55
Mutation Research, 249 (1991) 55-70 © 1991 Elsevier Science Publishers B.V. 0027-5107/91/$03.50 ADONIS 002751079100127H
MUT 04979
Structure-activity relationships of epoxides: induction of sister-chromatid exchanges in Chinese hamster V79 cells Wilhelm vonder Hude, Silke Carstensen and Gtinter Obe 1 lnstitut fiir Allgemeine Genetik, Freie Universitiit Berlin, D-IO00 Berlin 33 and 1 Fb 9~ Genetik, Universitiit-GH Essen, D-4300 Essen 1 (F.R.G.)
(Received 18 September 1990) (Revision received 29 November 1990) (Accepted 3 December 1990)
Keywords: Structure-activity relationship; Epoxides; Sister-chromatid exchange; Chinese hamster V79 cells
Summary Analysis of SCE frequencies in Chinese hamster V79 cells was used to investigate structure-activity relationships of epoxides in mammalian cells. For this purpose the SCE-inducing potency of 58 epoxides was determined. Of these, 16 failed to induce SCE in V79 cells. According to the substitution of the oxirane ring the results show general agreement with results obtained in the Ames test. Mono-substituted epoxides had the highest genotoxic potency compared to di- and tri-substituted epoxides. In detail, there are differences in genotoxic potency between bacteria and mammalian cells which can be explained by differences in the cellular uptake of the compounds and by detoxification reactions.
Epoxides are generally direct-acting mutagens in Salmonella typhimurium (Wade et al., 1978; Watabe et al., 1980; Frantz and Sinsheimer, 1981; Canter et al., 1986; von der Hude et al., 1990) and some of them have been shown to be rodent carcinogens (van Duuren et al., 1963, 1965, 1966, 1967). Several studies have been performed to elaborate structure-activity relationships between the mutagenic potency of epoxides in bacterial mutagenicity tests and physico-chemical properties (Sugiura and Goto, 1981; Hemminki and Falck, 1979; Neau et al., 1982; Rosman et al.,
Correspondence: Dr. W. v o n d e r Hude, Max von PettenkoferInstitut des BGA, Postfach 33 00 13, D-1000 Berlin 33 (Germany).
1986, 1987, 1988). A more general study was performed by Wade et al. (1978), who reported a dependence of the mutagenic activity on the degree of substitution around the oxirane ring. Monosubstituted epoxides had the highest mutagenic activity. Furthermore, the mutagenic activity of monosubstituted epoxides is dependent on further electron-withdrawing groups adjacent the oxirane ring. Despite the known direct bacterial mutagenicity of most epoxides, little is known about their mutagenic action in mammalian cells. To investigate structure-activity relationships for genotoxic effects caused by epoxides in mammalian cells the SCE-inducing potencies (SCEIP) in V79 cells were determined for 58 epoxides. This test system allows the rather rapid screening of many substances and it gives reproducible results, allowing
56
a quantitative comparison of independent experiments. Materials and methods Test substances
The test substances, their Chemical Abstract Service (CAS) registry numbers, purities and suppliers are listed in Table 1. S C E test
The Chinese hamster V79 cell line was grown in minimal essential medium with Earle's salts (MEM) supplemented with 10% heat-inactivated fetal calf serum and penicillin (100 U / m l ) , streptomycin (0.1 m g / m l ) at 3 7 ° C and 5% CO 2. V79 cells (5 × 105 cells) were seeded into 25-cm2 flasks and after 18 h the test substances were added in appropriate concentrations. The medium with the test substance was discarded 2 h later, the cells were washed 2 times with fresh medium, which was then replaced by fresh medium containing 5-bromo-2'-deoxyuridine (10-5 M; BrdU). Mitotic cells were harvested by shake-off after 28 h of incubation with Colcemid (2 × 10 -7 M) for the last 4 h. The cells were fixed on slides and stained according to standard protocols (Latt et al., 1981).
