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Environmental fate & pathways

Biodegradation in soil

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Reference
Endpoint:
biodegradation in soil: simulation testing
Type of information:
calculation (if not (Q)SAR)
Remarks:
calculation using EAWAG-BBD Pathway Prediction System
Adequacy of study:
weight of evidence
Study period:
2021
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

The EAWAG-BBD Pathway Prediction System predicts microbial catabolic reactions using substructure searching, a rule-base, and atom-to-atom mapping. The system is able to recognize organic functional groups found in a compound and predict transformations based on biotransformation rules. The biotransformation rules are based on reactions found in the EAWAG-BBD database or in the scientific literature.

2. MODEL
The pathway prediction system can be accessed at the EAWAG-BBD Pathway Prediction page, which can be reached from the "Pathway Prediction" link on the EAWAG-BBD home page, or by using the following URL: http://umbbd.ethz.ch/predict/.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Substance name: 2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid
CAS No.: 2202-98-4
Molecular formula: C12H14O6
Molecular weight: 254.24 g/mol
Smiles notation: OCCOCCOC(=O)C1=C(C=CC=C1)C(O)=O



4. SCIENTIFIC VALIDITY OF THE MODEL
- Defined endpoint:
likelyhood of reaction

1. Very likely reaction.
This is to be reserved for reactions that will almost certainly occur and occur with the highest priority. For example, if an acid chloride is generated, these compounds almost invariably undergo spontaneous hydrolysis in water very rapidly. So this would likely occur as the next step in any metabolic pathway in any bacterium. EAWAG-BBD btrule bt0026, Acid chloride -> Carboxylate is an example of this type of rule.
2. Likely reaction.
This is to be used when almost all bacteria can catalyze a given reaction with a functional group present in a molecule. For example, if the substrate has an ester linkage, it is often hydrolyzed by very common esterases, found both extracellularly and intracellularly. So giving an ester hydrolysis rule a score of 2 would give it a high priority but after an acid chloride hydrolysis reaction. You should also use 2 for a reaction that is significantly likely to occur once a certain intermediate has been generated. For example, aromatic ring cis-dihydrodiols are likely to be dehydrogenated to form catechols. Most organisms that make cis-dihydrodiols will also catalyze their dehydrogenation, thus the latter reaction is likely due to the linkage. EAWAG-BBD btrule bt0255, Dihydrodihydroxyaromatic -> 1,2-Dihydroxyaromatic is an example of this type of rule.
3. Possible reaction (neutral).
This applies to reactions that are common but not certain to occur in every system. For example, hydrocarbon oxygenation reactions are quite possible, but may or may not be likely to occur depending on what the substrate is. These must be looked at individually. Some may be likely, some may be possible and some may be unlikely based on current knowledge (an example of the latter may be oxygenases that work on 5-ring polycyclic aromatic hydrocarbons). EAWAG-BBD btrule bt0002, secondary Alcohol -> Ketone is an example of this type of rule.
4. Unlikely reaction.
This would be the case for reactions that clearly might occur, but are either very rarely catalyzed in bacterial and fungal populations, or that don't seem likely to occur because of the initial conditions we are using or other chemical/biochemical reason. EAWAG-BBD btrule bt0029, organoHalide -> RH, which is unlikely to occur under aerobic conditions, is an example of this type of rule.
5. Very unlikely reaction.
These reactions are ones, for example, that have never been observed under aerobic conditions and the enzymes are oxygen sensitive. Thus, given our initial conditions, we would expect that these reactions are highly unlikely. EAWAG-BBD btrule bt0270, Toluene -> Benzylsuccinate is an example of this type of rule.
6. No decision.

- unambigous algorithm:
The PPS predicts plausible pathways for microbial degradation of chemical compounds. Predictions use biotransformation rules, based on reactions found in the EAWAG-BBD database or in the scientific literature.

