Reaction products of ((5E)-5-ethylidenebicyclo[2.2.1]hept-2-ene and (5Z)-5-ethylidenebicyclo[2.2.1]hept-2-ene) and 2-methyl-1,3-butadiene, epoxidized

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2018

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 Programme Interface (EPI) Suite programme for Microsoft Windows v4.11
Contact EPISuite:
U.S. Environmental Protection Agency
1200 Pennsylvania Ave.
N.W. (Mail Code 7406M)
Washington, DC 20460

2. MODEL (incl. version number)
ECOSAR v1.11 - Algae 96h EC50
19 June 2012 (model development)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See attached: ‘Aquatic Toxicity Predictions: Reaction products of ((5E)-5-ethylidenebicyclo[2.2.1]hept-2-ene and (5Z)-5-ethylidenebicyclo[2.2.1]hept-2-ene) and 2-methyl-1,3-butadiene, epoxidized)’ version 2.0; updated 01 March 2018.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Full details of the method are provided in the attached QMRF named ‘QMRF Title: ECOSAR v1.11 Green Algae 96h EC50’ version 1.11; updated 01 March 2018.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See attached: ‘Aquatic Toxicity Predictions: Reaction products of ((5E)-5-ethylidenebicyclo[2.2.1]hept-2-ene and (5Z)-5-ethylidenebicyclo[2.2.1]hept-2-ene) and 2-methyl-1,3-butadiene, epoxidized)’ version 2.0; updated 01 March 2018.

6. ADEQUACY OF THE RESULT
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. Specifically when combined with further information such as physico-chemistry and environmental fate testing and modelling.

Guideline:

other: REACH Guidance on QSARs R.6, May/July 2008

Guideline:

EPA OPPTS 850.5400 (Algal Toxicity, Tiers I and II) (January 2012)

Version / remarks:

This guideline is preferred for the training set but not obligatory

Principles of method if other than guideline:

1. ECOSAR v1.11 - Green Algae 96h EC50 ; Mono Epoxides Class, Poly-epoxides Class, Neutral Organics Class (baseline-toxicity)
2. Aquatic Toxicity Assessment of UVCB substances using the Additivity Approach
3. Assessment of Degradability for the purpose of Classification and Labelling

Specific details on test material used for the study:

Detailed information on the 'test material identity' is provided in the attached QSAR Prediction Reporting Format (QPRF) document including information on individual constituents according to point '2. Aquatic Toxicity Assessment of UVCB substances using the Additivity Approach' requirements.

Duration:

96 h

Dose descriptor:

EC50

Effect conc.:

2.18 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

growth rate

Remarks on result:

other: Additive Endpoint Values calculated in line with Block Method Approach

1. Defined Endpoint:

QMRF 3. Ecotoxic effects

QMRF 3.2. Short-term toxicity to algae (inhibition of the exponential growth rate)

Reference to type of model used and description of results:

ECOSAR v1.11 – Green Algae 96h EC50 ; Mono Epoxides Class, Poly-Epoxides Class, Neutral Organics (baseline toxicity) 19 June 2012

Note: Effect levels for each trophic group derived from the associated ECOSAR v1.11 model classes above are provided here for completeness. Adequate data were not available to develop a QSAR for green algae. Consequently, toxicity predictions must be made using either the closest analogue or the two closest analogues which bracket the polyepoxide in question. The nearest analogue “epoxides, mono” was used for this endpoint in-line with the block method approach.

 

2. Description of results and assessment of reliability of the prediction:

The test item Reaction products of ((5E)-5-ethylidenebicyclo[2.2.1]hept-2-ene and (5Z)-5-ethylidenebicyclo[2.2.1]hept-2-ene) and 2-methyl-1,3-butadiene, epoxidized is a substance of Unknown or Variable composition, Complex reaction products or Biological Materials (UVCB). This complex substance falls under the category of substances difficult to test defined in ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R7.b: Endpoint Specific Guidance, Appendix R.7.8-1. As the test item is also hydrolytically unstable (aqueous DT50 = ≤ 4.8 hours at environmentally relevant pH), the toxicity of the known hydrolysis products has also been conducted using the block method (reference: Redman et al. PETROTOX: An Aquatic Toxicity Model for Petroleum Substances.: Env, Toxicol. Chem. 31: 2487-2506).

