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Environmental fate & pathways

Biodegradation in water: screening tests

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Reference
Endpoint:
biodegradation in water: ready biodegradability
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
Remarks:
The value is not an experimental result, 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 substance (characterised by a generic SMILES code) is fully characterised towards the applicability domain.
Justification for type of information:
1. SOFTWARE
EPIWIN software by US-EPA

2. MODEL (incl. version number)
BIOWIN v4.10

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O(c(ccc(NC(C=C1C)(C)C)c12)c2)CC
CAS 91-53-2

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- The model and the training and validation sets are published by US Environmental Protection Agency (USA). Details in addition to the summary provided here can be found in the program.

The Biowin program is part of the Estimation Programs Interface (EPI) Suite© and contains six models whose purpose is to provide screening-level estimates of aerobic biodegradability for organic chemicals:
Biowin1 = linear probability model;
Biowin2 = nonlinear probability model;
Biowin3 = expert survey ultimate biodegradation model;
Biowin4 = expert survey primary biodegradation model;
Biowin5 = Japanese Ministry of International Trade and Industry (MITI) linear model; and
Biowin6 = MITI nonlinear model.
Biowin1 and 2 constitute the original Biodegradation Probability Program and were the first two models developed (Howard et al., 1992). Biowin3 and 4 estimate the time required to achieve complete ultimate (Biowin3) or primary (Biowin4) biodegradation in a typical, or ‘evaluative’, aquatic environment. They were developed from estimates of biodegradability for 200 substances, provided by a panel of experts (Boethling et al., 1994). The output of the model for any given chemical is a number fromone to five (continuous scale; fractional values permitted) that either can be used as it is, or if desired can be related to the words (e.g. ‘days’, ‘weeks’) used in the expert survey. In Biowin3 values N2.75 and b=3.25 are assigned the term‘weeks’. Here 2.75 was used as the criterion for ready biodegradability, so that a calculated value N2.75 is a prediction of RB and is equivalent to a prediction of ‘weeks’ or an even shorter timeframe. For Biowin4 a criterion of 3.6 (i.e., b=3.6 is NRB) yielded a reasonable separation of RB and NRB compounds. Biowin5 and 6 are linear and nonlinear probability models developed exclusively from the MITI data (MITI, 2014). Biowin5/6 classify a substance as either RB or NRB based on the MITI ready biodegradation test (OECD 301C).
Characteristics of this test, as well as details of model development and validation, are given by Tunkel et al. (2000). The model estimates the likelihood that a chemical will degrade under the test conditions. Values of the dependent variable N0.5 usually are taken as predicting that the chemical will be RB in the OECD 301C test, but as with other Biowin models the user can set the RB/NRB criterion at any value desired.

Predicting Ready Biodegradability
The following line appears at the end of the Biowin prediction results: Ready Biodegradability Prediction:  (YES or NO)
The criteria for the YES or NO prediction are as follows:  If the Biowin3 (ultimate survey model) result is "weeks" or faster (i.e. days, days to weeks, or weeks) AND the Biowin5 (MITI linear model) probability is >= 0.5, then the prediction is YES (readily biodegradable).  If this condition is not satisfied, the prediction is NO (not readily biodegradable).
This method is based on the application of Bayesian analysis to ready biodegradation data for US Premanufacture Notification (PMN) chemicals, derived collectively from all six OECD301 test methods plus OECD310.  The approach is fully described in Boethling et al. (2004).
The linear and nonlinear MITI models (Biowin5 and 6) also predict ready biodegradability, but for degradation in the OECD301C test only, and based exclusively on data from the Chemicals Evaluation and Research Institute Japan (CERIJ) database (http://www.cerij.or.jp/ceri_en/otoiawase/otoiawase_menu.html).

5. APPLICABILITY DOMAIN
The EPI Suite data files are files containing the experimental data sets used to derive and validate program methodologies or test program accuracy.  In EPI Suite v4.00, the data files were available in either the appendices of the individual program help files or via Internet download from: http://esc.syrres.com/interkow/EpiSuiteData.htm

6. ADEQUACY OF THE RESULT
The accuracy of the models is described in detail in the program itself and e.g. by Boethling (Science of the Total Environment 497–498 (2014) 60–67) and suffices to give suitable predictions for substances falling into the applicability domain of the model.

