ars.els-cdn.com · Web viewbDr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi,...

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: [email protected] Email: [email protected]

mailto:[email protected]

mailto:[email protected]

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

9a 0.405Non-

Carcinogen 0.405Non-


Carcinogen 0.514Carcinogen

9b 0.430Non-




9c 0.517Non-




9d 0.512Non-




10a 0.437Non-




10b 0.437Non-




10c 0.505Non-




10d 0.429Non-




10e 0.578Carcinogen

0.172Non-



10f 0.529Non-




Carcinogen

3a 0.372Non-




3b 0.356Non-




Carcinogen

3c 0.365Non-




3d 0.262Non-




3e 0.406Non-




Carcinogen

3f 0.517Non-




3g 0.434Non-




Carcinogen

FDA Rodent Carcinogenicity (v 3.1)

Com

Male mouse Female mouse Male rat Female rat

Computed probability




Effect

9a 0.183Non-


Carcinogen 0.369 Carcinogen 0.260 Carcinogen

9b 0.178Non-



9c 0.179Non-


Carcinogen 0.361 Carcinogen 0.212Non-

Carcinogen

9d 0.174Non-



Carcinogen

10a 0.173Non-



Carcinogen

10b 0.173Non-



Carcinogen

10c 0.172Non-



Carcinogen

10d 0.172Non-



Carcinogen

10e 0.168Non-



Carcinogen

10f 0.169Non-




Carcinogen

3a 0.188Non-



Carcinogen

3b 0.199Non-



Carcinogen

3c 0.199Non-



3d 0.193Non-



3e 0.194Non-



3f 0.188Non-



Carcinogen

3g 0.187Non-



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



10c 0.198 0.0406 0.056 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



3c 1.033 0.0096 0.604 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

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