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Partition coefficient

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Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
28/06/2010 - 20/07/2010
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The substance is manufactured and supplied as an aqueous solution. For the purposes of REACH compliance, attempts were made to freeze dry a sample of the substance so that some of the applicable physico-chemical testing could be completed. NMR and IR was used to confirm that the freeze drying process had not degraded the substance immediately after drying. However, some of the phys-chem tests, such as water solubility, gave unexpected results. Further analytical work subsequently confirmed that the dry substance had degraded to some extent, forming the free amine. Thus the reliability of this study cannot be assessed as the purity of the substance at the time of testing is unknown. Furthermore, the shake flask method is not suitable for surfactants.
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient)
Deviations:
no
GLP compliance:
yes
Type of method:
shake-flask method to: flask method
Partition coefficient type:
octanol-water
Analytical method:
high-performance liquid chromatography
Type:
log Pow
Partition coefficient:
0.93
Temp.:
20 °C
pH:
10.11 - 10.22
Details on results:
Mean partition coefficient result (Log Pow): 0.93
Endpoint:
partition coefficient
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Study period:
From Sept. 23, 2003 to Sept. 28, 2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, in accordance with good scientific principles. Results based on measured values (solubility in octanol) and literature values (critical micelle concentration in aqueous system).
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
The partition coefficient of amine oxide can be estimated by calculating the ratio of its solubility in octanol to its solubility in water. However, since surfactant molecules such as amine oxide tend to aggregate into micellar structures, it is likely that the partition coefficient estimated by this approach is not accurate. A more accurate partition coefficient may be estimated by using the aqueous critical micelle concentration (CMC) instead of the aqueous solubility. Since the CMC is the concentration at which isolated molecules of surfactant have saturated the aqueous solution, and any additional molecules added to the system will form micellar aggregates, the CMC provides the best measure of the solubility limit for a surfactant. In this study, the CMC’s of aqueous surfactant systems were taken from the literature, and ratioed to solubility in octanol, which was determined in the laboratory.
GLP compliance:
no
Type of method:
estimation method (solubility ratio)
Remarks:
The octanol/water partition coefficient was estimated by calculating the ratio of the solubility in octanol, determined in the laboratory, to the critical micelle concentration (CMC) in aqueous solution, obtained from the literature.
Partition coefficient type:
octanol-water
Analytical method:
other: The concentration of soluble GTS02902 in octanol was quantified using two methods: (1) DBAS (disulfide blue active substances), and (2) nitrogen determination (Dr. Lange photometric analysis).
Type:
log Pow
Partition coefficient:
0.95
Remarks on result:
other: C10 DMAO
Type:
log Pow
Partition coefficient:
1.42
Remarks on result:
other: C11 DMAO
Type:
log Pow
Partition coefficient:
1.85
Remarks on result:
other: C12 DMAO
Type:
log Pow
Partition coefficient:
2.69
Remarks on result:
other: C14 DMAO
Type:
log Pow
Partition coefficient:
< 2.7
Remarks on result:
other: C12-14 DMAO
Type:
log Pow
Partition coefficient:
< 2.7
Remarks on result:
other: C6-C14 DMAO
Details on results:
PARTITION COEFFICIENT BY HPLC METHOD (Van der Geest-van de Ruit):
- Good chromatograms were obtained with the reference substances. However, no peaks were detected in any of the chromatograms of the test substance. Based on these results, it was concluded that the partition coefficient of the test substance (C12/C14 DMAO) could not be determined by the HPLC method.

PARTITION COEFFICIENT BY HPLC METHOD (Smith & Price):
- The reference substances displayed good chromatographic behavior for all chromatographic conditions tested.
- The C14, C16, and C18-dimethyl amine oxide standards had poor peak shape (non-gaussian) under all testing conditions, and is likely an indication of column interactions typical of surface active materials.
- Additionally, amine oxides with carbon chains greater than C12 did not elute without the addition of additives.
- Since the OECD guideline cautions that the HPLC method is not applicable to strong acids and bases, surface active agents or substances which react with the eluent, the results from this method are not considered to be reliable, and are not included in this summary.

COMPUTATIONAL MODELS:
Three of the four packages had difficulty in predicting the behavior of the amine oxide moiety with the dative N-O bond. Chemoffice and ClogP identified the issue and did not generate a prediction. Calculated values of KOWWIN showed variability based on SMILES notation used to represent the dative bond. CaChe performed the calculation, however it is not used as a common procedure as the other three packages. The computational models had difficulty estimating a reliable partition coefficient, mostly because the amine oxide structural unit is not well parameterized in the models, and the results from this method are not included in this summary.

PARTITION COEFFICIENT BY SOLUBILITY IN OCTANOL/SOLUBILITY IN WATER
- Solubility in water (409.5 g/L) and solubility in octanol (33.9 g/L) was determined by Lammens & Rottiers. However, these measurements did not account for the formation of micelles, especially applicable in the aqueous phase, and therefore greatly overestimated solubility. Partition coefficient calculated by the ratio of these two values is unreliable and is not reported here.

