1,4-diazabicyclooctane

Partition coefficient

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2007

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

Estimation Programs Interface (EPI) Suite for Microsoft Windows, v4.11 (US EPA, 2012)

2. MODEL (incl. version number)

KOWWIN version 1.68 (Sept 2010)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL

CAS: 280-57-9
SMILES: N(CCN(C1)C2)(C1)C2


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The logKow value for 1,4-diazabicyclooctane was calculated using the KOWWIN v1.68 module of the EPISuite computer model.

KOWWIN™ estimates the log octanol-water partition coefficient, log Kow, of chemicals using an atom/fragment contribution method. EPISuite and its modules (including KOWWIN) have been utilized by the scientific community for prediction of phys/chem properties and environmental fate and effect properties since the 1990’s. The program underwent a comprehensive review by a panel of the US EPA’s independent Science Advisory Board (SAB) in 2007. The SAB summarized that the EPA used sound science to develop and refine EPISuite. The SAB also stated that the property estimation routines (PERs) satisfy the Organization for Economic Cooperation and Development (OECD) principles established for quantitative structure-activity relationship ((Q)SAR) validation.
The EPISuite modules (including KOWWIN) have been incorporated into the OECD Toolbox. Inclusion in the OECD toolbox requires specific documentation, validation and acceptability criteria and subjects EPISuite to international use, review, providing a means for receiving additional and ongoing input for improvements. KOWWIN is listed as one of the QSARs for use in predicting partition coefficient (Kow) of organic compounds values in the literature referenced in Guidance on information requirements and chemical safety assessment Chapter R.7a: Endpoint specific guidance. In summary, the EPISuite modules (including KOWWIN) have had their scientific validity established repeatedly.
https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface

- Defined endpoint and unambiguous algorithm:
KOWWIN uses a "fragment constant" methodology to predict log P. In a "fragment constant" method , a structure is divided into fragments (atom or larger functional groups) and coefficient values of each fragment or group are summed together to yield the log P estimate. KOWWIN’s methodology is known as an Atom/Fragment Contribution (AFC) method. Coefficients for individual fragments and groups were derived by multiple regression of 2447 reliably measured log P values. KOWWIN’s "reductionist" fragment constant methodology (i.e. derivation via multiple regression) differs from the "constructionist" fragment constant methodology of Hansch and Leo (1979) that is available in the CLOGP Program (Daylight, 1995). See the attached QMRF and Meylan and Howard (1995) journal article for a more complete description of KOWWIN’s methodology.

- Defined domain of applicability:
According to the KOWWIN documentation, there is currently no universally accepted definition of model domain. However, the documentation does provide information for reliability of the calculations. Estimates will possibly be less accurate for compounds that 1) have a MW outside the ranges of the training set compounds and 2) 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.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Total Training Set Statistics:
number in dataset = 2447
correlation coef (r2) = 0.982
standard deviation = 0.217
absolute deviation = 0.159
avg Molecular Weight = 199.98

Training Set Molecular Weights:
Minimum MW: 32.04
Maximum MW: 665.02
Average MW: 224.4

Validation Molecular Weights:
Minimum MW: 73.14
Maximum MW: 504.12
Average MW: 277.8

5. APPLICABILITY DOMAIN
Currently there is no universally accepted definition of model domain. However, users may wish to consider the possibility that log Koc estimates are less accurate for compounds outside the MW 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 or correction factor was developed. These points should be taken into consideration when interpreting model results.

In general, the intended application domain for all models embedded in EPISuite is organic chemicals. Specific compound classes, besides organic chemicals, require additional correction factors. Indicators for the general applicability of the KOWWIN model a re the molecular weight of the target substance and the identified number of individual fragments in comparison to the training set. The training set molecular weights are within the range of 18.02 - 719.92 with an average molecular weight of 199.98 (Validation set molecular weights: 27.03 - 991.15 a nd average of 258.98).