- Defined domain of applicability:
Chemicals that are out of the scope of the model
1. Readily Degraded and Selected Other Compounds
PPS predictions will terminate when they reach certain small, readily degraded compounds. If one of these is entered, its biodegradation will not be predicted, and, if possible, the user will be given a link to a KEGG pathway that includes this compound. These compounds also include dead-end compounds that are not degraded and accumulate in the environment. A list of termination compounds in the current system is available. The PPS will not display many small molecules with few or no carbon atoms, and certain common enzyme cofactors and derivates, produced in a prediction. This limits the list of predicted compounds to the more important ones.
2. Inorganic Chemicals
The rules used for the PPS were designed and developed for organic chemicals. Results for inorganic chemicals will be unreliable and their biodegradation should not be predicted using the PPS. This class of chemicals includes all chemicals that do not contain carbon. It includes neutral species such as titanium dioxide (TiO2) and inorganic salts, such as sodium chloride (NaCl) or potassium permanganate (KMnO4). This class of chemicals also includes organo-metallic chemicals (chemicals that contain carbon bonded to a metal species).
3. High Molecular Weight Compounds
Polymers and chemicals with a molecular weight greater than 1,000 should not have their biodegradation predicted as the PPS was not developed for these types of compounds. However, many polymers may be made up of dimers, trimers, and oligomers that have a molecular weight of less than 1,000. These smaller molecules may contain the same components as the larger polymers, and, therefore, could be run through the PPS. The results should be interpreted with due caution, however, as the biodegradation characteristics of chemicals with a molecular weight of >1,000 are likely to be significantly different from that of much smaller compounds, even if they have similar structures. This is due at least in part to the greatly reduced bioavailability of high molecular weight compounds.
4. Chemicals with Unknown or Variable Composition
The PPS was developed for discrete organic chemicals. That is, organic chemicals that can be represented by a single, precisely known chemical structure. If the compound has a variable composition (such as oligomers, natural fats, or a product mixture that changes composition depending on environmental conditions), a representative structure may be entered. However, in that case, it is possible that PPS results do not reflect the true nature of the biodegradation products.
5. Mixtures
Mixtures cannot be run through the PPS because it uses a single, discrete chemical structure as its input. If the chemical whose biodegradation you want to predict is a mixture of discrete organic substances, then each substance can be run through the PPS separately. Results should be interpreted with caution, as the biodegradation pathways predicted for substances separately will possibly be very different if they were degraded together.
6. Highly Fluorinated Compounds
Many highly fluorinated chemicals (those that have more fluorines than non-fluorine atoms bonded to carbon), including fully fluorinated organics (those that have all hydrogens on carbon replaced with fluorine), possess biodegradation properties that are vastly different than their non-substituted analogs. The rules used by the PPS do not accurately predict the unique characteristics of these materials. All per- and highly- fluorinated chemicals should not have their biodegradation predicted.

Reactions the EAWAG-PPS does not predict:
Some known environmental reactions are not predicted. Some reactions are too complex to predict. Important classes of these reactions contain, but are not limited to:

- Detoxification reactions. These include, but are not limited to, conjugation with xylose, glucuronate and sulfate.
- Dimerizations. These include, but are not limited to, disulfides formed from sulfide (-SH) groups, or azo compounds formed from primary amide (-NH2) groups.
- Methylation of hydroxyl groups.
- Acetylation of primary amines.
- Formation of intramolecular rings.
- Hydroxylation of aliphatic carbon atoms at positions where pure cultures of organisms that metabolize similar compounds do not hydroxylate, though environmental non-specific monooxygenases may.

- Mechanistic interpretation:
The EAWAG-BBD contains 332 biotransformation descriptions for 249 biotransformation rules. These include 46 descriptions (*) for 25 super rules, and 39 rules subsumed by them (status June 29, 2017). The reaction rules to be evaluated are considered for biodegradation under aerobic conditions, in soil (moderate moisture) or water, at neutral pH, 25°C, with no competing or toxic other compounds. Biotransformation rules are prioritized using a five-point Likkert scoring scale.

5. APPLICABILITY DOMAIN
The substance is a multi-constituent substance, which consists of two constituents: the main constituent, 2,2'-oxydiethanol, CAS No. 111-46-6, EC No.: 203-872-2 with a range of 50 – 62 %, and 1,2 Benzenedicarboxylic acid, 1-(2-(2-hydroxyethoxy)ethyl)ester, CAS No.: 2202-98-4, EC No.: 218-610-2 with a typical range of 38 – 50 %. Additionally, Phthalic acid, CAS No.: 88-99-3, EC No.: 201-873-2 is present as Impurity with up to 0.9 %.
As the main constituent 2,2'-oxydiethanol, CAS No.: 111-46-6, EC No.: 203-872-2 is known to be readily biodegradable, as well as the Impurity, phthalic acid, CAS No: 88-99-3, EC No.: 201-873-2 the minor constituent has to be assessed regarding its degradability behaviors. The molecule is suitable for the model, as none of the criteria laid out for chemicals being out of scope are met.

