Reaction mass of rel-(2R,3aR,6R,7aR)-2,6-dimethyl-3a-(propan-2-yl)octahydro-1-benzofuran and rel-(2R,3aR,6S,7aR)-2,6-dimethyl-3a-(propan-2-yl)octahydro-1-benzofuran and rel-(2R,3aS,6S,7aS)-2,6-dimethyl-3a-(propan-2-yl)octahydro-1-benzofuran

Partition coefficient

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was conducted between 10 November 2015 and 04 April 2016.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was considered to be a reliability 1 as it has been conducted according to OECD Test Guideline 123 using the slow stirring method and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 123 (Partition Coefficient (1-Octanol / Water), Slow-Stirring Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

slow-stirring method

Partition coefficient type:

octanol-water

Analytical method:

gas chromatography

Key result

Type:

log Pow

Partition coefficient:

4.32

Temp.:

25 °C

pH:

>= 5.8 - <= 9.8

 Results

The mean peak areas obtained for the stock solution analysis, organic phase analysis and aqueous phase analysis are shown in the following tables:

 

Stock Analysis

 

Solution	Mean Peak Area
Standard 167 mg/L	2.0036 x 10^7
Standard 164 mg/L	1.9762 x 10^7
Organic phase matrix blank	No significant response
Stock solution A	1.7627 x 10^7
Stock solution B	1.7983 x 10^7
Stock solution C	1.8612 x 10^7

 

Organic Phase Analysis

 

Solution	Mean Peak Area
Standard 176 mg/L	2.0263 x 10^7
Standard 160 mg/L	1.8249 x 10^7
Organic phase matrix blank	No significant response
Vessel A, 48.5 Hr organic phase sample	1.8471 x 10^7
Standard 153 mg/L	1.6243 x 10^7
Standard 151 mg/L	1.6609 x 10^7
Organic phase matrix blank	No significant response
Vessel A, 70.5 Hr organic phase sample	1.6260 x 10^7
Standard 163 mg/L	1.9894 x 10^7
Standard 161 mg/L	1.9887 x 10^7
Organic phase matrix blank	No significant response
Vessel A, 94.5 Hr organic phase sample	1.9139 x 10^7
Standard 151 mg/L	1.9032x 10^7
Standard 163 mg/L	2.0081x 10^7
Organic phase matrix blank	No significant response
Vessel A, 162.5 Hr organic phase sample	18731x 10^7
Vessel B, 162.5 Hr organic phase sample	1.8834x 10^7
Vessel C, 162.5 Hr organic phase sample	1.9176x 10^7
Vessel A, 168 Hr organic phase sample	1.8682x 10^7
Vessel B, 168 Hr organic phase sample	1.9265x 10^7
Vessel C, 168 Hr organic phase sample	1.8972x 10^7

  Organic Phase Analysis (continued)

 

Solution	Mean Peak Area
Standard 152 mg/L	1.8554 x 10^7
Standard 151 mg/L	1.8752 x 10^7
Organic phase matrix blank	No significant response
Vessel A, 210 Hr organic phase sample	1.9591 x 10^7
Vessel B, 210 Hr organic phase sample	1.8862 x 10^7
Vessel C, 210 Hr organic phase sample	1.9009 x 10^7
Vessel A, 215 Hr organic phase sample	1.9493 x 10^7
Vessel B, 215 Hr organic phase sample	1.9667 x 10^7
Vessel C, 215 Hr organic phase sample	1.8934 x 10^7
Standard 157 mg/L	1.9859 x 10^7
Standard 151 mg/L	1.9135 x 10^7
Organic phase matrix blank	No significant response
Vessel A, 234 Hr organic phase sample	1.9072 x 10^7
Vessel B, 234 Hr organic phase sample	1.9429 x 10^7
Vessel C, 234 Hr organic phase sample	1.9081 x 10^7

 

Table 9– Aqueous Phase Analysis

 

Solution	Mean Peak Area
Standard 1.14 mg/L	2.4541 x 10^5
Standard 1.01 mg/L	2.1132 x 10^5
Aqueous phase matrix blank	No significant response
Vessel A, 48.5 Hr aqueous phase sample	1.0081 x 10^6
Standard 1.07 mg/L	2.1688x 10^5
Standard 1.06 mg/L	2.1416x 10^5
Aqueous phase matrix blank	No significant response
Vessel A, 70.5 Hr aqueous phase sample	7.9793x 10^5
Standard 4.23 mg/L	8.8734x 10^5
Standard 4.12 mg/L	8.8298x 10^5
Aqueous phase matrix blank	No significant response
Vessel A, 94.5 Hr aqueous phase sample	1.0085x 10^6

Table – Aqueous Phase Analysis (continued)

 