metabolizing system. All compounds were tested up to cytotoxic concentrations which were detected by delay in the replication index (R1) or up to the highest soluble concentration of the test compound. All results were confirmed by independent experiments. The detailed results of all experiments are given in the Appendix. Table 2 shows the results obtained with the solvent DMSO and epichlorohydrin [4] which was run as a positive control substance concurrently with each individual experiment. The narrow range of results obtained with DMSO and the good reproducibility of the dose-response relationship with epichlorohydrin shows the reliability of the V 7 9 / S C E test for studies on structure-activity relationships in mammalian cells. Furthermore, by these results it becomes obvious that quantitative comparisons of the results obtained from different experiments are possible. The results concerning the SCEIP are included in the last column of Table 1. It can be seen that 16 epoxides did not induce SCE in V79 cells although they had clear cytotoxic properties. The dose-response relationships for the positive substances are shown in detail in Figs. 1-4. Fig. 1 shows the concentration-dependent increase of the SCE in V79 cells induced by 1,2-
Statistical evaluation
Twenty-five metaphases with harlequin-stained chromosomes were scored for SCE per experimental point. All results were confirmed in independent experiments and mean values of 2 experiments with a total of 50 metaphases scored per experimental point were analyzed by pair-wise comparison of the solvent control, using one-tailed Student's t test. The distribution of first, second and third mitoses was determined by counting 100 metaphases per experimental point to calculate the replication index (RI). To calculate the SCEIP the slopes of the d o s e response relationships were calculated by a computed linear regression analysis of the pooled resuits of the 2 independent experiments. Results
In this study 58 epoxides were tested for SCEIP with V79 cells in vitro without an external
30
3t
~ 20 ~u
t
[ O.Ol
L
I
i
o.1 _ m mo
I 1,0
t
I
|
lO.O
1,/I
Fig. l. Concentration-dependent increases of the SCE frequencies in V79 cells induced by 1,2-epoxypropyl derivatives. [2] 1,2-epoxypropane, [3] epifluorohydrin, [4] epichlorohydrin, [5] 1,2-epoxy-3,3,3-trichloropropane, [6] epibromohydrin, [7] 1,2epoxypropyl-3-trimethylammoniumchloride, [8] N-(2,3-epoxypropyl)-phthalamide.
57 TABLE 1 LIST OF CHEMICALS, C H E M I C A L A B S T R A C T SERVICE N U M B E R S (CAS Nos.), M O L E C U L A R W E I G H T S (MW), PURITIES, SUPPLIERS A N D T H E TEST R E S U L T ( S C E - I N D U C I N G POTENCY; SCEIP) No. chemical
Cas No.
MW
Purity
Supplier
SCEIP