Two independent training sets were used to develop four mathematical models for predicting aerobic biodegradability from chemical structure.  All four of the models are based on multiple regressions against counts of 36 preselected chemical substructures plus molecular weight.  Two of the models, based on linear and nonlinear regressions, calculate the probability of rapid biodegradation and can be used to classify compounds as rapidly or not rapidly biodegradable.  The training set for these models consisted of qualitative summary evaluations of all available experimental data on biodegradability for 295 compounds.  The other two models allow semi-quantitative prediction of primary and ultimate biodegradation rates using multiple linear regression.  The training set for these models consisted of estimates of primary and ultimate biodegradation rates for 200 compounds, gathered in a survey of 17 biodegradation experts.  The two probability models correctly classified 90% of the compounds in their training set, whereas the two survey models calculated biodegradation rates for the survey compounds with R2 = 0.7.  These four models are intended for use in chemical screening and in setting priorities for further review.
Reference:
Composition 0
Guideline:
other: REACH guidance on QSARs Chapter R.6
Version / remarks:
May 2008
GLP compliance:
no
Remarks:
not applicable
Test material information:
Composition 1
Key result
Parameter:
probability of ready biodegradability (QSAR/QSPR)
Remarks on result:
not readily biodegradable based on QSAR/QSPR prediction
Details on results:
BIOWIN (v4.10) Program Results:
==============================
SMILES : O(c(ccc(NC(C=C1C)(C)C)c12)c2)CC
CHEM : Quinoline, 6-ethoxy-1,2-dihydro-2,2,4-trimethyl-
MOL FOR: C14 H19 N1 O1
MOL WT : 217.31
--------------------------- BIOWIN v4.10 Results ----------------------------

Biowin1 (Linear Model Prediction) : Does Not Biodegrade Fast
Biowin2 (Non-Linear Model Prediction): Does Not Biodegrade Fast
Biowin3 (Ultimate Biodegradation Timeframe): Weeks-Months
Biowin4 (Primary Biodegradation Timeframe): Days-Weeks
Biowin5 (MITI Linear Model Prediction) : Does Not Biodegrade Fast
Biowin6 (MITI Non-Linear Model Prediction): Does Not Biodegrade Fast
Biowin7 (Anaerobic Model Prediction): Does Not Biodegrade Fast
Ready Biodegradability Prediction: NO

------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin1 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | -0.1839 | -0.1839
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -0.2338 | -0.2338
Frag | 1 | Aromatic ether [-O-aromatic carbon] | 0.1319 | 0.1319
MolWt| * | Molecular Weight Parameter | | -0.1035
Const| * | Equation Constant | | 0.7475
============+============================================+=========+=========
RESULT | Biowin1 (Linear Biodeg Probability) | | 0.3583
============+============================================+=========+=========

------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin2 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | -1.7232 | -1.7232
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -1.9070 | -1.9070
Frag | 1 | Aromatic ether [-O-aromatic carbon] | 2.2483 | 2.2483
MolWt| * | Molecular Weight Parameter | | -3.0859
============+============================================+=========+=========
RESULT | Biowin2 (Non-Linear Biodeg Probability) | | 0.1886
============+============================================+=========+=========

A Probability Greater Than or Equal to 0.5 indicates --> Biodegrades Fast
A Probability Less Than 0.5 indicates --> Does NOT Biodegrade Fast

------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin3 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | -0.2121 | -0.2121
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -0.1349 | -0.1349
Frag | 1 | Aromatic ether [-O-aromatic carbon] | -0.0581 | -0.0581
MolWt| * | Molecular Weight Parameter | | -0.4802
Const| * | Equation Constant | | 3.1992
============+============================================+=========+=========
RESULT | Biowin3 (Survey Model - Ultimate Biodeg) | | 2.3137
============+============================================+=========+=========

------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin4 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | -0.1534 | -0.1534
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -0.1084 | -0.1084
Frag | 1 | Aromatic ether [-O-aromatic carbon] | 0.0771 | 0.0771
MolWt| * | Molecular Weight Parameter | | -0.3135
Const| * | Equation Constant | | 3.8477
============+============================================+=========+=========
RESULT | Biowin4 (Survey Model - Primary Biodeg) | | 3.3495
============+============================================+=========+=========

Result Classification: 5.00 -> hours 4.00 -> days 3.00 -> weeks
(Primary & Ultimate) 2.00 -> months 1.00 -> longer