Solution	Mean Peak Area
Standard 4.22 mg/L	9.6384x 10^5
Standard 4.12 mg/L	9.4660x 10^5
Aqueous phase matrix blank	No significant response
Vessel A,162.5Hr aqueous phase sample	1.0196x 10^6
Vessel B,162.5Hr aqueous phase sample	9.9429x 10^5
Vessel C,162.5Hr aqueous phase sample	1.0278x 10^6
Vessel A, 168 Hr aqueous phase sample	1.0540x 10^6
Vessel B, 168 Hr aqueous phase sample	1.2491x 10^6
Vessel C, 168 Hr aqueous phase sample	1.0371x 10^6
Standard 4.34 mg/L	9.9546 x 10^5
Standard 4.40 mg/L	1.0015 x 10^6
Aqueous phase matrix blank	No significant response
Vessel A, 210 Hr aqueous phase sample	1.0579x 10^6
Vessel B,210Hr aqueous phase sample	1.0674x 10^6
Vessel C,210Hr aqueous phase sample	1.0221x 10^6
Vessel A, 215 Hr aqueous phase sample	1.1387x 10^6
Vessel B, 215 Hr aqueous phase sample	1.0893x 10^6
Vessel C, 215 Hr aqueous phase sample	1.1210x 10^6
Standard 4.08 mg/L	9.5123x 10^5
Standard 4.10 mg/L	9.4640x 10^5
Aqueous phase matrix blank	No significant response
Vessel A, 234 Hr aqueous phase sample	1.0903x 10^6
Vessel B,234Hr aqueous phase sample	1.0730x 10^6
Vessel C,234Hr aqueous phase sample	1.0457x 10^6

The sampling times, analyzed concentration (mg/L) of the respective phases, aqueous phase pH and resulting partition coefficient values (as log₁₀P_ow) are shown in the following tables.  The mean stock solution concentration on analysis was 1.50 x 10⁴mg/L.

 

Vessel A

Sample Number	Equilibration Time (Hours)	Organic Phase Concentration (mg/L)	Aqueous Phase Concentration (mg/L)	Aqueous Phase  pH	Log10Pow
1	48.5	1.61 x 10^4	0.760	7.1	4.33
2	70.5	1.50 x 10^4	0.631	7.1	4.38
3	94.5	1.56 x 10^4	0.760	9.8	4.31
4	162.5	1.50 x 10^4	0.712	7.1	4.32
5	168	1.50 x 10^4	0.736	7.0	4.31
6	210	1.59 x 10^4	0.741	7.1	4.33
7	215	1.58 x 10^4	0.797	7.1	4.30
8	234	1.51 x 10^4	0.752	7.2	4.30

 

Vessel B

Sample Number	Equilibration Time (Hours)	Organic Phase Concentration (mg/L)	Aqueous Phase Concentration (mg/L)	Aqueous Phase  pH	Log10Pow
1	162.5	1.51 x 10^4	0.695	6.2	4.34
2	168	1.54 x 10^4	0.873	5.8	4.25
3	210	1.53 x 10^4	0.747	6.0	4.31
4	215	1.60 x 10^4	0.762	6.4	4.32
5	234	1.54 x 10^4	0.740	6.1	4.32

 

Vessel C

Sample Number	Equilibration Time (Hours)	Organic Phase Concentration (mg/L)	Aqueous Phase Concentration (mg/L)	Aqueous Phase  pH	Log10Pow
1	162.5	1.54 x 10^4	0.718	9.8	4.33
2	168	1.52 x 10^4	0.724	6.8	4.32
3	210	1.54 x 10^4	0.715	7.0	4.33
4	215	1.54 x 10^4	0.785	6.7	4.29
5	234	1.51 x 10^4	0.721	6.8	4.32

For each of the three test vessels, the slope of the correlation was tested statistically to ensure it did not differ significantly from zero. This was performed using the t test and a probability value of P = 0.05 (critical value = 2.45 for 6 degrees of freedom (vessel A) and 3.18 for 3 degrees of freedom (vessel B and vessel C)). The results are summarized in the following table:

 

Table

Vessel	A	B	C
Slope	-1.98 x 10^-4	3.53 x 10^-4	-1.81 x 10^-4
Value of t	1.67	0.586	0.632
Slope Statistically Different From Zero	No	No	No

                                                                                              

As equilibrium was confirmed, the mean log₁₀partition coefficient value, the standard deviation and variance was calculated for each vessel. This then allowed the final variance weighted average and standard deviation to be calculated as the definitive result for the test. The results are summarized in the following table:

Table14

Vessel	A	B	C
Mean Log10Pow	4.32	4.31	4.32
Standard Deviation	2.50 x 10^-2	3.44x 10^-2	1.65x 10^-2
Variance	6.24 x 10^-4	1.18 x 10^-3	2.71x 10^-4

 

Weighted average log₁₀P_ow                                                     : 4.32

Partition coefficient (P_ow)                                                         : 2.08 x 10⁴

Variance weighted log₁₀P_owstandard deviation       : 3.37 x 10^-3

Validation

The linearity of the detector response with respect to concentration was assessed over relevant concentration ranges for each matrix analyzed during the determination of partition coefficient. In each case, the results were satisfactory with a correlation coefficient of at least 0.9998 being obtained. The results are summarized in the following table:

 

Table

Analysis	Matrix	Nominal Concentration Range (mg/L)	Correlation Coefficient (r)
Stock solution and organic phases	Acetone: water saturated n‑octanol (99:1 v/v)	50 to 250	0.9998
Aqueous phases	iso-Octane	0.5 to 8.0	0.9999

 

Recovery of analysis of the aqueous phase sample extraction procedure was assessed and proved adequate for the test. At a nominal concentration of 0.2 mg/L, a mean percentage recovery of 86.4 % was obtained (n = 5, range 82.4 to 90.9%, RSD = 3.7%).