(%) Monosubstituted epoxides 1. Styrene oxide 2. 1,2-Epoxypropane 3. Epifluorohydrin 4. Epichlorohydrin 5.1,2-Epoxy-3,3,3-trichloropropane 6. Epibromohydrin 7.2,3-Epoxypropyltrimethylammonium chloride (Glycidyltrimethylammonium chloride) 8. N-(2,3-Epoxypropyl)-phthalamide 9. 2,3-Epoxy-l-propanol 10. 2,3-Epoxypropyl-methylether 11.2,3-Epoxypropyl- 1-allylether 12. 2,3-Epoxypropyl-isopropylether 13.2,3-Epoxypropyl-tert.-butylether 14. 2,3-Epoxypropyl-n-butylether 15.2,3-Epoxypropyl- fur furylether 16.2,3-Epoxypropyl-(2-ethylhexyl)-ether 17.2,3-Epoxypropyl-phenylether 18.2,3-Epoxypropyl-4-nitro-phenylether 19. 2,3-Epoxypropyl-4-chloro-phenylether 20. 2,3-Epoxypropyl-4-methoxy-phenylether 21.2,3-Epoxypropyl-tert.-butyl-phenylether 22. 2,3-Epoxypropyl-methacrylic acid ester 23.2,3-Epoxypropyl-acrylic acid ester 24. 1,2-Epoxy-3-butene 25.1,2-Epoxy-5-hexene 26. 1,2-Epoxy-7-octene 27. 1,2-Epoxybutane 28. 1,2-Epoxyhexane 29. 1,2-Epoxyoctane 30. 1,2-Epoxydecane 31.1,2-Epoxydodecane 32. 1,2-Epoxyhexadecane 33.1,2 : 3,4-Diepoxybutane 34. 1,2 : 5,6-Diepoxyhexane 35.1,2 : 7,8-Diepoxyoctane 36. 1,2-Bis-(2,3-epoxypropoxy)-ethane 37. 1,4- Bis(2,3-epoxypropoxy)-butane
96-09- 3 75-56-9 503-09-3 106-89-8 3083-23-6 3132-64-7
120.15 58.08 76.07 92.53 161.42 136.98
97 99 90 99 nd 97
Aldrich Aldrich Aldrich Merck Sigma Merck
33.4 3.0 11.7 28.8 163.8 121.8
3033-70-0 5455-98-1 556-52-5 930-37-0 106-92-3 4016-14-2 7 665-72-7 2 426-08-6 5 380-87-0 2461-15-6 122-60-1 5 255-75-4 2 212-05 - 7 2 211-94-1 3101-60-8 106-91-2 106-90-1 930-22-3 10353-53-4 19600-63-6 106-88-7 1436-34-6 2 984-50-1 2 404-44- 6 2855-19-8 7 320-37-8 298-18-0 1888-89-7 2 426 - 0 7 - 5 2 224-15-9 2425-79-8
151.63 203.20 74.08 88.11 114.14 116.16 130.19 130.19 154.17 186.30 150.18 195.17 184.62 180.20 206.29 142.15 128.13 70.09 98.15 126.2 72.11 100.16 128.22 156.27 184.32 240.43 86.09 114.16 142.20 174.2 202.25
97 98 98 99 99 98 99 98 98 98 98 nd 99 99 99 97 95 98 99 97 99 98 99 98 98 85 97 96 98 nd 95
Fluka Aldrich Merck Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Merck Kodak Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Merck Merck Merck Aldrich Aldrich Aldrich Merck own syn. Merck Aldrich Aldrich
7.1 57.0 4.1 3.4 4.3 2.3 1.9 2.0 12.0 0.0 14.2 324.7 39.6 25.0 18.8 70.7 389.5 7.3 4.9 37.1 1.6 1.8 3.1 0.0 0.0 0.0 2150.0 28.9 1418.0 972.4 666.2
285-67-6 286-20-4 279-49-2 3146-39-2 286-62-4 286-99-7 286-75-9 943-93-1 16533-72-5 1 758-33-4
84.12 98.15 98.15 110.16 126.20 182.31 140.18 178.28 132.07 72.12
96 98 98 98 98 95 97 99 90 97
Merck Merck Aldrich Aldrich Merck Aldrich Aldrich Aldrich Fluka Aldrich
1,2-Disubstituted epoxides 38. Epoxycyclopentane 39. Epoxycyclohexane 40. 1,4-Epoxycyclohexane 41. exo-2,3-Epoxynorbonane 42. Epoxycyclooctane 43. Epoxycyclododecane 44. 1,2 : 5,6-Diepoxycyclooctane 45.1,2-Epoxy-5,9-cyclododecanediene 46. cis-2,3-Epoxysuccinic acid 47. cis-2,3-Epoxybutane
0.1 0.8 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.3
58 TABLE 1 (continued) No. chemical
Cas No.
