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EC number: 945-910-7 | CAS number: -
The results of the HPLC method are given in the Table 2 methanol/buffer pH 7 and Table 3 acetonitrile/buffer pH 7 as mobile phase, respectively.
methanol/buffer pH 7: The calibration curve of the log k’ of the reference substances as function of log Pow had an regression line represented by the equation: log k’ = 0.295 ´ log Pow – 0.644 (r = 0.998, n = 14)
acetonitrile/buffer pH 7: The calibration curve of the log k’ of the reference substances as function of log Pow had an regression line represented by the equation: k’ = 0.217 ´ log Pow – 0.524 (r = 0.995, n = 14).
Table 2. Pow of the substance - methanol/buffer pH 7
#1: Estimated value , calculated by extrapolation of the calibration curve.
Table 3. Pow of the substance - acetonitrile/buffer pH 7
Comments: The substance possesses constituents with weak basic functional groups although at pH 7 the substance is considered to be typically in a non-ionised form of the substance. Therefore on this basis the HPLC test was conducted with appropriate buffer to pH 7.0. Additional buffers were deemed unnecessary.
The n-octanol-water partition coefficient was determined using the HPLC method of EU Method A.8, OECD Method 117 and OPPTS 830.7570. The partition coefficient of the substance was determined to be log Pow = 7.1 at 35 °C and neutral pH. Applicant assessment indicates the oxydipropanol constituent is beyond the range of the HPLC method (calculated Log P = -0.64, US EPA, KOWWIN v1.68). Peak 1 is one of two known hydrolysis degradation products which has limit values of: Log P = 2.85 (measured and predicted). The main constituents have log P > 6.0 and were measured by a scientifically acceptable amendment to the OECD TG 117 guideline by interpolation using benzo[ghi]perylene (Log P = 7.2).
1. Defined Endpoint:
QMRF 1. Physical Chemical Properties
QMRF 1.6. Octanol-water partition coefficient (Kow)
Reference to type of model used and description of results:
KOWWIN v1.68; integrated within the Estimation Programme Interface (EPI) Suite programme for Microsoft Windows v4.11; September 2010 (model development); November 2012 (model publication)
2. Description of results and assessment of reliability of the prediction:
The predicted values are provided within the QPRF attached: ‘QPRF Title: Reaction mass of methyl 2-[[(E)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and methyl 2-[[(Z)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and oxydipropanol using the model KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow)’ version 1.0; 30 May 2017 which has been newly compiled.
The range of constituents Log Kow was: -0.64 to 6.23
Oxydipropanol: Log Kow = -0.64 ;
Hydrolysis Product 1: 2.26 , experimental Log P: 1.88, Hansch, C et al. (1995)
Hydrolysis Product 2: 2.85
Constituent 1 and 2: 6.23
The majority of constituents had log Kow = 6.23. All hydrolytic degradants and other constituents have predictions for log Kow < 4.0.
It is noted by the applicant there is no universally acknowledged applicability domain for the model. However, assessment of the substance within the applicability domains recommended by the developers is documented within the corresponding QMRF named ‘QMRF Title: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow)’ version 1.01, 01 September 2015 – section 5; indicates the substance (constituents):
(i) All constituents fall within the Molecular Weight range domain.
(ii) No substances have functional groups or features not in the training set of the model and/or for which no fragment constants and correction factors available. No constituents contain multiple fragment instances than the maximum of the training set (see QMRF title section 9.3 for more information).
It is however acknowledged that above Log P 6.0 to 7.0 there is lower numbers of substances in the training set although significant numbers of substances in the validation set. Above Log P 8.0 the model should be treated with additional caution. It is also acknowledged for the secondary amine constituents there are limited number of amine analogues within the training set. Which would improve the prediction. There is very good correlation between predictions and measured values on the ECHA REACH dissemination portal (checked 30 May 2017) for measured values of Log P for the hydrolysis products and oxydipropanol.