 

1) ECOSAR v1.11 – Green Algae 96h EC50 ; Mono Epoxides Class, Poly-epoxides Class, Neutral Organics (baseline toxicity)

2) Aquatic Toxicity Assessment of UVCB substances using the Additivity Approach

Inputs Used for Test Item: All modelling was based on input of SMILES notation for each constituent of the test item and respective hydrolysis products (presented in the attached Aquatic Toxicity Predictions 01-03-2018 QPRF report), meaning that the process relied on modelled values for Kow and water solubility to define the blocks. This approach is in line with the PETROTOX methodology and ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R7.b for hazard assessment of complex mixtures.

Table 1. ECOSAR Output for Consolidated Blocks of Test Item Constituents

Block	Block Identifier	Typical Concentration in Test Item (% (w/w))	Log Kow KOWWIN	Water Solubility (mg/L) WSKOWWIN	Daphnid 48 h EC50 (mg/L)	Algae 96 h EC50 (mg/L)	Fish 96 h LC50 (mg/L)
1	Mono-epoxide	70	3.85	21.6	2.59	1.83	2.01
2	Poly-epoxide	14.7	2.45	276	7.32	25.6	12.5

Note: Concentration in the test item contributing to the additive endpoint values are presented in the attached Aquatic Toxicity Predictions 01-03-2018 QPRF report.

 

For the purpose of concluding on classification and labelling for this substance the additivity formula from Annex I, Section 4.1.3.5.2 of CLP Regulation (EC) 1272/2008 is applied to data on the known components of the substance. The effect values for the test item for each relevant trophic group are presented in the following table.

Table 2. Additive Endpoint Values for the Test Item for each Trophic Group

Trophic Level	Endpoint	Endpoint Value (mg/L)
Algae	96 h EC50	2.18
Daphnid	48 h EC50	2.92
Fish	96 h LC50	2.35

Substance rapidly degradable: NO

Log Kow: < 4.0

 

3) Assessment of Degradability for the purpose of Classification and Labelling

In accordance with CLP Regulation (EC) 1272/2008 as amended, degradation covers both biotic and abiotic forms of degradation. Although not readily biodegradable, the test item is hydrolytically unstable with a DT50 of ≤ 4.8 hours at environmentally relevant pH. As such the substance fulfils the following criteria set by CLP for rapid (primary) degradability. The data presented in appendix to the attached Aquatic Toxicity Predictions 01-03-2018 QPRF report suggests that the hydrolysis products are potentially not classified as hazardous to the aquatic environment. However, at the present time there is inadequate evidence to support the regulatory conclusion as ‘rapidly degradable’. The applicant concludes that for the purpose of classification & labelling that for the hydrolysis products there is presently inadequate evidence of: (i) their rapid mineralisation (they may be ultimately degraded) and/or confirmation of (ii) an absence of hazard to the aquatic compartment.Based on the above considerations, the substance is precautionarily classified as hazardous to the environment under CLP Regulation (EC) 1272/2008: Chronic Category 2: H411 - Toxic to aquatic life with long lasting effects. Further evidence, generated at a later date may confirm the suggestion that no classification and labelling is warranted. For example: at REACH Regulation (EC) 1907/2006: Annex IX information requirements.

