Registration Dossier

Administrative data

Endpoint:
melting point/freezing point
Type of information:
(Q)SAR
Adequacy of study:
key study
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 adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE US EPA Episuite

2. MODEL (incl. version number)
MBPVP module version 1.43
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O=C(c1c(c(c(c(c1C(=O)OCCOCCO)Br)Br)Br)Br)OCC(C)O, C15H16Br4O7, mol. wt 627.91
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
- Defined endpoint: yes
- Unambiguous algorithm: weighted value of 3 models is used
- Defined domain of applicability:
- Appropriate measures of goodness-of-fit and robustness and predictivity:
For the current EPI Suite, the accuracy of the "suggested" MPBPWIN melting point estimate was tested on a large dataset of 10,051 compounds containing a diverse mix of simple, moderate and very complex structural compounds (includes many pesticides and pharmaceutical compounds).  The dataset was taken from the PHYSPROP Database used by the EPI Suite.  Compounds having "decompose" designations with MP values were excluded.  The complete dataset with experimental values and estimates is available at:
http://esc.syrres.com/interkow/EpiSuiteData.htm
Substructure searchable data set of melting point test is available at:
http://esc.syrres.com/interkow/EpiSuiteData_ISIS_SDF.htm
The accuracy statistics of the test are:
number 10051
r2 0.63
std deviation 63.9 deg C
avg deviation 48.6 deg C
- Mechanistic interpretation:
MPBPWIN estimates melting point by two different methods.  The first is an adaptation of the Joback group contribution method for melting point (Joback, 1982; Reid et al; 1987) and the second is a simple Gold and Ogle method suggested by Lyman (1985).
The original Joback methodology used a data set of 388 compounds to derive 41 chemical structure group descriptors via multiple linear regression (Joback, 1982).  The Joback adaptation in MPBPWIN is an extension of the original method to include the same groups as in the adapted Stein and Brown boiling point method (see Boiling Point).  In addition, MPBPWIN also uses melting point correction factors for specific structures. Appendix F contains a complete list the group descriptors and coefficient values.
The second estimation method (Gold and Ogle, 1969), simply relates melting point (Tm) to boiling point (Tb) as follows (both values in K):
Tm  =  0.5839 Tb
MPBPWIN averages the adapted Joback and the Gold and Ogle estimates and reports the average estimate as well as both individual estimates.
MPBPWIN then goes one step further.  It reports a "suggested" melting point (MP) that is based upon the two individual estimates and several criteria.  First, MPBPWIN looks at the difference between the two estimates.  If the difference is small (< 30 K), the suggested MP is simply the average.  When this criteria fails (which occurs quite often), MPBPWIN examines the structure type and the magnitude of the difference.  It then decides which estimate is more likely to be accurate and "weights" the suggested MP accordingly.  For example, when MPBPWIN detects an amino-acid structure, it uses a 75% weighting factor for the higher estimate and 25% for the lower estimate to derive the suggested MP.  Weighting factors in MPBPWIN were approximated through observation of estimated versus experimental MP.
The adapted Joback method can significantly over-estimate MP for some structures.  A similar error occurs in the Stein and Brown (1994) boiling point method (when BP > 500 K) before a  quadratic or linear equation corrects the error.  This type of correction was not developed for MPBPWIN.  Instead, MPBPWIN applies a "cut-off" MP at approximately 350 deg C; that is, any MP estimate above 350 deg C is reduced to 350 deg C.  When MPBPWIN detects a large difference between a very high adapted Joback estimate and a much lower Gold and Ogle estimate, it usually weights the suggested MP strongly to the Gold and Ogle estimate (again, it depends on structure).  When used alone, the adapted Joback MP method can be very inaccurate for some structures (usually by estimating too high).  The simplistic Gold and Ogle method is also inaccurate for various structures.  However, when combined in the MPBPWIN format, estimation accuracy  improves significantly for very large, diverse datasets.

5. APPLICABILITY DOMAIN
Currently there is no universally accepted definition of model domain.  However, users may wish to consider the possibility that property estimates are less accurate for compounds outside the Molecular Weight range of the training set compounds, and/or that have more instances of a given fragment than the maximum for all training set compounds.  It is also possible that a compound may have a functional group(s) or other structural features not represented in the training set, and for which no fragment coefficient was developed.  These points should be taken into consideration when interpreting model results.
The complete training sets for MPBPWIN's estimation methodology are not available.  Therefore, describing a precise estimation domain for this methodology is not possible.
The strucutre contains substructures that are all part of the training set and the molecular weight is within the range as well.
6. ADEQUACY OF THE RESULT
As the substance is a UVCB no distict melting point is to be expected. In fact it is a highly viscious liquid that will be comparable to glss when cooled down. The lower molecular weight component modeleld here gives the meltin point of this component, but it is higher than that of the UVCB.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
no guideline required
Version / remarks:
QSAR estimation method
Principles of method if other than guideline:
- Software tool(s) used including version: EPISuite US EPA 2000-20012
- Model(s) used: MPVPBP version 1.43
- Model description: see field 'Justification for non-standard information'
- Justification of QSAR prediction: see field 'Justification for type of information'
GLP compliance:
no
Type of method:
other: QSAR estimation

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O=C(c1c(c(c(c(c1C(=O)OCCOCCO)Br)Br)Br)Br)OCC(C)O, C15H16Br4O7, mol. wt 627.91
lowest molecular weight fraction

Results and discussion

Melting / freezing point
Key result
Melting / freezing pt.:
ca. 230.13 °C
Atm. press.:
ca. 1 016 hPa
Decomposition:
no

Any other information on results incl. tables

Adapted Joback Method estimation : 349.84 deg C

Gold and Ogle Method estimation: 200.20 deg. C

Mean MP: 275.02 deg C

Selected MP by method: 230.13 deg. C

Applicant's summary and conclusion

Conclusions:
As the substance is a UVCB, no distinct melting point can be expected from a mixture. The episuite QSAR estimate was used to predict the melting point of the lowest molecular weight structure with one aromatic ring and one each of the side chains. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODELO=C(c1c(c(c(c(c1C(=O)OCCOCCO)Br)Br)Br)Br)OCC(C)O, C15H16Br4O7, mol. wt 627.91.
The weighted average of the melting point using two different estimation methods was 230.13 deg. C. However, the UVCB is a highly viscous liquid consistent with a melting point depression.
Executive summary:

As the substance is a UVCB, no distinct melting point can be expected from a mixture. The episuite QSAR estimate was used to predict the melting poitn of the lowest molecular weight structure with one aromatic ring and one each of the side chains. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODELO=C(c1c(c(c(c(c1C(=O)OCCOCCO)Br)Br)Br)Br)OCC(C)O, C15H16Br4O7, mol. wt 627.91.

The weighted average of the melting point using two different estimation methods was 230.13 deg. C.