6. ADEQUACY OF THE RESULT
The results are useful for regulatory purposes.
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
other:
Version / remarks:
ECHA Guidance Document R.6 (2008)
Principles of method if other than guideline:
Gao J, Ellis LBM, Wackett LP (2010) "The University of Minnesota Biocatalysis/Biodegradation Database: improving public access" Nucleic Acids Research 38: D488-D491.
GLP compliance:
no
Test type:
other: calculation using EAWAG-BBD Pathway Prediction System
Specific details on test material used for the study:
Substance name: 2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid
CAS No.: 2202-98-4
Molecular formula: C12H14O6
Molecular weight: 254.24 g/mol
Smiles notation: OCCOCCOC(=O)C1=C(C=CC=C1)C(O)=O
Radiolabelling:
no
Oxygen conditions:
aerobic
Soil classification:
other: calculation using EAWAG-BBD Pathway Prediction System
Remarks:
Standard conditions assumed for aerobic biotransformations are: exposed to air, in moist soil or water, at neutral pH, 25°C, with no competing or toxic other compounds.
Parameter followed for biodegradation estimation:
other: likelyhood of reaction
Soil No.:
#1
Temp.:
25
Humidity:
yes
Microbial biomass:
not specified
Details on experimental conditions:
The reaction rules to be evaluated are considered for biodegradation under aerobic conditions, in soil (moderate moisture) or water, at neutral pH, 25°C.
Parent/product:
parent
Remarks on result:
other: likelyhood of reaction and possible degradation products modelled
Transformation products:
not measured
Details on transformation products:
First transformation step
The formed alcohol, 2,2'-oxydiethanol, CAS No.: 111-46-6, EC No.: 203-872-2 is also the major constituent of the substance.
The formed carboxylate is phthalate, the deprotonated form of phthalic acid, CAS No.: 88-99-3, EC No. 201-873-2. Both products are known to be readily biodegradable.
The third product formed is 2‐{[2‐(2‐oxoethoxy)ethoxy]carbonyl}benzoate.

Second transformation step
The degradation product resulting from oxidation of 2‐{[2‐(2‐oxoethoxy)ethoxy]carbonyl}benzoate is 2‐{[2‐(carboxylatomethoxy)ethoxy]carbonyl}benzoate.
Evaporation of parent compound:
no
Remarks:
due to high watersolubility
Volatile metabolites:
not measured
Residues:
not measured
Details on results:
First transformation step
In a first transformation step two different possible biotransformation (bt0001 and bt0024) were found, which both are considered likely (score 2). Rule bt0024 handles the saponification of esters to alcohol and carboxylate. In this case the formed alcohol, 2,2'-oxydiethanol, CAS No.: 111-46-6, EC No.: 203-872-2 is also the major constituent of the substance. The formed carboxylate is phthalate, the deprotonated form of phthalic acid, CAS No.: 88-99-3, EC No. 201-873-2. Both products of degradation path bt0024 are known to be readily biodegradable. Hence, further degradation steps do not need to be regarded for the persistency assessment of the substance.
The second biotransformation applied by rule bt0001 takes into account the oxidation of the alcohol to the corresponding aldehyde, 2‐{[2‐(2‐oxoethoxy)ethoxy]carbonyl}benzoate.

Second transformation step
In the second transformation step five possible biotransformations were found, of which four (bt0003, bt0001, bt0005*) are to be considered as likely (score 2). However, as only the degradation path resulting from predicted product 2‐{[2‐(2‐oxoethoxy)ethoxy]carbonyl}benzoate is relevant. It is further oxidized following rule bt0003, which handles reaction from aldehyde to carboxylate, forming 2‐{[2‐(carboxylatomethoxy)ethoxy]carbonyl}benzoate.

In addition to the outcome of the EAWAG-BBD Pathway Prediction System (PPS) further arguments can be brought forward which render the determination of the biodegradation behavior of the substance unnecessary. In a ready biodegradability study according to OECD TG 301F by Neuhahn (2012) a degradation of 60 % could be found after 28 days. However, degradation failed the 10-day window. Hence the substance was regarded as “not readily biodegradable” even though it reached the pass level (≥ 60 %).