CALCULATION OF Pow BASED ON CMC:
This approach provided a reliable, scientifically defensible prediction despite several potential limitations:
- The solubility of amine oxide in octanol was determined using a commercial sample of amine oxide which was comprised of C12 and C14 alkyl chainlengths. Calculating the partition coefficient for shorter or longer alkyl chain length amine oxides, using the solubility of the C12-C14 amine oxide material, assumes that the octanol solubility is independent of chain length. One would assume that the octanol solubility would increase with increasing chain length.
- It only considers the micellar aggregation in the aqueous system, not in the octanol system. It is possible that a similar form of aggregation may occur in the octanol solution. By disregarding the potential aggregation in octanol, the calculated value may show a high bias when compared to measured values.
- Even with these potential limitations, calculating the partition coefficient using the CMC and octanol solubility is superior to the HPLC method, the computational approaches, or the solubility in octanol/solubility in water method. Details on the results with this method (using CMC’s) are in the “any other information on results incl. tables” section below.

Partition Coefficient of Amine Oxide: Determined by Ratio of Solubility in Octanol

to CMC in Water (study # 68317)

DMAO Compound

Alkyl chain length

CMC

Octanol Solubility (g/L)

Octanol Sol/CMC

Log

Hexyl

6

2.06E+01

33.9

1.13E-02

-1.95

Heptyl

7

6.27E-01

33.9

3.39E-01

-0.47

Octyl

8

1.60E-02

33.9

1.22E+01

1.09

Nonyl

9

5.40E-02

33.9

3.35E+00

0.53

Decyl

10

1.90E-02

33.9

8.86E+00

0.95

Undecyl

11

6.03E-03

33.9

2.61E+01

1.42

Dodecyl

12

2.10E-03

33.9

7.04E+01

1.85

Tetradecyl

14

2.70E-04

33.9

4.88E+02

2.69

CMC = critical micelle concentration in aqueous solution.

DMAO = dimethyl amine oxide.               

CMC’s from literature. Octanol solubility measured in lab (of the test material, C12-14 DMAO).

Conclusions:
The partition coefficient of C12/14 alkyl dimethyl amine oxide in octanol/water was below 2.7 (log Pow). The partition coefficient was calculated by the ratio of solubility in n-octanol to the critical micelle concentration in water.
Executive summary:

The Partition Coefficient of C12/14 alkyl dimethyl amine oxide in octanol/water was determined by four different methods: (1) HPLC according to OECD 117; (2) computational models; (3) solubility in octanol divided by solubility in water; and (4) solubility in octanol divided by the aqueous critical micelle concentration (CMC).

The HPLC method was unsuitable for determining the partition coefficient of amine oxide, due to poor peak shape and poor elution. The computational models had difficulty estimating a reliable partition coefficient since the amine oxide structural unit is not well parameterized in these models.  The partition coefficient by solubility in octanol divided by solubility in water is unreliable because a large portion of the test material is present as micelles in water, and not as a true solution.

Calculating the partition coefficient of amine oxide by the ratio of solubility in octanol to the aqueous CMC was superior to these other approaches, because the CMC is the concentration at which the test material is a saturated solution, and begins to form micelles. The CMC is the aqueous solubility limit of the test material.

The partition coefficient (n-octanol/water) of C12/14 alkyl dimethyl amine oxide, determined by the ratio of solubility in octanol to the CMC in water, was below 2.7 (log Pow).

Description of key information

The log Kow  is estimated conservatively to be < 2.7.

Key value for chemical safety assessment

Log Kow (Log Pow):
2.7
at the temperature of:
20 °C

Additional information

The log Kow of C12 -14 AO has been estimated on the basis of experimental data for the solubility of this substance in n-octanol and literature data for the critical micelle concentrations of the C12 and C14 alkyl dimethylamine oxides. The result was log Kow < 2.7. This is considered to be a worse case value for the following reasons:

Surfactants can form different types of solutions in water (e.g. mono-molecular-, micellar-, hexagonal or lamellar solutions) depending on concentration and temperature. The mono-molecular solubility of a surfactant is defined by the critical micelle concentration (cmc). If cmc data are available, they may be used as a worst-case approach in cases where the resulting log Pow is not critical. However, from a physico-chemical point of view, the cmc is not a good descriptor for the water solubility, as the micelles themselves completely dissolve in water. The rationale behind using the octanol/water solubility ratio as a measure for the octanol/water partitioning coefficient is that material insoluble in octanol would be “pushed” into the water phase while material insoluble in water would be “pushed” into the octanol phase. With micelles, this is definitely not true. Micelles form an isotropic, homogeneous solution in water and cannot partition into an organic phase due to their hydrophilic nature. Further, the typical lifetime of surfactant micelles is only a few ms, and the lifetime of micelle/bulk exchange of surfactant molecules is only a few µs, i.e. there is a very rapid exchange between mono-molecular dissolved and micellar dissolved surfactant molecules. This is in stark contrast to classical undissolved material, which has molecular lifetimes of several seconds or longer. Thus, the cmc underestimates the total solubility of a surfactant and hence overestimates the partition coefficient.

The study performed by Younis (2010) was disregarded as the test substance ( a freeze-dried sample of the amine oxide) was shown to have degraded to some extent prior to testing. In addition, the definitive study was performed using the shake flask method which is not suitable for surfactants.