------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin5 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | 0.0676 | 0.0676
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -0.1577 | -0.1577
Frag | 1 | Aromatic ether [-O-aromatic carbon] | 0.1952 | 0.1952
Frag | 3 | Aromatic-H | 0.0082 | 0.0247
Frag | 4 | Methyl [-CH3] | 0.0004 | 0.0016
Frag | 1 | -CH2- [linear] | 0.0494 | 0.0494
Frag | 1 | -C=CH [alkenyl hydrogen] | 0.0062 | 0.0062
MolWt| * | Molecular Weight Parameter | | -0.6465
Const| * | Equation Constant | | 0.7121
============+============================================+=========+=========
RESULT | Biowin5 (MITI Linear Biodeg Probability) | | 0.2527
============+============================================+=========+=========

------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin6 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | 0.3990 | 0.3990
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -1.2264 | -1.2264
Frag | 1 | Aromatic ether [-O-aromatic carbon] | 1.3227 | 1.3227
Frag | 3 | Aromatic-H | 0.1201 | 0.3604
Frag | 4 | Methyl [-CH3] | 0.0194 | 0.0777
Frag | 1 | -CH2- [linear] | 0.4295 | 0.4295
Frag | 1 | -C=CH [alkenyl hydrogen] | 0.0285 | 0.0285
MolWt| * | Molecular Weight Parameter | | -6.2736
============+============================================+=========+=========
RESULT |Biowin6 (MITI Non-Linear Biodeg Probability)| | 0.0866
============+============================================+=========+=========

A Probability Greater Than or Equal to 0.5 indicates --> Readily Degradable
A Probability Less Than 0.5 indicates --> NOT Readily Degradable


------+-----+--------------------------------------------+---------+---------
TYPE | NUM | Biowin7 FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 1 | Carbon with 4 single bonds & no hydrogens | -0.3342 | -0.3342
Frag | 1 | Aromatic amine [-NH2 or -NH-] | -0.2778 | -0.2778
Frag | 1 | Aromatic ether [-O-aromatic carbon] | 0.1780 | 0.1780
Frag | 3 | Aromatic-H | -0.0954 | -0.2863
Frag | 4 | Methyl [-CH3] | -0.0796 | -0.3183
Frag | 1 | -CH2- [linear] | 0.0260 | 0.0260
Frag | 1 | -C=CH [alkenyl hydrogen] | -0.0735 | -0.0735
Const| * | Equation Constant | | 0.8361
============+============================================+=========+=========
RESULT | Biowin7 (Anaerobic Linear Biodeg Prob) | | -0.2501
============+============================================+=========+=========

A Probability Greater Than or Equal to 0.5 indicates --> Biodegrades Fast
A Probability Less Than 0.5 indicates --> Does NOT Biodegrade Fast

Ready Biodegradability Prediction: (YES or NO)
----------------------------------------------
Criteria for the YES or NO prediction: If the Biowin3 (ultimate survey model) result is "weeks" or faster (i.e. "days", "days to weeks", or "weeks" AND the Biowin5 (MITI linear model) probability is >= 0.5, then the prediction is YES (readily biodegradable). If this condition is not satisfied, the prediction is NO (not readily biodegradable). This method is based on application of Bayesian analysis to ready biodegradation data (see Help). Biowin5 and 6 also predict ready biodegradability, but for degradation in the OECD301C test only; using data from the Chemicals Evaluation and Research Institute Japan (CERIJ) database.
Validity criteria fulfilled:
yes
Interpretation of results:
not readily biodegradable
Conclusions:
The study report describes a scientifically accepted calculation method for the ready biodegradability using the US-EPA software BIOWIN v1.40. No GLP criteria are applicable for the usage of this tool and the QSAR estimation is easily repeatable. The substance falls within the applicability domain of the QSAR model, hence, the result can be considered as reliable. The result is adequate for the regulatory purpose.
Executive summary:

The ready biodegradability of the substance ethoxyquin was determined by the QSAR program BIOWIN v1.40 (EPIWIN software) by US-EPA.

BIOWIN estimates the probability of rapid aerobic and anaerobic biodegradation of an organic compound in the presence of mixed populations of environmental microorganisms. Two independent training sets were used to develop four mathematical models for predicting aerobic biodegradability from chemical structure.  All four of the models are based on multiple regressions against counts of 36 preselected chemical substructures plus molecular weight.  Two of the models, based on linear and nonlinear regressions, calculate the probability of rapid biodegradation and can be used to classify compounds as rapidly or not rapidly biodegradable.  The training set for these models consisted of qualitative summary evaluations of all available experimental data on biodegradability for 295 compounds.  The other two models allow semi-quantitative prediction of primary and ultimate biodegradation rates using multiple linear regression.  The training set for these models consisted of estimates of primary and ultimate biodegradation rates for 200 compounds, gathered in a survey of 17 biodegradation experts.  The two probability models correctly classified 90% of the compounds in their training set, whereas the two survey models calculated biodegradation rates for the survey compounds with R2= 0.7. In this case ethoxyquin was estimated to be not readily biodegradable.