MW
Purity
Supplier
SCEIP
(%) 1, 2 -Disubstituted epoxides 48. cis-Stilbeneoxide 49. DL-Cis-2-Methyl-7,8-octadecenoxide 50. trans-2,3-Epoxybutane 51. trans-Stilbeneoxide 52. DL-trans-4-Chlorostilbeneoxide 53. trans-2,3-Epoxy-3-(4-methoxyphenyl)propionic acid methylester 54. ( + )-2,3-Epoxy-3-phenylpropionic acid ethylester, cis/trans1,1 -Disubstitut ed epoxides 55. fl-Pinaneoxide 1,1,2 - Trisubstituted epoxides 56.2,2- Dimethyl-l-methoxy-ethyleneoxide 57. ~-Pinaneoxide 58. ( + )-Limoneneoxide
1689-71-0 29 804-22-6 21490-63-1 1 439-07-2 28 291-10- 3
196.25 282.51 72.12 156.25 230.70
97 90 98 99 98
Aldrich Aldrich Aldrich Aldrich Aldrich
0.0 0.0 0.3 0.0 0.0
42 245-42-1
208.10
99
Aldrich
0.0
121-39-1
192.21
95
Aldrich
16.9
6 931-54-0
152.24
90
Aldrich
13.9
26196-04-3 1686-14-2 1 195-92-2
102.13 152.24 152.24
97 98 97
Aldrich Aldrich Aldrich
0.1 5.5 0.0
epoxypropane [2] and its halogenated derivatives. The SCEIP increases by means of the electronwithdrawing properties of the halogen substituent in the order
Fig. 2 shows the concentration-dependent increases of SCE frequencies in V79 cells induced by 2,3-epoxypropylethers, 2,3-epoxypropylphenyl-
- e l 3 [51 > -Br [6] > -C1 [4] > - F [3] > - H [2].
Glycidyl trimethylammonium chloride [7] contains a cationic group which also increases the genotoxic properties compared to 1,2-epoxypropane [2] and SCEs are induced more effectively by N-(2,3epoxypropyl)-phthalamide [8] than by the reference epoxide.
Mutation Research, 249 (1991) 55-70 © 1991 Elsevier Science Publishers B.V. 0027-5107/91/$03.50 ADONIS 002751079100127H
MUT 04979
Structure-activity relationships of epoxides: induction of sister-chromatid exchanges in Chinese hamster V79 cells Wilhelm vonder Hude, Silke Carstensen and Gtinter Obe 1 lnstitut fiir Allgemeine Genetik, Freie Universitiit Berlin, D-IO00 Berlin 33 and 1 Fb 9~ Genetik, Universitiit-GH Essen, D-4300 Essen 1 (F.R.G.)
(Received 18 September 1990) (Revision received 29 November 1990) (Accepted 3 December 1990)
Keywords: Structure-activity relationship; Epoxides; Sister-chromatid exchange; Chinese hamster V79 cells
Summary Analysis of SCE frequencies in Chinese hamster V79 cells was used to investigate structure-activity relationships of epoxides in mammalian cells. For this purpose the SCE-inducing potency of 58 epoxides was determined. Of these, 16 failed to induce SCE in V79 cells. According to the substitution of the oxirane ring the results show general agreement with results obtained in the Ames test. Mono-substituted epoxides had the highest genotoxic potency compared to di- and tri-substituted epoxides. In detail, there are differences in genotoxic potency between bacteria and mammalian cells which can be explained by differences in the cellular uptake of the compounds and by detoxification reactions.
Epoxides are generally direct-acting mutagens in Salmonella typhimurium (Wade et al., 1978; Watabe et al., 1980; Frantz and Sinsheimer, 1981; Canter et al., 1986; von der Hude et al., 1990) and some of them have been shown to be rodent carcinogens (van Duuren et al., 1963, 1965, 1966, 1967). Several studies have been performed to elaborate structure-activity relationships between the mutagenic potency of epoxides in bacterial mutagenicity tests and physico-chemical properties (Sugiura and Goto, 1981; Hemminki and Falck, 1979; Neau et al., 1982; Rosman et al.,
Correspondence: Dr. W. v o n d e r Hude, Max von PettenkoferInstitut des BGA, Postfach 33 00 13, D-1000 Berlin 33 (Germany).