According to OECD (2006) “the 10-day window should not be applied for mixtures consisting of structurally similar constituents as there could be sequential, overlapping biodegradation of the single constituents which might be the case here. Hence, the 10-day window would be masked. The OECD 301 test methods have not been developed to identify such potentially overlapping biodegradation curves.”

This is exactly the case here. The substance “Reaction mass of 2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid and 2,2'-oxydiethanol”, EC No: 700 -993 -7 consists of the constituents 2,2'-oxydiethanol, CAS No. 111-46-6, and 1,2 Benzenedicarboxylic acid, 1-(2-(2-hydroxyethoxy)ethyl)ester, CAS No.: 2202-98-4. As 2,2'-oxydiethanol is a breakdown product of 1,2 Benzenedicarboxylic acid, 1-(2-(2-hydroxyethoxy)ethyl)ester it is anticipated that sequential biodegradation took place in the test.

Additionally, the inherent biodegradability of the substance was evaluated in a study according to OECD TG 302C by Neuhahn (2012a). Here, a degradation of 68 % was observed after 28 days. This is notably close to the pass level of ≥ 70 % based on DOC content.

An experimental study on the adsorption/desorption behavior of the substance was performed (Garcia-Sanchez, 2013) yielding a log Koc of -0.7, rendering the substance not adsorptive. Therefore, accumulation in the terrestrial compartment is not expected.

Conclusions:
Applying the EAWAG-BBD Pathway Prediction System (PPS) to the molecule “2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid” yields valuable information about the putative environmental fate of the substance. From the vast amount of possible biotransformation processes not even one could be found, which can be considered as very likely (score 1) to occur. For the applied molecule most of the possible biotransformations are rated likely (score 2) and only one transformation pathway can be considered as neutral to occur. Many of the identified biodegradation products are well characterized and readily biodegradable. Thus, the model predicts a significant potential for ultimate biodegradation.
It has to be noted that the investigated molecule acts only as a representative candidate for the registered substance. The arising transformation products a2,2'-oxydiethanol, CAS No.: 111-46-6, EC No.: 203-872-2 , and phthalate, the deprotonated form of phthalic acid, CAS No.: 88-99-3, EC No. 201-873-2 are also constituents of the substance. Taking this into account the obtained model data strongly point at a high potential for biodegradation for the representative molecule “2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid” and as a consequence also for the registered substance “Reaction mass of 2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid and 2,2'-oxydiethanol” (EC no.:700 -993 -7).
Executive summary:

Applying the EAWAG-BBD Pathway Prediction System (PPS) to the molecule “2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid” yields valuable information about the putative environmental fate of the substance. From the vast amount of possible biotransformation processes not even one could be found, which can be considered as very likely (score 1) to occur. For the applied molecule most of the possible biotransformations are rated likely (score 2) and only one transformation pathway can be considered as neutral to occur. Many of the identified biodegradation products are well characterized and readily biodegradable. Thus, the model predicts a significant potential for biodegradation.

It has to be noted that the investigated molecule acts only as a representative candidate for the registered substance. The arising transformation products 2,2'-oxydiethanol, CAS No.: 111-46-6, EC No.: 203-872-2 , and phthalate, the deprotonated form of phthalic acid, CAS No.: 88-99-3, EC No. 201-873-2 are also constituents of the substance. Taking this into account the obtained model data strongly point at a high potential for biodegradation for the representative molecule “2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid” and as a consequence also for the registered substance “Reaction mass of 2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid and 2,2'-oxydiethanol” (EC No 700 -993 -7).

The combination of the outcome of the EAWAG model, which is included in its successor envipath, with the biodegradation behavior in screening tests of the substance “Reaction mass of 2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid and 2,2'-oxydiethanol” (EC no.:700 -993 -7)

strongly suggests a high potential for ultimate biodegradation in soil.

Therefore, the substance should not be classified as P or even vP.

Description of key information

Applying the EAWAG-BBD Pathway Prediction System (PPS) to the molecule “2-{[2-(2-hydroxyethoxy)ethoxy]carbonyl}benzoic acid” yields valuable information about the putative environmental fate of the substance. From the vast amount of possible biotransformation processes not even one could be found, which can be considered as very likely (score 1) to occur. For the applied molecule most of the possible biotransformations are rated likely (score 2) and only one transformation pathway can be considered as neutral to occur. Many of the identified biodegradation products are well characterized and readily biodegradable. Thus, the model predicts a significant potential for ultimate biodegradation.

Key value for chemical safety assessment

Additional information