Adequacy of the QSAR:

- QSAR model is scientifically valid.

- The substance falls within the applicability domain of the QSAR model.

- The prediction is fit for regulatory purpose.

Further testing is not relevant, as during the substance' service life under REACH only negligible amounts are released into the environment, all further release does not fall under substance' service life under REACH.

Description of key information

Calculation with BIOWIN v4.10 (EPIWIN software by US-EPA): not readily biodegradable

Key value for chemical safety assessment

Additional information

The ready biodegradability of the substance ethoxyquin was determined by the QSAR program BIOWIN v1.40 (EPIWIN software) by US-EPA.

BIOWIN estimates the probability of rapid aerobic and anaerobic biodegradation of an organic compound in the presence of mixed populations of environmental microorganisms. Two independent training sets were used to develop four mathematical models for predicting aerobic biodegradability from chemical structure.  All four of the models are based on multiple regressions against counts of 36 preselected chemical substructures plus molecular weight.  Two of the models, based on linear and nonlinear regressions, calculate the probability of rapid biodegradation and can be used to classify compounds as rapidly or not rapidly biodegradable.  The training set for these models consisted of qualitative summary evaluations of all available experimental data on biodegradability for 295 compounds.  The other two models allow semi-quantitative prediction of primary and ultimate biodegradation rates using multiple linear regression.  The training set for these models consisted of estimates of primary and ultimate biodegradation rates for 200 compounds, gathered in a survey of 17 biodegradation experts.  The two probability models correctly classified 90% of the compounds in their training set, whereas the two survey models calculated biodegradation rates for the survey compounds with R2= 0.7.In this case ethoxyquin was estimated to be not readily biodegradable.

Adequacy of the QSAR:

- QSAR model is scientifically valid.

- The substance falls within the applicability domain of the QSAR model.

- The prediction is fit for regulatory purpose.

Further testing is not relevant, as during the substance' service life under REACH only negligible amounts are released into the environment, all further release does not fall under substance' service life under REACH.

The substance is manufactured as a feed additive only, no other uses were identified. Ethoxyquin as such is listed in the European Union Register of Feed Additives pursuant to Regulation (EC) No 1831/2003, on Annex I: List of additives (Released 19.09.2016, Edition 241), by the DIRECTORATE-GENERAL FOR HEALTH AND FOOD SAFETY, Directorate E - Food and feed safety, innovation, Unit E5 – Animal nutrition, veterinary medicines. As an approved feed additive, it is hence completely covered under the feed and food law and so not under the scope of REACH. Due to a change of the therein legally specified impurity profile, the substance as it is produced, does not fulfill these requirements any more, and is therefore, as a chemical substance not covered by other legislations, subject to REACH. After manufacture however, the substance will be directly purified to match the legal requirements for a feed additive. Hence, after purification the feed and food law will be applicable again, and the substance is no longer subject to REACH. Hence, only the very short service life of manufacture and transport needs to be regarded under REACH. During that period, sufficient precautions and safety measures are taken to avoid a release of the substance in the environment, so nearly no exposure of the environment to the substance is given and only negligible amounts are released, so only negligible amounts of the registered substance are contained in the waste water treated by the STP, there are no other ways that may lead to the exposure of the water compartment in general; liquid waste of the process is burned in a waste incineration unit. Prior to the emission into the STP, waste water is (pre)treated in a water-oil separator (two-phase system). Due to the higher LogPow value of the substance, ethoxyquin (CAS 91-53-2) will be dissolved in the oil phase to a great extent and only negligible amounts are expected to stay in the water phase. Therefore, significant exposure of the substance into the water compartment can be excluded. As biotic degradation of the substance by environmental organisms (i.e. other species than humans) becomes really relevant only outside the applicability of and the substance’ subjection to REACH, testing for this endpoint is not relevant for the substance’ registration. The service life of the substance under REACH ends prior to the point of time where biotic degradation becomes relevant. Degradation of the substance in humans is sufficiently covered by IUCLID chapter 7.1.1, basic toxicokinetics.