Post on 07-Sep-2020
Rational design, synthesis and biological screening of
triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents
Ehtesham Jameela, Poonam Meenab, Mudasir Maqboola, Jitendra Kumara, Waqar Ahmeda, Syed
Mumtazuddinc, Manisha Tiwarib*, Nasimul Hodaa* and B. Jayaramd,e,f
aDepartment of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi
110025, IndiabDr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007,
IndiacDepartment of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, IndiadDepartment of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016,
IndiaeKusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, IndiafSupercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi
110016, India.
* Corresponding authors.
#Nasimul Hoda, Ph.D. $Manisha Tiwari, Ph.D.Professor Assistant ProfessorDepartment of Chemistry Dr. B. R. Ambedkar Jamia Millia Islamia, Centre for Biomedical Research, Jamia Nagar, New Delhi- 110025, University of Delhi, New Delhi- 110007, India India Email: nhoda@jmi.ac.in Email: mtiwari07@gmail.com
Supporting Information
1H-NMR of 5-methyl-7-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (8)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)
3.00
4.13
4.98
1.08
0.99
2.51
53.
042
3.05
43.
067
3.63
53.
714
3.72
63.
738
6.08
9
7.24
4
8.23
0
13C-NMR of 5-methyl-7-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (8)
1H-NMR of 4-chloro-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine 9 (a).
-7-6-5-4-3-2-101234567891011121314151617f1 (ppm)
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
3.16
8.00
1.00
1.01
1.01
1.16
1.04
1.10
1.01
2.46
0
3.38
2
6.59
67.
356
7.37
67.
544
7.82
67.
847
8.14
28.
431
10.4
71
13C-NMR of 4-chloro-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine 9 (a).
-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)
-0.01
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
0.11
0.12
0.13
0.14
0.1526.0
39.3
39.5
39.7
39.9
40.2
40.4
40.6
43.1
47.6
95.4
116.
911
9.8
123.
312
4.3
126.
012
7.8
129.
713
0.5
132.
114
0.0
149.
915
4.4
157.
116
4.8
Mass spectra of 4-chloro-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine 9 (a).
1H-NMR of 4-chloro-N-(4-methoxyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (b).
-7-6-5-4-3-2-101234567891011121314151617f1 (ppm)
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
3.02
8.00
3.02
1.00
2.01
2.01
1.01
1.00
2.46
0
3.69
63.
894
6.61
36.
877
6.89
97.
521
7.54
28.
445
10.0
27
Mass spectra of 4-chloro-N-(4-methoxyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (b).
1H-NMR of 4-chloro-N-(4-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (c).
-9-8-7-6-5-4-3-2-101234567891011121314151617181920f1 (ppm)
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
3.05
8.01
1.04
2.04
2.01
1.08
1.00
2.45
8
3.93
3
6.58
87.
152
7.63
38.
430
10.2
03
13C-NMR of 4-chloro-N-(4-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (c).
-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
25.1
39.4
39.6
39.8
40.0
40.2
40.4
40.6
43.0
47.5
95.4
105.
5
115.
711
5.9
122.
5
135.
514
9.9
153.
615
4.4
157.
115
9.7
160.
916
3.8
164.
7
Mass spectra of 4-chloro-N-(4-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (c).
1H of 4-chloro-N-(2-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (d).
-7-6-5-4-3-2-101234567891011121314151617f1 (ppm)
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
3.10
4.00
4.01
1.18
1.01
1.09
2.03
1.00
1.01
2.60
8
3.80
33.
923
6.19
27.
081
7.09
97.
147
7.16
87.
250
7.31
28.
192
8.34
3
13C of 4-chloro-N-(2-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)
piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (d).
-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
0.30
0.32
0.34
0.36
0.38
25.4
43.0
47.6
76.8
77.1
77.4
95.0
117.
212
2.1
122.
412
4.4
126.
112
9.5
134.
014
9.5
150.
115
2.2
154.
516
4.0
165.
3
Mass spectra of 4-chloro-N-(2-fluoroyphenyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)- 1,3,5-triazin-2-amine 9 (d).
