PHYS-CHEM SCREENING :

SMALL STUDIES ........... BIG CONSEQUENCES

Gordon SANDERS

Givaudan International SA, Geneva, Switzerland

US-EPA / Industry Workshop, Arlington VA, 10 – 11 September 2014
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“Chemicals are used to make most of the 

products that we rely on in our daily lives. 

When used safely, chemicals significantly 

contribute to the improvement of our quality 

of life, health, and well-being.”
3

“Chemicals are used to make most of the 

products that we rely on in our daily lives. 

When used safely, chemicals significantly 

contribute to the improvement of our quality 

of life, health, and well-being.”

US-EPA : CDR – Basics Fact Sheet (June, 2014)

- Strict minimum of product comprehension required

- Intrinsic properties + Environmental Release  Acceptable Risk
PHYS-CHEM SCREENING :

SMALL STUDIES ........... BIG CONSEQUENCES

4

Content

Be Prepared - Chemical Composition and Identity

The Utility of Phys-Chem Data

Deriving Phys-Chem Data for Difficult to Test Substances and 

Challenges Related to Interpretation and Application

1

2

3

4 Impact on Other Testing and Needs Moving Forward
PHYS-CHEM SCREENING :

SMALL STUDIES ........... BIG CONSEQUENCES

5

Content

Be Prepared - Chemical Composition and Identity

The Utility of Phys-Chem Data

Deriving Phys-Chem Data for Difficult to Test Substances and 

Challenges Related to Interpretation and Application

1

2

3

4 Impact on Other Testing and Needs Moving Forward
BE PREPARED

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 Chemical Identity :

Class 1

“Well Defined”

Class 2

UVCB

Polymers

Non-Ionic, Anionic, 

Cationic, Amphoteric

-Low Mol. Wt.

-Low + High Mol. Wt.

-High Mol. Wt.

-Mono- or Multi-Constituent ?

-Chem. Abs. nomenclature(s)

-CAS No(s)

-Molecular Formula

-Molecular Weight

-Structure(s)

-Precursor(s) + CAS No(s)

-Description of process

-Detail of typical composition

-Structures / partial structures

-MWn

-LMW (500, 1000)

-Details of Monomer and 

reactants
REPRESENTATIVE SAMPLE + SPECTRALANALYSES

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RT: 10.00 - 70.00

10 15 20 25 30 35 40 45 50 55 60 65 70 Time (min)

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100 Relative Abundance

57.39 NL: 1.45E7 m/z= 35.0-350.0 - m/z= 39.5-40.5+

43.5-44.5 MS K82645D

Signal Apex RT Area % Area

1 57.39 92780026 99.69

K82645D #6436-6450 RT: 57.29-57.40 AV: 15 SB: 87 57.70-57.96 , 56.59-57.06 NL: 3.39E6 T: + c EI Q1MS [25.00-350.00]

40 60 80 100 120 140 160 180 200 220 240 m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100 Relative Abundance

120

138

121

220

139 55

67 41 92 39 65 93

29 54 64 82 122 221

Constituent A

MW 220, 

C13H16O3

UV-VIS Scan

FT-IR

1H, 13C-NMR

MS
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RT: 25.61 - 73.65

26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72

Time (min)

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100 Relative Abundance

53.10

50.26 41.96

51.96

47.96

40.13

44.21 45.99 56.54 48.47 55.79

59.47

58.42

38.35 42.92

26.99 60.66 29.91 34.23 62.11 29.32 30.99 36.36 62.59 65.25 69.61 71.60 72.51

NL:

1.35E8

m/z= 

35.00-350.00 - m/z= 

39.50-40.50+

43.50-44.50 MS K86776

RT: 10.00 - 70.00

10 15 20 25 30 35 40 45 50 55 60 65 70

Time (min)

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100 Relative Abundance

57.39 NL:

1.45E7

m/z= 

35.0-350.0 - 

m/z= 

39.5-40.5+

43.5-44.5 

MS K82645D
IMPURITIES – DEFINITION AND ASSESSMENT

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 Definition :

 CAS RN + CA nomenclature if known

 Source material if appropriate

 Class or Structural range

 Class 1 – How low ?

 List all present; regardless of percentage

 Knowns and Unknowns should be included

 Characterize using :

 Chemical and instrumental analyses

 Knowledge of manufacturing process chemistry

 Quality Control procedures
PHYS-CHEM SCREENING :

SMALL STUDIES ........... BIG CONSEQUENCES

10

Content

Be Prepared - Chemical Composition and Identity

The Utility of Phys-Chem Data

Deriving Phys-Chem Data for Difficult to Test Substances and 

Challenges Related to Interpretation and Application

1

2

3

4 Impact on Other Testing and Needs Moving Forward
WHERE ARE PHYS-CHEM VALUES USED ?

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EPI SuiteTM ECOSARTM

logKow

WS

VP

MPt

BPt

Acute & 

Chronic 

AquaTox

Acute-COC

Chronic-COC

Acute & 

Chronic 

AquaTox

Acute-COC

Chronic-COC

MEASURED PREDICTED

E-FAST

-PEC-

-ExceedenceSTP

Removal 

Rate

BCF

Environmental

Distribution

!