The molecular weight of 1,4-diazabicyclooctane is 112.18 , which falls within the range of both, the training set and the validation set.The substance is organic.

The maximum number of instances of that fragment in any of the 2447 training set compounds and 10946 validation set compounds (the minimum number of instances is zero, since not all compounds had every fragment) are available in the model documentation (see attached QMRF). The following numbers of fragments were found in the target chemical, the respective maximum training set numbers for each fragment are given in the last column:

TYPE | NUM | LOGKOW FRAGMENT DESCRIPTION | COEFF | VALUE | MAx. number training set (validation set)
-------+-----+--------------------------------------------+---------+--------
Frag | 6 | -CH2- [aliphatic carbon] | 0.4911 | 2.9466 | 18 (28)
Frag | 2 | -N< [aliphatic attach] |-1.8323 | -3.6646 | 4 (6)
Const Equation Constant | 0.2290

Out of the two identified fragments, neither exceeded the maximum number found in the training set substances, as well as in the validation set.
In addition to the fragment identification, no correction factors had to be applied. As a result 1,4-diazabicyclooctane would not be considered outside the estimation domain.

6. ADEQUACY OF THE RESULT
Based on the experimental difficulties for certain compound classes, the KOWWIN calculations are fit for the purpose of identifiying a certain partition coefficient range.
The estimated logKow (calculation based on fragment contribution) was -0.49.
The representative SMILES notation used for the predictions was: N(CCN(C1)C2)(C1)C2
The KOWWIN predicted partition coefficient value is considered valid and fit for purpose.

7. BIBLIOGRAPHY
Documentation of the KOWWIN model is provided in the attachd QMRF.

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

US EPA (2007) Estimation Program Interface (EPI) Suite version 3.20. (United States Environmental Protection Agency)

GLP compliance:

not specified

Type of method:

other: calculation

Partition coefficient type:

octanol-water

Specific details on test material used for the study:

CAS: 280-57-9
SMILES: N(CCN(C1)C2)(C1)C2

Key result

Type:

log Pow

Partition coefficient:

-0.49

Temp.:

20 °C

pH:

7

KOWWIN Program (v1.68) Results:
===============================
Log Kow(version 1.68 estimate): -0.49

SMILES : N(CCN(C1)C2)(C1)C2
CHEM  : 1,4-Diazabicyclo 2.2.2 octane
MOL FOR: C6 H12 N2
MOL WT : 112.18
-------+-----+--------------------------------------------+---------+--------
 TYPE | NUM |       LOGKOW FRAGMENT DESCRIPTION        | COEFF | VALUE
-------+-----+--------------------------------------------+---------+--------
 Frag | 6 | -CH2-  [aliphatic carbon]               | 0.4911 | 2.9466
 Frag | 2 | -N<    [aliphatic attach]               |-1.8323 | -3.6646
 Const |    | Equation Constant                        |        | 0.2290
-------+-----+--------------------------------------------+---------+--------
Log Kow  = -0.4890

Conclusions:

Value of log Pow estimated by KOWWIN v1.68 US EPA (2010) Estimation Program Interface (EPI) Suite version 4.1 is -0.49

Executive summary:

Value of log Pow estimated by KOWWIN v1.68 US EPA (2010) Estimation Program Interface (EPI) Suite version 4.1 is -0.49

Reference 2

Endpoint:

partition coefficient

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

supporting study

Study period:

1992

Reliability:

2 (reliable with restrictions)

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: other (calculated)

GLP compliance:

not specified

Type of method:

other: Theoretical calculation

Partition coefficient type:

octanol-water

Type:

log Pow

Partition coefficient:

-1.13

Temp.:

20 °C

pH:

7

Conclusions:

Calculated value using fragment method of Hansch & Leo is -1.13

Executive summary:

Calculated value using fragment method of Hansch & Leo is -1.13

Description of key information

Value of log Pow determined by calculation methods is -0.49

Key value for chemical safety assessment

Log Kow (Log Pow):

-0.49

at the temperature of:

20 °C