1H NMR of N2-cyclopropyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (a).
-8-7-6-5-4-3-2-10123456789101112131415161718192021f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
3.01
4.07
4.00
2.05
2.02
1.00
2.01
2.06
2.04
2.08
2.60
23.
855
4.07
35.
084
5.48
46.
187
7.25
57.
278
7.36
37.
416
7.50
57.
532
8.34
3
13C NMR of N2-cyclopropyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (a).
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
55007.2
21.3
23.5
25.2
42.6
47.8
76.6
77.0
77.5
94.6
116.
811
9.0
122.
412
6.0
129.
113
0.7
131.
213
9.9
150.
215
4.2
157.
116
4.8
165.
1
175.
9
Mass spectra of N2-cyclopropyl-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (a).
1H NMR of 6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N2-(p-tolyl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (b).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.05
3.00
8.00
1.05
2.02
1.07
1.02
2.04
1.01
1.04
1.05
1.02
1.00
2.30
2
3.10
93.
742
3.78
4
6.42
66.
882
6.90
97.
072
7.09
87.
305
7.38
57.
411
7.80
97.
830
8.00
38.
256
8.99
89.
335
13C NMR of 6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N2-(p-tolyl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (b).
0102030405060708090100110120130140150160170180190200f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
19000
20.8
25.0
39.2
39.5
39.7
40.0
40.3
40.6
40.9
42.7
47.8
95.3
116.
411
8.2
120.
912
3.7
126.
612
9.3
129.
512
9.9
131.
513
7.7
141.
515
0.0
154.
315
7.0
164.
516
5.0
Mass spectra of 6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N2-(p-tolyl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (b).
1H NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (c).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.00
8.00
1.00
2.02
1.01
1.00
2.02
1.00
1.00
1.03
1.02
2.50
7
3.95
73.
990
6.65
07.
303
7.32
97.
536
7.68
27.
992
8.00
78.
158
8.47
59.
512
9.67
1
13C NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (c).
`
102030405060708090100110120130140150160170f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
25.0
39.2
39.4
39.7
40.0
40.3
40.6
40.8
42.7
47.7
95.3
100.
211
6.5
116.
811
7.1
118.
611
9.2
120.
712
1.8
123.
912
9.5
130.
113
7.7
141.
2
150.
015
4.4
164.
416
4.5
164.
616
4.9
Mass spectra of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (c).
1H NMR of N2-(4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (d).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.01
8.00
1.03
2.06
1.08
1.01
2.04
1.01
1.03
1.02
1.02
1.03
2.27
8
3.72
53.
763
6.39
06.
888
7.05
27.
077
7.28
67.
501
7.52
37.
761
7.78
27.
974
8.22
29.
073
9.31
3
13C NMR of N2-(4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (d).
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-2000
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
22000
2400029.4
39.2
39.4
39.7
40.0
40.3
40.6
40.8
42.7
47.7
95.3
115.
211
5.5
116.
411
8.3
122.
412
3.0
123.
712
6.6
129.
513
0.0
136.
614
1.4
150.
015
4.4
156.
515
7.2
164.
616
4.7
165.
017
2.4
Mass spectra of N2-(4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (d).
1H NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(p-tolyl)-1,3,5-triazine-2,4diamine 10 (e).
-4-3-2-1012345678910111213141516f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
3.09
3.17
8.00
1.02
2.11
1.07
2.12
2.03
1.10
1.08
1.01
2.26
82.
507
3.31
33.
942
3.97
5
6.62
47.
100
7.12
77.
310
7.56
27.
588
8.04
88.
070
8.45
19.
196
9.37
4
13C NMR of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(p-tolyl)-1,3,5-triazine-2,4diamine 10 (e).
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
7500
20.9
25.1
39.2
39.4
39.7
40.0
40.3
40.5
40.8
42.7
47.8
95.3
108.
511
6.8
117.
011
9.1
121.
012
1.5
129.
413
1.5
137.
713
8.0
150.
015
4.4
157.
216
4.4
164.
716
5.0
173.
4
Mass spectra of N2-(3-chloro-4-fluorophenyl)-6-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)-N4-(p-tolyl)-1,3,5-triazine-2,4diamine 10 (e).
