Comparative mutagenicity of aliphatic epoxides in Salmonella

Canter, Dorothy A.; Zeiger, Errol; Haworth, Steve; Lawlor, Timothy E.; Mortelmans, Kristien; Speck, William T.

doi:10.1016/0165-1218(86)90069-8

Cited by 108 publications

(40 citation statements)

References 23 publications

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“…Although Canter et al (1986) reported negative results in TA100 incubated with ethyl 3-phenylglycidate at ≤ 2,200 µg/plate with and without metabolic activation, positive results were reported with and without metabolic activation in other studies (Voogd et al, 1981;Wild et al, 1983;Tilch and Elias, 1984;Wagner and Walton, 1999). In the study of Voogd et al (1981), positive results were found only at the two highest concentrations (1,000 and 2,000 µg/ml), with and without metabolic activation.…”

Section: In Vitromentioning

confidence: 90%

“…(Richold et al, 1979) Reverse mutation S. typhimurium TA1535, TA1537, TA98 and TA100 0, 10, 50, 100 or 500 µg/plate Negative (a,c) (Richold et al, 1979) 16.018 1576 (Canter et al, 1986) Reverse mutation S. typhimurium TA98, TA100, TA1535 and TA1537 0, 10 to 2,200 µg/plate Negative (f,g) (Canter et al, 1986) Reverse mutation S. typhimurium TA98, TA100,TA1535, TA1537 and TA1538 0, 80, 400, or 2,000 µg/plate Negative (d,h) (Tilch and Elias, 1984) Negative / Positive (f,i) Reverse mutation S. typhimurium TA98, TA100,TA1535, TA1537 and TA1538 0, 400, 2,000, or 10,000 µg/plate (j) Negative (a) (Tilch and Elias, 1984) Reverse mutation S. typhimurium TA100 0, 200, 500, 1,000, or 2,000µg/mL Negative /Positive (a,k) (Voogd et al, 1981) Reverse mutation S. typhimurium TA100 and TA98 (Tilch and Elias, 1984) Sister chromatid exchange Chinese hamster ovary-K1-BH4 cells 0 or 3,280 µg/mL (3.28 mg/mL) Negative (a) (Tilch and Elias, 1984) Sister chromatid exchange (Canter et al, 1986) Reverse mutation S. typhimurium TA100 0, 200, 500, 1,000, 2,000, or 5,000 µg/mL Negative (a) (Voogd et al, 1981) Reverse mutation S. typhimurium TA1535, TA1537, TA1538, TA98 and TA100…”

Section: Resultsmentioning

confidence: 99%

“…Ethyl 3-phenylglycidate (ethyl-3-phenyl-2,3-epoxyproprionate) .018] gave inconsistent results in this test: at ≤ 4,000 µg/plate, it did not induce reverse mutations in S. typhimurium TA1535, TA1537 or TA1538 with or without metabolic activation (Wild et al, 1983;Tilch and Elias, 1984;Canter et al, 1986); however negative results were reported in several studies in TA98 incubated with ethyl 3-phenylglycidate at concentrations ≤ 4,000 µg/plate, irrespective of metabolic activation (Wild et al, 1983;Tilch and Elias, 1984;Canter et al, 1986;Wagner and Walton, 1999), whereas increased mutagenicity was found in TA98 with metabolic activation (≤ 5,000 µg/plate). In the absence of metabolic activation, the frequency of revertants was comparable to that of controls (Wagner and Walton, 1999).…”

Section: In Vitromentioning

confidence: 99%

“…In standard assays for reverse mutation in Salmonella typhimurium, ethyl methylphenylglycidate [FLno: 16.015] and caryophyllene oxide (beta-caryophyllene epoxide) .043] were consistently non-mutagenic in strains TA98, TA100, TA1535, TA1537 and TA1538 at concentrations of up to 10,000 μg/plate, with and without metabolic activation (S9) (Richold et al, 1979;Voogd et al, 1981;Wild et al, 1983;Canter et al, 1986). Ethyl 3-phenylglycidate (ethyl-3-phenyl-2,3-epoxyproprionate) .018] gave inconsistent results in this test: at ≤ 4,000 µg/plate, it did not induce reverse mutations in S. typhimurium TA1535, TA1537 or TA1538 with or without metabolic activation (Wild et al, 1983;Tilch and Elias, 1984;Canter et al, 1986); however negative results were reported in several studies in TA98 incubated with ethyl 3-phenylglycidate at concentrations ≤ 4,000 µg/plate, irrespective of metabolic activation (Wild et al, 1983;Tilch and Elias, 1984;Canter et al, 1986;Wagner and Walton, 1999), whereas increased mutagenicity was found in TA98 with metabolic activation (≤ 5,000 µg/plate).…”