Conclusions:

The partition coefficient (Pow) of the test item has been determined at a test temperature of 25.0 ± 0.5°C, using the slow-stirring method. The results are summarized in the following table:

Vessel A B C
Mean Log10 Pow 4.32 4.31 4.32
Standard Deviation 2.50 x 10-2 3.44 x 10-2 1.65 x 10-2
Variance 6.24 x 10-4 1.18 x 10-3 2.71 x 10-4

Weighted average log10 Pow : 4.32
Partition coefficient (Pow) : 2.08 x 104
Variance weighted log10 Pow standard deviation : 3.37 x 10-3

Executive summary:

The partition coefficient of the test item, IFF 215 (Floriane), was determined to be 4.32, log10 Pow 2.08 x 10⁴ according to OECD Test Guideline 123 using the stirring method.

Reference 2

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

The study was conducted between 22 May 2014 and 23 August 2014.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The st udy was considered to be a reliability 1 as it has been conducted according to OECD Test Guideline 117 using the HPLC method and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

HPLC method

Partition coefficient type:

octanol-water

Analytical method:

high-performance liquid chromatography

Type:

log Pow

Partition coefficient:

>= 5.06 - <= 5.59

Temp.:

30 °C

pH:

ca. 7

Details on results:

Preliminary estimate
The log10 Pow value was calculated to be 4.50.

Definitive test
Overall log10 Pow range: 5.06 to 5.59
Overall partition coefficient range: 1.13E+05 to 3.86E+05

In the absence of any relevant dissociating functional groups, no specific manipulation of the mobile phase pH was necessary to ensure that the test item was in an unionized form. Therefore the determination was performed at an approximately neutral pH.

Identification of the peaks of interest was performed with the assistance of analytical data provided by the Sponsor.

Calibration

The retention times of the dead time and the retention times, capacity factors (k') and log₁₀P_owvalues for the reference standards are shown in the following tables:

Dead Time	Retention Time (mins)		Mean Retention Time (mins)
	Injection 1	Injection 2
Thiourea	2.088	2.095	2.092

Standard	Retention Time (mins) Injection 1	Retention Time (mins) Injection 2	Mean Retention Time (mins)	Capacity Factor (k')	Log10k'	Log10Pow
Benzene	3.362	3.362	3.362	0.607	-0.216	2.1
Toluene	4.162	4.169	4.166	0.992	-3.65 x 10^-3	2.7
Naphthalene	4.939	4.946	4.943	1.363	0.135	3.6
Phenanthrene	8.611	8.604	8.608	3.115	0.494	4.5
Triphenylamine	17.122	17.114	17.118	7.185	0.856	5.7
DDT	22.882	22.882	22.882	9.940	0.997	6.5

Partition coefficient of sample

The retention times, capacity factor and log₁₀P_owvalue determined for the sample are shown in the following table:

Component	Injection	Retention Time (mins)	Capacity Factor (k')	Log10k'	Log10Pow	Mean Log10Pow
1	1	10.879	4.202	0.623	5.06	5.06
	2	10.879	4.202	0.623	5.06
2	1	11.599	4.546	0.658	5.18	5.18
	2	11.599	4.546	0.658	5.18
3	1	13.284	5.351	0.728	5.43	5.43
	2	13.291	5.355	0.729	5.43
4	1	14.522	5.943	0.774	5.59	5.59
	2	14.522	5.943	0.774	5.59

The percentage area normalization of the four peaks quantified is summarized in the following table:

Component	Mean Percentage Area (%)	Mean Log10Pow
1	2.7	5.06
2	88.0	5.18
3	5.5	5.43
4	3.8	5.59

Conclusions:

The partition coefficient range of the test item has been determined to be 1.13E+05 to 3.86E+05, log10 Pow 5.06 to 5.59.

Executive summary:

The partition coefficient of the test item, IFF 215 (Floriane), was determined to be 1.13E+05 to 3.86E+05, log10 Pow 5.06 to 5.59 according to OECD Test Guideline 117 using the HPLC method.

Description of key information

Two studies were carried out to determine the partition coefficient of the test item IFF 215 (Floriane). The results were as follows:

Study 41401226 (2014): The partition coefficient of the test item, IFF 215 (Floriane), was determined to be 1.13E+05 to 3.86E+05, log10 Pow 5.06 to 5.59 according to OECD Test Guideline 117 using the HPLC method

Study 41502515 (2016): The partition coefficient of the test item, IFF 215 (Floriane), was determined to be 2.08 x 10⁴, log10 Pow 4.32 according to OECD Test Guideline 123 using the slow stirring method.

Key value for chemical safety assessment

Log Kow (Log Pow):

4.32

at the temperature of:

25 °C