1986, 1987, 1988). A more general study was performed by Wade et al. (1978), who reported a dependence of the mutagenic activity on the degree of substitution around the oxirane ring. Monosubstituted epoxides had the highest mutagenic activity. Furthermore, the mutagenic activity of monosubstituted epoxides is dependent on further electron-withdrawing groups adjacent the oxirane ring. Despite the known direct bacterial mutagenicity of most epoxides, little is known about their mutagenic action in mammalian cells. To investigate structure-activity relationships for genotoxic effects caused by epoxides in mammalian cells the SCE-inducing potencies (SCEIP) in V79 cells were determined for 58 epoxides. This test system allows the rather rapid screening of many substances and it gives reproducible results, allowing
56
a quantitative comparison of independent experiments. Materials and methods Test substances
The test substances, their Chemical Abstract Service (CAS) registry numbers, purities and suppliers are listed in Table 1. S C E test
The Chinese hamster V79 cell line was grown in minimal essential medium with Earle's salts (MEM) supplemented with 10% heat-inactivated fetal calf serum and penicillin (100 U / m l ) , streptomycin (0.1 m g / m l ) at 3 7 ° C and 5% CO 2. V79 cells (5 × 105 cells) were seeded into 25-cm2 flasks and after 18 h the test substances were added in appropriate concentrations. The medium with the test substance was discarded 2 h later, the cells were washed 2 times with fresh medium, which was then replaced by fresh medium containing 5-bromo-2'-deoxyuridine (10-5 M; BrdU). Mitotic cells were harvested by shake-off after 28 h of incubation with Colcemid (2 × 10 -7 M) for the last 4 h. The cells were fixed on slides and stained according to standard protocols (Latt et al., 1981).
metabolizing system. All compounds were tested up to cytotoxic concentrations which were detected by delay in the replication index (R1) or up to the highest soluble concentration of the test compound. All results were confirmed by independent experiments. The detailed results of all experiments are given in the Appendix. Table 2 shows the results obtained with the solvent DMSO and epichlorohydrin [4] which was run as a positive control substance concurrently with each individual experiment. The narrow range of results obtained with DMSO and the good reproducibility of the dose-response relationship with epichlorohydrin shows the reliability of the V 7 9 / S C E test for studies on structure-activity relationships in mammalian cells. Furthermore, by these results it becomes obvious that quantitative comparisons of the results obtained from different experiments are possible. The results concerning the SCEIP are included in the last column of Table 1. It can be seen that 16 epoxides did not induce SCE in V79 cells although they had clear cytotoxic properties. The dose-response relationships for the positive substances are shown in detail in Figs. 1-4. Fig. 1 shows the concentration-dependent increase of the SCE in V79 cells induced by 1,2-
Statistical evaluation
Twenty-five metaphases with harlequin-stained chromosomes were scored for SCE per experimental point. All results were confirmed in independent experiments and mean values of 2 experiments with a total of 50 metaphases scored per experimental point were analyzed by pair-wise comparison of the solvent control, using one-tailed Student's t test. The distribution of first, second and third mitoses was determined by counting 100 metaphases per experimental point to calculate the replication index (RI). To calculate the SCEIP the slopes of the d o s e response relationships were calculated by a computed linear regression analysis of the pooled resuits of the 2 independent experiments. Results
In this study 58 epoxides were tested for SCEIP with V79 cells in vitro without an external
30
3t
~ 20 ~u
t
[ O.Ol
L
I
i
o.1 _ m mo
I 1,0
t
I
|
lO.O
1,/I
Fig. l. Concentration-dependent increases of the SCE frequencies in V79 cells induced by 1,2-epoxypropyl derivatives. [2] 1,2-epoxypropane, [3] epifluorohydrin, [4] epichlorohydrin, [5] 1,2-epoxy-3,3,3-trichloropropane, [6] epibromohydrin, [7] 1,2epoxypropyl-3-trimethylammoniumchloride, [8] N-(2,3-epoxypropyl)-phthalamide.
