In three of these cases the stereoisomeric composition has not been specified.Twenty-eight of the flavouring substances have been assigned to structural class I and 15 substances belong to structural class II.Thirty-nine of the flavouring substances in the present group of 43 flavouring substances 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 43 flavouring substances in this group have intakes in Europe from 0.0012 to 1.3 microgram/capita/day, which are below the threshold of concern value for both structural class I (1800 microgram/person/day) and structural class II (540 microgram/person/day) substances.On the basis of available data from in vitro and in vivo tests on candidate and supporting substances, it can be concluded that the 43 flavouring substances included in this group exhibit no genotoxic potential.Among the 43 flavouring substances, 42 would be expected to be metabolised to innocuous products at the estimated levels of intake as flavouring substances. The remaining flavouring substance, 5-methylheptan-3-one .182], may be oxidised to a potential neurotoxic gamma-diketone. However, this metab...

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Mutagenic properties of allylic and α,β-unsaturated compounds: Consideration of alkylating mechanisms

Cited by 155 publications

References 19 publications

Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity.

Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity.

Flavouring Group Evaluation 7, Revision 2 (FGE.07Rev2) : Saturated and unsaturated aliphatic secondary alcohols, ketones and esters of secondary alcohols and saturated linear or branched-chain carboxylic acids from chemical group 5

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