Section: In Vitromentioning

confidence: 99%

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Scientific Opinion on Flavouring Group Evaluation 82, Revision 1 (FGE.82Rev1): Consideration of Epoxides evaluated by the JECFA (65th meeting)

Flavourings¹

2014

EFS2

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This revision is made due to inclusion of one additional substance, beta-ionone epoxide ], cleared for genotoxicity concern and due to additional toxicity data have become available for beta-caryophyllene epoxide ]. Since publication of FGE.82 one substance epoxy oxophorone .051] is no longer supported for use as flavouring substances in Europe by Industry and will therefore not be considered any further. 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 four substances 16.018, 16.040 and 16.043] the Panel agreed with the JECFA conclusion, "No safety concern at estimated levels of intake as flavouring substances" based on the MSDI approach. For one substance .170] additional toxicity data are required. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered and for four substances, the information is adequate; but for the substance The Panel concluded that no structurally related substances evaluated by EFSA are available for these five epoxides in FGE.82, evaluated in the JECFA flavouring group of epoxides.Of the further four substances evaluated by the JECFA in this group one is not in the Register and two are α,β-unsaturated aldehydes and ketones. These two will be evaluated together with other α,β -unsaturated aldehydes and ketones.The Panel does not agree with the application of the Procedure for the five epoxides as performed by the JECFA. For the five substances 16.015, 16.018, 16.040 and 16.043] it cannot be concluded that they are metabolised to innocuous substances and therefore their evaluation must proceed via the B-side of the Procedure scheme.A 90-day study on beta-caryophyllene epoxide .043] has become available and a NOAEL of 109 mg/kg bw/day to provide adequate margin of safety is derived.The Panel considered that four of the five substances 16.015, 16.018 and 16.040] evaluated through the Procedure via the B-side of the Procedure scheme were of no safety concern at the estimated levels of intake based on the MSDI approach.The evaluation of beta-ionone epoxide ] cannot be finalised at step B4 of the Procedure because a NOAEL from a 90-day study is not available.For the three substances 16.018 and 16.040], evaluated through the Procedure, use levels are needed to calculate the mTAMDIs in order to identify those flavouring substances that need more refined exposure assessment and to finalise their evaluation.In order to determine whether the conclusion for the five JECFA evaluated substances can be applied to the materials of commerce, it is necessary to consider the available specifications. Adequate specifications including complete purity criteria and identity tests are available for four JECFA evaluated substances 16.018, 16.040 and 16.043]. For one substances .170] information on stereoisomeric composition is not ...

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Section: In Vitromentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: In Vitromentioning

confidence: 99%

Section: In Vitromentioning

confidence: 99%

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Scientific Opinion on Flavouring Group Evaluation 82, Revision 1 (FGE.82Rev1): Consideration of Epoxides evaluated by the JECFA (65th meeting)

Flavourings¹

2014

EFS2

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“…Im Ames-Test war iGE positiv mit und ohne metabolische Aktivierung an den Stämmen TA100 und TA1535 [5]. Es bewirkte Mutationen an Escherichia coli WP2uvrA [6] und war im SOS-Chromotest an Escherichia coli PQ37 positiv [7].…”

Section: Untersuchungen Zur Gentoxischen Wirkungunclassified

iso‐Propylglycidylether [MAK Value Documentation in German language, 1992]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 18. Lieferung, Ausgabe 1992 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Angaben zur Pharmakokinetik Erfahrungen beim Menschen Tierexperimentelle Befunde Akute Toxizität Subchronische Toxlzltät Reproduktions‐ und Teratogenitätsstudien Untersuchungen zur gentoxischen Wirkung Untersuchungen zur kanzerogenen Wirkung Zur Frage eines MAK‐Wertes

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Epoxy Compounds—Olefin Oxides, Aliphatic Glycidyl Ethers and Aromatic Monoglycidyl Ethers