57 TABLE 1 LIST OF CHEMICALS, C H E M I C A L A B S T R A C T SERVICE N U M B E R S (CAS Nos.), M O L E C U L A R W E I G H T S (MW), PURITIES, SUPPLIERS A N D T H E TEST R E S U L T ( S C E - I N D U C I N G POTENCY; SCEIP) No. chemical
Cas No.
MW
Purity
Supplier
SCEIP
(%) Monosubstituted epoxides 1. Styrene oxide 2. 1,2-Epoxypropane 3. Epifluorohydrin 4. Epichlorohydrin 5.1,2-Epoxy-3,3,3-trichloropropane 6. Epibromohydrin 7.2,3-Epoxypropyltrimethylammonium chloride (Glycidyltrimethylammonium chloride) 8. N-(2,3-Epoxypropyl)-phthalamide 9. 2,3-Epoxy-l-propanol 10. 2,3-Epoxypropyl-methylether 11.2,3-Epoxypropyl- 1-allylether 12. 2,3-Epoxypropyl-isopropylether 13.2,3-Epoxypropyl-tert.-butylether 14. 2,3-Epoxypropyl-n-butylether 15.2,3-Epoxypropyl- fur furylether 16.2,3-Epoxypropyl-(2-ethylhexyl)-ether 17.2,3-Epoxypropyl-phenylether 18.2,3-Epoxypropyl-4-nitro-phenylether 19. 2,3-Epoxypropyl-4-chloro-phenylether 20. 2,3-Epoxypropyl-4-methoxy-phenylether 21.2,3-Epoxypropyl-tert.-butyl-phenylether 22. 2,3-Epoxypropyl-methacrylic acid ester 23.2,3-Epoxypropyl-acrylic acid ester 24. 1,2-Epoxy-3-butene 25.1,2-Epoxy-5-hexene 26. 1,2-Epoxy-7-octene 27. 1,2-Epoxybutane 28. 1,2-Epoxyhexane 29. 1,2-Epoxyoctane 30. 1,2-Epoxydecane 31.1,2-Epoxydodecane 32. 1,2-Epoxyhexadecane 33.1,2 : 3,4-Diepoxybutane 34. 1,2 : 5,6-Diepoxyhexane 35.1,2 : 7,8-Diepoxyoctane 36. 1,2-Bis-(2,3-epoxypropoxy)-ethane 37. 1,4- Bis(2,3-epoxypropoxy)-butane
96-09- 3 75-56-9 503-09-3 106-89-8 3083-23-6 3132-64-7
120.15 58.08 76.07 92.53 161.42 136.98
97 99 90 99 nd 97
Aldrich Aldrich Aldrich Merck Sigma Merck
33.4 3.0 11.7 28.8 163.8 121.8
3033-70-0 5455-98-1 556-52-5 930-37-0 106-92-3 4016-14-2 7 665-72-7 2 426-08-6 5 380-87-0 2461-15-6 122-60-1 5 255-75-4 2 212-05 - 7 2 211-94-1 3101-60-8 106-91-2 106-90-1 930-22-3 10353-53-4 19600-63-6 106-88-7 1436-34-6 2 984-50-1 2 404-44- 6 2855-19-8 7 320-37-8 298-18-0 1888-89-7 2 426 - 0 7 - 5 2 224-15-9 2425-79-8
151.63 203.20 74.08 88.11 114.14 116.16 130.19 130.19 154.17 186.30 150.18 195.17 184.62 180.20 206.29 142.15 128.13 70.09 98.15 126.2 72.11 100.16 128.22 156.27 184.32 240.43 86.09 114.16 142.20 174.2 202.25
97 98 98 99 99 98 99 98 98 98 98 nd 99 99 99 97 95 98 99 97 99 98 99 98 98 85 97 96 98 nd 95
Fluka Aldrich Merck Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Merck Kodak Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Aldrich Merck Merck Merck Aldrich Aldrich Aldrich Merck own syn. Merck Aldrich Aldrich