1H NMR of N2-cyclopropyl-6-(piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (f).
-7-6-5-4-3-2-101234567891011121314151617f1 (ppm)
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2
4.96
7.97
2.00
1.98
1.06
1.00
1.00
2.73
23.
400
3.76
1
7.17
07.
188
7.40
27.
780
8.68
69.
497
13C NMR of N2-cyclopropyl-6-(piperazin-1-yl)-N4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4diamine 10 (f).
-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.26.7
14.5
23.9
39.3
39.5
39.7
39.9
40.1
40.3
40.5
43.0
116.
011
7.8
120.
812
3.1
123.
612
6.3
129.
814
2.0
164.
716
7.5
Table S1. Predicted ADMET properties of the target compounds (9a-9d, 10a-10f and 3a-3g).
Compound Mol_MWa
(0-500)HB
donorsa
(0-6)
HB acceptorsa
(2-20)
QPlog Po/wa
(-2 to 6.5)
Rotatable bondsa
(0-15)
PSAa
(7-200)SASAa
(300-1000)
CNSa
9a 490.877 2 5 1.509 0 30.432 249.973 2
9b 452.905 0 5 0.947 0 30.433 296.126 2
9c 440.87 2 5 1.327 0 30.63 266.445 2
9d 440.87 2 5 1.306 0 30.092 262.254 2
10a 511.511 3 5.5 1.633 0 37.219 278.263 2
10b 561.571 4 5.5 1.78 0 35.401 333.911 2
10c 599.98 4 5.5 1.728 0 35.401 293.011 2
10d 565.535 4 5.5 1.473 0 35.401 286.618 2
10e 546.009 4 5.5 1.623 0 35.471 280.543 2
10f 379.387 4 3.5 -0.622 0 28.47 186.809 -2
3a 401.726 4 2.5 0.675 0 19.458 247.302 -1
3b 383.735 4 2.5 1.032 0 19.8 279.084 -1
3c 379.771 4 2.5 0.637 0 19.8 243.895 -1
3d 395.771 2 2.5 1.708 0 19.8 315.448 2
3e 418.18 4 2.5 1.556 0 19.8 289.458 -1
3f 364.209 4 2.5 1.107 0 19.799 274.318 -1
3g 380.208 2 2.5 1.836 0 19.799 340.145 2
Compound Rule of three
Rule offive
QPPcacoa (<25 poor, >500
great)
QPlogBBa
(-3 to 1.2)
QPPMDCKa
(<25poor, >500great)
QPlogKhSaa
(-1.5 to 1.5)% Human Oral
Absorptiona
(>80% high,<25% poor)
9a 0 0 9551.714 0.784 10000 -0.237 100
9b 0 1 5832.431 0.591 6940.4 -0.925 86.931
9c 0 0 9641.762 0.701 10000 -0.302 100
9d 0 0 9551.714 0.699 10000 -0.3 100
10a 0 2 9641.99 0.706 10000 -0.064 81.898
10b 0 2 9735.452 0.707 10000 -0.082 82.833
10c 0 2 9735.195 0.767 10000 -0.038 82.532
10d 0 2 9735.195 0.644 8927.9 -0.046 81.036
10e 0 2 9641.822 0.682 10000 0.014 81.838
10f 0 0 9906.038 -1.155 10000 -0.099 94.824
3a 0 0 9906.038 -0.599 10000 -0.561 100
3b 0 0 9906.038 -0.535 10000 -0.57 100
3c 0 0 9906.038 -0.606 10000 -0.503 100
3d 0 0 5718.929 0.583 8013.4 -0.317 100
3e 0 0 9906.038 -0.615 10000 -0.549 100
3f 0 0 9906.038 -0.576 10000 -0.54 100
3g 0 0 5718.929 0.603 9782.1 -0.306 100
aMW: molecular weight, HBA: hydrogen-bond acceptor atoms, HBD: hydrogen-bond donor atoms, PSA: polar surface area, SASA: total solvent accessible surface area, QPlogPo/w: Predicted octanol/water partition coefficient, QPlogS: Predicted aqueous solubility, CNS: Predicted central nervous system activity on a –2 (inactive) to +2 (active) scale, QPPCaco: Caco-2 cell permeability in nm/sec, QPPMDCK: Predicted apparent MDCK cell permeability in nm/sec, QPlogBB: brain/blood partition coefficient, QPlogKhsa: binding to human serum albumin, Percent Human-Oral Absorption: human oral absorption on 0 to 100% scale.