3. Uncertainty of the prediction and mechanistic domain:
The training set of the model has the following statistics and coefficients of determination:
Total Training Set Statistics: number in dataset = 2447 ; correlation coef (r2) = 0.982 ; standard deviation = 0.217 ; absolute deviation = 0.159 and avg Molecular Weight = 199.98
The model has been externally validated on a set of 10,946 substances and the following statistics and coefficients of determination are presented:
Total Validation Set Statistics: number in dataset = 10946 ; correlation coef (r2) = 0.943 ; standard deviation = 0.479 ; absolute deviation = 0.356 ; avg Molecular Weight = 258.98
Data for the training set are available via external validation (see attached QMRF prepared by the applicant for full citations).
There is no overt mechanistic basis for the model. The model correlates thermodynamic relationships of surrogates to chemical activity. The KOWWIN v1.68 run in standalone mode allows Log Kow to be estimated based on measured values of analogues within the training set (if available). Then the model applies by adding/subtracting fragment constants and correction factors from the measured value. This therefore improves prediction since calculations are based on structural differences between target and analogue. The model domain ideally has at least one or more structurally similar substances to target substances on which to then apply ACF methodology. Whilst there appears to be no direct analogues within the training set. The model has been has been extensively validated externally (using > 10,000) substances with a correlation coefficient (r2) = 0.943. The model is non-proprietary and the training sets and validation sets can be downloaded from the internet. A summary of this information is presented by the applicant. Expert review of the data on relevant structural analogues in the validation dataset indicate that in general they over predict Log Kow compared to measured data.
Model predictivity could be improved by the assignment of additional substances into the training set. Inclusion of additional structural fragments and expansion of sub-structure correction factors and related rules. In addition, rules for stereochemical effects could feasibly improve modelling.
KOWWIN v1.68 (model publication: November 2012)
Log Kow range (all constituents): -0.64 to 6.23
Value represents range of Log P for impurities and hydrolysis degradation products and is based on a combination of measured and experimental reference citations.
Value also represents range for all constituents including model predictions.
Summary of individual predictions:
Oxidipropanol: Log Kow = -0.64 ;
Adequacy of the QSAR:
1) QSAR model is scientifically valid. 2) The substance falls within the applicability domain of the QSAR model. 3) The prediction is fit for regulatory purpose.
The prediction is adequate for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The assessment indicates that the prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements specifically when combined with further information available such as environmental toxicity and environmental fate testing.
Weight of evidence: Log Kow (all constituents) range: -0.64 to 7.1 at 25 °C and pH 7, 2017
Log Kow constituents at 25 °C:
Hydrolysis Product 1 / Impurity 1: 2.26
Hydrolysis Product 2 / Impurity 2: 2.85
Constituent 1 and 2 (isomers): 7.1
The above constituents are indicated by a combination of predicted (log Kow < 4.0) and measured (Log Kow > 4.0) methods in a weight of evidence approach.
In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 7.8 the study does not need to be conducted if the test cannot be performed (e.g. the substance decomposes). A calculated value for log P as well as details of the calculation method shall be provided. The test substance has been demonstrated to be hydrolytically unstable. The applicant confirms that Log P determination according to OECD TG 117 HPLC method was attempted however evidence of on-column degradation (hydrolysis) was observed. The applicant adapts the information by providing an endpoint study record for hydrolysis in conjunction to HPLC measurement of specific constituents with log P > 4.0 along with calculated values for log P. Testing according to the Flask Method OECD 107 or Slow Stirring Methods OECD TG 123 is inapplicable due to instability and physical properties of the test item. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.126.96.36.199, December 2016) the study does not need to be conducted.
Oxydipropanol: -0.64 (QSAR Prediction)
Hydrolysis Product 1 / Impurity 1: 2.26 (QSAR Prediction)
Hydrolysis Product 2 / Impurity 2: 2.85 (QSAR Prediction)
Constituent 1 and 2 (isomers): 7.1 (Measured)
The above constituents are indicated by a combination of predicted (log Kow < 4.0) and measured (Log Kow > 4.0) methods in a weight of evidence approach and using expert judgement.
References for further information:
1. QMRF Title: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow) : version 1.01, 01 September 2015
2. QPRF Title: Reaction mass of methyl 2-[[(E)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and methyl 2-[[(Z)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and oxydipropanol using the model KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow) : version 1.0, 30 May 2017
3. Experimental Study: Anon., OECD TG 117, 2016
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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