Resinoid of Cistus ladaniferus (Cistaceae) obtained from labdanum gum by organic solvents extraction

Partition coefficient

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

partition coefficient

Data waiving:

study technically not feasible

Justification for data waiving:

other:

Justification for type of information:

The substance is a complex mixture, which contains a large number of constituents, which are mostly unkown and which have different solubility (often low solubility) and volatility. In addition its physical state leads to difficulties for physico-chemical testing: It is described as brown to brown red not flowable very hard sticky paste like a resin.

A GLP study has been conducted on another labdanum resinoid substance according to OECD 117 showing a non reliable result (the major peak of the test item detected with a logKow < 0.3 while the substance is mainly insoluble in water)(see disregarded study on labdanum resinoid(ethanol). In addition a feasibiliity studies conducted on other natural complex substances showed that this method is difficult to applicate for this kind of substances due to the very low response of the test items with the HPLC detectors tested (Diode Array Detector and Mass Spectrometry).
Another strategy based on the application of the OECD 123 method and the quantification of the test item in both octanol and water phases by a GC-FID analytical method was considered. However, this approach does not allow to detect the totality of the test item constituents and was not considered as appropriate to define a range of logKow for the whole substance.
Finally the standard tests for partition coefficient endpoint are intended for single substances and are not appropriate for such complex substances because of the limited knowledge of composition and the physical state of the substance.

Reason / purpose for cross-reference:

data waiving: supporting information

Reference 2

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

run on 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

QSAR prediction : The values obtained on known constituents of the substance are not experimental results, however the QSAR model is recommended by the ECHA guidance document on information requirements, is well documented with regard to validation parameters according to OECD principles. Moreover, the constituents of the substance are fully characterised towards the applicability domain.

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

QSAR estimation

Partition coefficient type:

octanol-water

Type:

log Pow

Partition coefficient:

>= 2.29 - <= 15.57

Remarks on result:

other: Temperature and pH not provided (QSAR estimation)

Remarks:

Range of logKow estimated on a the known constituents of the substance

Temperature and pH values are not considered in this model.

The estimation is based on the non-ionised form of the molecule.

No Experimental Value Adjustment was made.

The molecular weight of the constituents are between 150.17 and 436.84 g/mol, hence within the estimation domain of the validation set (27.03 -991.15 g/mol), all the functional groups are included in the list of descriptors, and, the occurence of each fragment is below or very closed to the maximum number in the training/validation sets (Appendix D), such as:

		Training Set		Validation Set
Fragment Descriptor & Correction Factor Descriptor	Coef	Max	Number	Max	Number
-CH3 [aliphatic carbon]	0,5473	13	1401	20	7413
-CH2-   [aliphatic carbon]	0,4911	18	1083	28	7051
-CHO    [aldehyde, aliphatic attach]	-0,9422	1	8	2	30
-CH   [aliphatic carbon]	0,3614	16	460	23	3864
=CH- or =C<  [olefinc carbon]	0,3836	10	239	10	1847
-COOH   [acid, aliphatic attach]	-0,6895	3	126	3	672
-tert Carbon [3 ot more carbon attach]	0,2676	4	130	8	1381
Fused aliphatic ring unit correction	-0,3421	8	41	8	684
-OH   [hydroxy, aliphatic attach]	-1,4086	6	187	9	1525
-O- [oxygen, aliphatic attach]	-1,2566	5	108	12	1235
Aromatic carbon	0,294	24	1790	30	8792
-O-   [oxygen, one aromatic attach]	-0,4664	3	203	5	1770
-OH     [hydroxy, aromatic attach]	-0,4802	3	193	4	611
Ketone in a ring [olefin, aromatic attach]  -0,5497	-0,5497	2	11	2	104
Ortho-Hydroxy to misc. -C(=O)- correction	0,777	2	11	2	82
-C(=O)O [ester, aliphatic attach]	-0,9505	3	113	6	1178
-C(=O)- [carbonyl, aliphatic attach]	-1,5586	2	54	2	241
Cyclic ester  correction	-1,0577	1	14	2	144

Conclusions:

Log Kow of known constituents of the substance, representing a limited fraction of the composition, were estimated to be between 2.29 and 15.57 (estimated by QSAR)

Executive summary:

The partition coefficient of the known constituents of the substance were estimated using the recommended QSAR model KOWWIN v1.68, based on Atom/Fragment Contribution (AFC) method. The constituents of the test item were within the applicability domain (MW, descriptors).

This range of logKow was estimated between 2.29 and 15.57, with a standard deviation provided by the model of 0.48.

Reference 3

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

06-11 March 2014

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Justification for type of information:

A study has been conducted according to OECD 117 leading to a non reliable result (logKow < 0.3 while the substance is mainly insoluble in water) and showing that the conventional standard tests for partition coefficient endpoint are intended for single substances and are not appropriate for such complex substances because of the limited knowledge of composition and the physical state of the substance.