Table S2. Toxicity prediction analysis of triazine derivatives 9a-9d, 10a-10f and 3a-3g using TOPKAT module of Discovery studio 4.0.
NTP Rodent Carcinogenicity (v 3.2)
Com
Male mouse Female mouse Male rat Female rat
Computed probability
Effect Computed probability
Effect Computed probability
Effect Computed probability
Effect
9a 0.405Non-
Carcinogen 0.405Non-
Carcinogen 0.236Non-
Carcinogen 0.514Carcinogen
9b 0.430Non-
Carcinogen 0.177Non-
Carcinogen 0.365Non-
Carcinogen 0.522Carcinogen
9c 0.517Non-
Carcinogen 0.279Non-
Carcinogen 0.412Non-
Carcinogen 0.531Carcinogen
9d 0.512Non-
Carcinogen 0.290Non-
Carcinogen 0.351Non-
Carcinogen 0.524Carcinogen
10a 0.437Non-
Carcinogen 0.332Non-
Carcinogen 0.303Non-
Carcinogen 0.518Carcinogen
10b 0.437Non-
Carcinogen 0.112Non-
Carcinogen 0.334Non-
Carcinogen 0.545Carcinogen
10c 0.505Non-
Carcinogen 0.323Non-
Carcinogen 0.332Non-
Carcinogen 0.514Carcinogen
10d 0.429Non-
Carcinogen 0.284Non-
Carcinogen 0.342Non-
Carcinogen 0.536Carcinogen
10e 0.578Carcinogen
0.172Non-
Carcinogen 0.434Non-
Carcinogen 0.537Carcinogen
10f 0.529Non-
Carcinogen 0.501Non-
Carcinogen 0.335Non-
Carcinogen 0.480Non-
Carcinogen
3a 0.372Non-
Carcinogen 0.292Non-
Carcinogen 0.206Non-
Carcinogen 0.516Carcinogen
3b 0.356Non-
Carcinogen 0.303Non-
Carcinogen 0.224Non-
Carcinogen 0.505Non-
Carcinogen
3c 0.365Non-
Carcinogen 0.109Non-
Carcinogen 0.217Non-
Carcinogen 0.519Carcinogen
3d 0.262Non-
Carcinogen 0.225Non-
Carcinogen 0.216Non-
Carcinogen 0.522Carcinogen
3e 0.406Non-
Carcinogen 0.335Non-
Carcinogen 0.263Non-
Carcinogen 0.501Non-
Carcinogen
3f 0.517Non-
Carcinogen 0.151Non-
Carcinogen 0.341Non-
Carcinogen 0.519Carcinogen
3g 0.434Non-
Carcinogen 0.286Non-
Carcinogen 0.300Non-
Carcinogen 0.501Non-
Carcinogen
FDA Rodent Carcinogenicity (v 3.1)
Com
Male mouse Female mouse Male rat Female rat
Computed probability
Effect Computed probability
Effect Computed probability
Effect Computed probability
Effect
9a 0.183Non-
Carcinogen 0.255Non-
Carcinogen 0.369 Carcinogen 0.260 Carcinogen
9b 0.178Non-
Carcinogen 0.243Non-
Carcinogen 0.349 Carcinogen 0.263 Carcinogen
9c 0.179Non-
Carcinogen 0.211Non-
Carcinogen 0.361 Carcinogen 0.212Non-
Carcinogen
9d 0.174Non-
Carcinogen 0.218Non-
Carcinogen 0.352 Carcinogen 0.213Non-
Carcinogen
10a 0.173Non-
Carcinogen 0.236Non-
Carcinogen 0.305 Carcinogen 0.240Non-
Carcinogen
10b 0.173Non-
Carcinogen 0.250Non-
Carcinogen 0.367 Carcinogen 0.235Non-
Carcinogen
10c 0.172Non-
Carcinogen 0.253Non-
Carcinogen 0.368 Carcinogen 0.226Non-