 

Assessment of the substance within the applicability domain as documented within the corresponding QMRF named ‘QMRF Title: ECOSAR v1.11 Green Algae 96h EC50’ version 1.11; updated 01 March 2018 – section 5; indicates the substance:

(i) Falls within the Log Kow domain of < 5 (general domain for the model; and mono epoxide class and poly-epoxide specific cut off);

(ii) Molecular weights of all constituents are < 1000 g/mol and;

(iii) Effect levels are predicted below the water solubility. The substance constituents and hydrolysis products do not possess functional groups outside those included within the mono-epoxides, poly-epoxide classes and neutral organics training sets.

 

The ECOSAR QSAR model as detailed is not known to function by specific modes of action associated with the chemical class(es) assigned. Full references to training set data are presented within ECOSAR v1.1 Help System; if not proprietary (in such cases the chemical identification is listed as CBI, but the relevant descriptor data are provided). A summary of this information is presented by the applicant. The substances in the training set are considered analogues to the target substance since they possess relevant chemical groups and log Kow < 5 and MW < 1000 g/mol. The substance and the structural analogues share a common functional group and physico-chemical domains versus a neutral organics class (baseline toxicity). The ECOSAR class is based on similar relationships between toxicity and the various types of pharmacologic properties.

 

3. Uncertainty of the prediction and mechanistic domain:

No external validation set is available for the chemical class used in this prediction.

The coefficients of determination for each chemical class training set is published as presented below:

Neutral Organics: Coefficient of determination (r2) = 0.6782

Mono Epoxides: Coefficient of determination (r2) = 0.9784

Poly Epoxides: Coefficient of determination (r2) = Not available. See section 1. Mono Epoxides used as analogue.

Consistency of ECOSAR data compared to measured toxicity showed 60-64 % of green algae predictions (all chemical classes assessed) within a tolerance factor of 10, which is comparable to that seen in Hulzebos & Posthumus (2003).

 

Uncertainty in the prediction relates to:

1. Unknown constituents which consist mainly of mono-epoxides and di-epoxides and/or isomers of identified constituents. These constituents are not considered in the hazard assessment. However, given the structural similarity of the mono- and di-epoxides, and the known reactive nature of epoxides compared to normal ethers due to high ring strain, all constituents of this substance are expected to have a similar pH-mediated degree of hydrolytic instability. Consequently hydrolysis product assessment in each block provided by the applicant is viewed as sufficient to cover all foreseen degradation products. Measured data identifying these degradates would improve predictions further.

2. Limited external validation on the epoxide, mono class and the limited applicability of the model in relation to isomers. Model predictivity could be improved by the assignment of additional chemical categories and expansion of sub-structure rules, in addition further substances addition to the training set and rules for stereochemical effects within the model would improve predictivity. The ECOSAR QSAR model as detailed is not known to function by specific modes of action associated with the chemical class(es) assigned. ECOSAR classes are grouped based on similar relationships between toxicity and the various types of pharmacologic properties. The model does not apply a mechanistic approach to assessment of toxicity other than assignment of chemical classes (to identify potential toxicity in excess of baseline narcosis) using an expert decision tree. The selected classes appear appropriate to the substance based on expert assessment.

Validity criteria fulfilled:

yes

Conclusions:

The results are adequate for the for the regulatory purpose.

Executive summary:

ECOSAR v1.11 – Green Algae 96h EC50 ; Mono Epoxides Class, Poly-Epoxides Class (using Mono Epoxides Class as surrogate), Neutral Organics Class (baseline toxicity), 19 June 2012

Additive endpoint values: Green Algae 96-hr EC50: 2.18 mg/L

 

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 predictions do not indicate extreme acute toxicities relevant for classification and labelling. The assessment indicates that the prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements.

Description of key information

72h EC50 = 25.6 mg/L; ECOSAR v1.11

Key value for chemical safety assessment

EC50 for freshwater algae:

25.6 mg/L

Additional information

The 72h EC50 = 25.6 mg/L used for assessment entity 2 (of 2) is based on the predicted EC50 values of constituent 10-11 of the substance, using ECOSAR v1.11. Refer to the relevant QMRF and QPRF documents, and Section 0.4 of IUCLID for further information.