7.1 57.0 4.1 3.4 4.3 2.3 1.9 2.0 12.0 0.0 14.2 324.7 39.6 25.0 18.8 70.7 389.5 7.3 4.9 37.1 1.6 1.8 3.1 0.0 0.0 0.0 2150.0 28.9 1418.0 972.4 666.2
285-67-6 286-20-4 279-49-2 3146-39-2 286-62-4 286-99-7 286-75-9 943-93-1 16533-72-5 1 758-33-4
84.12 98.15 98.15 110.16 126.20 182.31 140.18 178.28 132.07 72.12
96 98 98 98 98 95 97 99 90 97
Merck Merck Aldrich Aldrich Merck Aldrich Aldrich Aldrich Fluka Aldrich
1,2-Disubstituted epoxides 38. Epoxycyclopentane 39. Epoxycyclohexane 40. 1,4-Epoxycyclohexane 41. exo-2,3-Epoxynorbonane 42. Epoxycyclooctane 43. Epoxycyclododecane 44. 1,2 : 5,6-Diepoxycyclooctane 45.1,2-Epoxy-5,9-cyclododecanediene 46. cis-2,3-Epoxysuccinic acid 47. cis-2,3-Epoxybutane
0.1 0.8 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.3
58 TABLE 1 (continued) No. chemical
Cas No.
MW
Purity
Supplier
SCEIP
(%) 1, 2 -Disubstituted epoxides 48. cis-Stilbeneoxide 49. DL-Cis-2-Methyl-7,8-octadecenoxide 50. trans-2,3-Epoxybutane 51. trans-Stilbeneoxide 52. DL-trans-4-Chlorostilbeneoxide 53. trans-2,3-Epoxy-3-(4-methoxyphenyl)propionic acid methylester 54. ( + )-2,3-Epoxy-3-phenylpropionic acid ethylester, cis/trans1,1 -Disubstitut ed epoxides 55. fl-Pinaneoxide 1,1,2 - Trisubstituted epoxides 56.2,2- Dimethyl-l-methoxy-ethyleneoxide 57. ~-Pinaneoxide 58. ( + )-Limoneneoxide
1689-71-0 29 804-22-6 21490-63-1 1 439-07-2 28 291-10- 3
196.25 282.51 72.12 156.25 230.70
97 90 98 99 98
Aldrich Aldrich Aldrich Aldrich Aldrich
0.0 0.0 0.3 0.0 0.0
42 245-42-1
208.10
99
Aldrich
0.0
121-39-1
192.21
95
Aldrich
16.9
6 931-54-0
152.24
90
Aldrich
13.9
26196-04-3 1686-14-2 1 195-92-2
102.13 152.24 152.24
97 98 97
Aldrich Aldrich Aldrich
0.1 5.5 0.0
epoxypropane [2] and its halogenated derivatives. The SCEIP increases by means of the electronwithdrawing properties of the halogen substituent in the order
Fig. 2 shows the concentration-dependent increases of SCE frequencies in V79 cells induced by 2,3-epoxypropylethers, 2,3-epoxypropylphenyl-
- e l 3 [51 > -Br [6] > -C1 [4] > - F [3] > - H [2].
Glycidyl trimethylammonium chloride [7] contains a cationic group which also increases the genotoxic properties compared to 1,2-epoxypropane [2] and SCEs are induced more effectively by N-(2,3epoxypropyl)-phthalamide [8] than by the reference epoxide.