Carcinogen
10d 0.172Non-
Carcinogen 0.223Non-
Carcinogen 0.380 Carcinogen 0.210Non-
Carcinogen
10e 0.168Non-
Carcinogen 0.234Non-
Carcinogen 0.241 Carcinogen 0.232Non-
Carcinogen
10f 0.169Non-
Carcinogen 0.255Non-
Carcinogen 0.334Non-
Carcinogen 0.211Non-
Carcinogen
3a 0.188Non-
Carcinogen 0.210Non-
Carcinogen 0.326 Carcinogen 0.213Non-
Carcinogen
3b 0.199Non-
Carcinogen 0.213Non-
Carcinogen 0.322 Carcinogen 0.229Non-
Carcinogen
3c 0.199Non-
Carcinogen 0.233Non-
Carcinogen 0.318 Carcinogen 0.263 Carcinogen
3d 0.193Non-
Carcinogen 0.215Non-
Carcinogen 0.301 Carcinogen 0.286 Carcinogen
3e 0.194Non-
Carcinogen 0.210Non-
Carcinogen 0.327 Carcinogen 0.259 Carcinogen
3f 0.188Non-
Carcinogen 0.217Non-
Carcinogen 0.290 Carcinogen 0.225Non-
Carcinogen
3g 0.187Non-
Carcinogen 0.210Non-
Carcinogen 0.284Non-
Carcinogen 0.257 Carcinogen
Com Rat oral LD50
(g/kg/body weight)
Chronic LOAEL
(g/kg/body weight)
Daphnia EC50
(mg/l)
Ames mutagenicity
Developmental toxicity potential
Aerobic biodegradability
Skin Irritancy
Ocular irritancy
9a 0.1729 0.190 0.458 Non-Mutagen Non-Toxic Non-Degradable None Mild
9b 0.125 0.503 0.336 Non-Mutagen Non-Toxic Non-Degradable None Mild
9c 0.196 0.513 0.385 Non-Mutagen Non-Toxic Non-Degradable None Severe
9d 0.174 0.564 0.333 Non-Mutagen Non-Toxic Non-Degradable None Mild
10a 0.296 0.196 0.465 Non-Mutagen Non-Toxic Non-Degradable None Mild
10b 0.502 0.0433 0.168 Non-Mutagen Non-Toxic Non-Degradable None Mild
10c 0.198 0.0406 0.056 Non-Mutagen Non-Toxic Non-Degradable None Mild
10d 0.464 0.040 0.135 Non-Mutagen Non-Toxic Non-Degradable None Mild
10e 0.835 0.176 4.799 Non-Mutagen Non-Toxic Non-Degradable None Mild
10f 0.248 0.120 0.0602 Non-Mutagen Non-Toxic Non-Degradable None Mild
3a 1.023 0.0067 0.266 Non-Mutagen Non-Toxic Non-Degradable None Mild
3b 0.844 0.0083 0.266 Non-Mutagen Non-Toxic Non-Degradable None Mild
3c 1.033 0.0096 0.604 Non-Mutagen Non-Toxic Non-Degradable None Mild
3d 0.364 0.0154 0.469 Non-Mutagen Non-Toxic Non-Degradable None Mild
3e 0.369 0.0085 0.113 Non-Mutagen Non-Toxic Non-Degradable None Mild
3f 0.504 0.0264 0.212 Non-Mutagen Non-Toxic Non-Degradable None Severe
3g 0.178 0.0422 0.165 Non-Mutagen Non-Toxic Non-Degradable None Mild
Abbreviations: US FDA, United States Food and Drug administration; NTP, National toxicity program; EC50, effective concentration 50%; LD50, lethal dose 50%; LOAEL, lowest observed adverse effect level.
Probability values:Low probability- 0.0-0.3High probability-0.7-1.0Indeterminate- 0.3-0.7