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2004

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method A.8 (Partition Coefficient - HPLC Method)

Version / remarks:

2008

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected on 29 and 30 November 2010 / signed on 11 April 2011

Type of method:

HPLC method

Partition coefficient type:

octanol-water

Type:

log Pow

Partition coefficient:

< 0.3

Temp.:

25 °C

pH:

ca. 6

Remarks on result:

not determinable because of methodological limitations

Remarks:

Assuming that the test item consists mainly of one peak, calculation of logKow, mean and standard deviation of the major component of test item was not possible because the retention time of measurements lay below the retention time of thiourea. So the log POW of the test item is stated as < 0.3.

Results:

Reference item:

For each reference item, the retention times, the calculated capacity factors K, logK and log Kow were presented in the following table:

Compound	Mean Retention Time (min)	K	log K	log POW
Thiourea	1,482	0
2-Butanone	1,981	0,3369	-0.4726	0.30
Benzylalcohol	2,407	0,6241	-0.2047	1.10
Acetophenone	3,016	1,0355	0.0152	1.70
Nitrobenzene	3,645	1,4599	0.1643	1.90
Benzene	5,286	2,567	0.4094	2.10
Toluene	8,596	4,8008	0.6813	2.70
Naphthalene	12,367	7,346	0.8660	3.60

Dead time is 1.482 ± 0.002 minutes, with RSD 0.1%.

The RSD of the retention times of the reference items lay all below 0.5 %.

Equation of the regression:

log k = 0.4399 * log POW – 0.6337 with a coefficient of determination r² = 0.9616

Test item:

Retention Times Test Item

Measurement	RT 1	RT 2	RT 3
	min.	min.	min.
Measurement 1	1.365	1.936	5.412
Measurement 2	1.36	1.946	5.405
Measurement 3	1.361	1.930	5.407
Mean	1.362	1.937	5.408
Standard Deviation	0.003	0.008	0.004

 

Areas Test Item

Measurement	Area Peak 1	Rel. 1	Area Peak 2	Rel. 2	Area Peak 3	Rel. Area Peak 3
	mAU*min	%	mAU*min	%	mAU*min	%
Measurement 1	17.4385	95.64	0.2898	1.59	0.1424	0.78
Measurement 2	17.4690	94.60	0.3843	2.08	0.1925	1.04
Measurement 3	17.3221	94.25	0.4228	2.30	0.1481	0.81
Mean	17.4099	94.83	0.3656	1.99	0.1610	0.88
Standard Deviation	0.45%	0.76%	18.73%	18.31%	17.05%	16.48%

As peaks 2 and 3, showed a relative area < 5%, they were considered as minor peaks.

The calculated values are presented in the following table:

Capacity Factor, log Capacity Factor, log P_OWTest Item Peaks

Peak	Measurement No.	K	log K	log POW
1	1	-0.0788	Not calculable*	Not calculable*
	2	-0.0822	Not calculable*	Not calculable*
	3	-0.0815	Not calculable*	Not calculable*
	Mean		Not calculable*	Not calculable*
	Stand. Dev.		Not calculable*	Not calculable*
2	1	0.3065	-0.5136	0.273
	2	0.3132	-0.5041	0.295
	3	0.3024	-0.5194	0.260
	Mean			0.276
	Stand. Dev.			0.017
3	1	2.6522	0.4236	2.403
	2	2.6475	0.4228	2.402
	3	2.6489	0.4231	2.402
	Mean			2.402
	Stand. Dev.			0.001

*As the retention time of peak 1 lies below the retention time of thiourea, the log P_OWof peak 1 is not calculable.

 

log P_OWwas calculated from the capacity factor as follows:

 

log P_OW= (log K + 0.6337) / 0.4399

Executive summary:

The partition coefficient of the test substance was measured according to the OECD 117/EU A8 guideline, HPLC method. The system was calibrated with seven different references substances.

The measurements of the test item solution were very reproducible ( very small variations in the retention times of reference items and test item) and correlation log K/Log POW is good (r² = 0.9616).

Nevertheless, the log POW of the major peak of test item was not calculable, because during the measurements its retention time lies below the retention time of thiourea and thus not within the range of log Kows of the reference items. The corresponding log Kow is stated as < 0.3 (log POW of 2-Butanone, the reference item with the lowest log POW).

Description of key information

No range of logKow representative of the test item can be determined (neither with an experimental approach nor with an estimation approach)

Additional information

The substance is a complex mixture, which contains a large number of constituents, which are mostly unkown but which have different solubility (often low solubility) and volatility. In addition its physical state leads to difficulties for physico-chemical testing: It is described as brown to brown red not flowable very hard sticky paste like a resin.

For such complex substances, the standard tests for partition coefficient endpoint are considered as not appropriate because of the limited knowledge of composition and the physical state of the substance. That is why the test has been waived.

In addition calculated values were provided on known constituents of the substance. However, only a range of logKow on a limited part of the composition of the substance can be calculated using QSAR estimations.

Therefore it is considered that no range logKow representative of the whole test item can be determined (neither with an experimental approach nor with an estimation approach).