Waechter¹,

Pottenger²,

Veenstra³

2001

Patty's Toxicology

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An epoxy compound is defined as any compound containing one or more oxirane rings. An oxirane ring (epoxide) consists of an oxygen atom linked to two adjacent (vicinal) carbon atoms. The term alpha‐epoxide is sometimes used for this structure to distinguish it from rings containing more carbon atoms. The alpha does not indicate where in a carbon chain the oxirane ring occurs. The oxirane ring is highly strained and is thus the most reactive ring of the oxacyclic carbon compounds. The strain is sufficient to force the four carbon atoms nearest the oxygen atom in 1,2‐epoxycyclohexane into a common plane, whereas in cyclohexane the carbon atoms are in a zigzag arrangement or boat structure. As a result of this strain, epoxy compounds are attacked by almost all nucleophilic substances to open the ring and form addition compounds. Among agents reacting with epoxy compounds are halogen acids, thiosulfate, carboxylic acids, hydrogen cyanide, water, amines, aldehydes, and alcohols. A major portion of this chapter presents information on the two olefin oxides, ethylene oxide and propylene oxide, which are produced in high volume and are largely used as intermediates in the production of the glycol ethers. In addition, these compounds are used in the production of several other important products (e.g., polyethylene glycols, ethanolamines, and hydroxypropylcellulose) and have minor uses as fumigants for furs and spices and as medical sterilants. The other olefin oxides discussed are used as chemical intermediates (e.g., vinylcyclohexene mono‐ and dioxide), as gasoline additives, acid scavengers, and stabilizing agents in chlorinated solvents (butylene oxide) or in limited quantities as reactive diluents for epoxy resins. The discussion of the toxicology of certain olefinic oxides may be pertinent to their respective olefin precursors. However, it must be pointed out that the olefinic precursors of these different oxides demonstrate widely varying degrees of toxicity in mammalian models, mostly attributable to pharmacokinetic/metabolism differences in metabolic conversion of olefins to their respective oxide metabolites. For example, chronic bioassay results range from repeated negatives (ethylene, propylene) to clear positives (butadiene). A major use of the glycidyl ethers discussed in this chapter are as reactive diluents in epoxy resin mixtures. However, some of these materials are also used as intermediates in chemical synthesis as well as in other industrial applications. The concept that epoxides, through their binding to nucleophilic biopolymers such as DNA, RNA, and protein, can produce toxic effects is well established. However, the magnitude and nature of physiological disruption depend on the reactivity of the particular epoxide, its molecular weight, and its solubility, all of which may control its access to critical molecular targets. In addition, the number of epoxide groups present, the dose and dose rate, the route of administration, and the affinity for the enzymes that can detoxify or activate the compound may affect the degree and nature of the physiologic response. A key enzyme for epoxide detoxification is microsomal epoxide hydrolase (EH), which is widely distributed throughout the body, but it is organ, species, and even strain variant. Acute toxic effects most commonly observed in animals have been dermatitis (either primary irritation or secondary to induction of sensitization), eye irritation, pulmonary irritation, and gastric irritation, which are found in these tissues after direct contact with the epoxy compound. Skin irritation is usually manifested by more or less sharply localized lesions that develop rapidly on contact, more frequently on the arms and hands. Signs and symptoms usually include redness, swelling, and intense itching. In severe cases, secondary infections may occur. Workers show marked differences in sensitivity. Most of the glycidyl ethers in this chapter have shown evidence of delayed contact skin sensitization, in either animals or humans. The animal and human data available on skin sensitization of epoxy compounds do not assist in determining the structural requirements necessary to produce sensitization, but do provide some practical guidance for industrial hygiene purposes. Although all of the compounds described in this chapter were mutagenic to bacteria (excluding epoxidized glycerides) as well as positive in other in vitro genotoxicity assays, not all have produced genotoxicity in in vivo studies. A number of these epoxide compounds have been found to be carcinogenic in rodents, although there has been no clear epidemiologic evidence for cancer in the workplace. In rats and/or mice, many epoxy compounds produce a carcinogenic response in the tissues of first contact. These compounds include ethylene oxide, butylene oxide, propylene oxide, styrene oxide allyl glycidyl ether, phenyl glycidyl ether, and neopentyl glycol diglycidyl ether. A few of them, such as ethylene oxide, butadiene dioxide, and vinylcyclohexene dioxide, have produced tumors at sites other than the “portal of entry.”

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Comparative mutagenicity of aliphatic epoxides in Salmonella

Cited by 108 publications

References 23 publications

Scientific Opinion on Flavouring Group Evaluation 82, Revision 1 (FGE.82Rev1): Consideration of Epoxides evaluated by the JECFA (65th meeting)

Scientific Opinion on Flavouring Group Evaluation 82, Revision 1 (FGE.82Rev1): Consideration of Epoxides evaluated by the JECFA (65th meeting)

iso‐Propylglycidylether [MAK Value Documentation in German language, 1992]

Epoxy Compounds—Olefin Oxides, Aliphatic Glycidyl Ethers and Aromatic Monoglycidyl Ethers

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