PRIMORDIAL 

for AquaTox

Planning !
PHYS-CHEM SCREENING :

SMALL STUDIES ........... BIG CONSEQUENCES

12

Content

Be Prepared - Chemical Composition and Identity

The Utility of Phys-Chem Data

Deriving Phys-Chem Data for Difficult to Test Substances and 

Challenges Related to Interpretation and Application

1

2

3

4 Impact on Other Testing and Needs Moving Forward
DERIVING PHYS-CHEM DATA FOR DIFFICULT TO TEST SUBSTANCES

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low Kow, soluble

high Kow, 

low solubility

soluble

insoluble

volatile

non-volatile

END-POINT OPPTS OECD OBSERVATIONS / LIMITATIONS

Octanol / Water Shake-Flask 830.7550 107 Range logKow of -2 to 4

Partition Coefficient

Generator Column 830.7560 - logKow > 1

HPLC 830.7570 117 Range logKow of 0 to 6

Slow-Stir - 123 Range logKow of 4 to 8.2

Water Solubility Flask & 830.7840 105

Column Elution Solubilities < 10 mg/L

Generator Column 830.7860 - Solubilities from 1 μg/L to 5 g/L 

Vapour Pressure Various 830.795 104 Dynamic : Range 1 -2 x 103 Pa

Static : Range 1 x 101 - 1 x 105 Pa

Isoteniscope : 1 x 102 - 1 x 105 Pa

Effusion / Balance : 1 x 10-3 - 1 x 100 Pa

Gas Saturation : < 1 x 10-3 - 1 x 100 Pa

TEST GUIDELINE

Formation of octanol microdroplets in aqueous phase

Efficient, practical, useable 

with UVCBs

Separation and filtration issues, 

hydrolytic stability

Correct choice of method for VP 

range, thermal stability, avoid 

extrapolation from high- to lowtemps
CHALLENGES RELATED TO INTERPRETATION AND APPLICATION

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 Octanol-Water Partition Coefficient :

 Intrinsic error stated as +/- 0.5 log units !

CH3

H

CH3

3C

CH2

O

CH3

O

H3C

CH2

CH3

CH3

N

O

O

CH3 N O

O

CH3

CH3

CH3

N

O

O

Measured logKow

Linalyl Acetate d-Limonene Musk Xylene

3.90 4.38 4.90

Potential logKow Range 3.40 – 4.40 3.88 – 4.88 4.40 – 5.40

EPISuite :

STP Removal Rate

BCF - Regression

Range

Range

53% 94% 74%

46 – 66% 93 – 95% 51 – 87%

174 L/kg 361 L/kg 794 L/kg

81 – 372 L/kg 169 – 771 L/kg 372 - 1700 L/kg
CHALLENGES RELATED TO INTERPRETATION AND APPLICATION

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 Water Solubility Determinations :

 Sub-ppm substances : Separation of dissolved from non-soluble

Application to AquaTox studies 

0

0.2

0.4

0.6

0.8

1

1.2

Water Solubility Time 0 24hr Renewal

ppm
CHALLENGES RELATED TO INTERPRETATION AND APPLICATION

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 Water Solubility Determinations :

 Sub-ppm substances : Separation of dissolved from non-soluble

Application to AquaTox studies

0

5

10

15

20

Water Solubility Time 0 24hr Renewal Pre-Test

ppm
PHYS-CHEM SCREENING :

SMALL STUDIES ........... BIG CONSEQUENCES

17

Content

Be Prepared - Chemical Composition and Identity

The Utility of Phys-Chem Data

Deriving Phys-Chem Data for Difficult to Test Substances and 

Challenges Related to Interpretation and Application

1

2

3

4 Impact on Other Testing and Needs Moving Forward
IMPACT ON OTHER TESTING AND NEEDS MOVING FORWARD

I

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 logKow :

 Directly related to Bioaccumulation potential

 Is the main driver for Bioaccumulation QSARs

 Is NOT, however, the main influencing characteristic

logKow

830.7550

830.7560

830.7570

Fish-BCF

850.1730

S9 fractions (-80°C)

larger debris removed

Liver Homogenate

In-vitro
IMPACT ON OTHER TESTING AND NEEDS MOVING FORWARD

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 WATER SOLUBILITY :

AquaTox Studies

Exposure Medium Prep

Analytics

-Direct Analysis-

-Extraction / ConcentrationDirect Dissolution 

in Media

Use of Solvent Saturated Solns. 

& WAFs

Reproducibility

Stirring time vs Stability
IMPACT ON OTHER TESTING AND NEEDS MOVING FORWARD

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 VAPOUR PRESSURE :

 AquaTox

 ADAPTED GUIDANCE FOR PHYS-CHEM TESTING AND

INTERPRETATION OF :

 UVCBS

 IONISABLES

What are the effects of using closed test systems ?
CONCLUSIONS

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 Determined Phys-Chem values are prone to intrinsic errors : + / - significant

 Some test substances ARE more difficult to test than others  increased relative error: 

low water solubility, high vapour pressure, UVCBs, ionisables

The World that we live in is not ideal .........

BUT

Comprehension of our products is our responsibility .........

 Prepare the terrain well : test substance quality, QSAR modelling / read-across, pre-test 

trials 

 Use existing guidelines or adapt where possible with justification

 Phys-chem values may not be suitable “surrogate” for extrapolation (e.g. logKow  BCF) 

– Development of parallel approach, or, move to higher-tier

 More guidance from Phys-Chem values through to AquaTox media preparation 
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