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

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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
The Neutral hydrolysis rate constant v.05.05; within OASIS CATALOGIC v.5.12.1
Contact LMC University:
Prof. As. Zlatarov,
LMC University,
Laboratory of Mathematical Chemistry,
Bourgas,
Bulgaria
URL: www.oasis-lmc.org
More information available at:
http://oasis-lmc.org/products/models/environmental-fate-and-ecotoxicity/

2. MODEL (incl. version number)
Neutral hydrolysis rate constant v.05.05
June 2014 (QMRF publication)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See QPRF attached: ‘QPRF Title: Substance: 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 using the model LMC OASIS CATALOGIC v5.12.1: Neutral hydrolysis rate constant v.05.05 for the endpoint: Hydrolysis’ version 1.0; 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: Neutral hydrolysis rate constant model predicts neutral hydrolysis rate constant (Kn)’ - model: Neutral hydrolysis rate constant v.05.05 - software package: OASIS CATALOGIC v.5.12.1, version 1.0; date: 01 June 2014; updated 01 July 2017.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See QPRF attached: ‘QPRF Title: Substance: 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 using the model LMC OASIS CATALOGIC v5.12.1: Neutral hydrolysis rate constant v.05.05 for the endpoint: Hydrolysis’ version 1.0; 01 March 2018.
- Descriptor domain: All constituents are in domain.
- Structural and mechanistic domains: All constituents are either 100% or > 80% correctly predicted ACF (in domain). All constituents are within the mechanistic domain.
- Similarity with analogues in the training set: There are comparable analogues in the training set and the results are consistent with established chemical/environmental fate literature.
- Other considerations (as appropriate): The result should be considered in relation to corresponding information presented and in accordance with the tonnage driven information requirements of REACH Regulation (EC) 1907/2006 in a weight of evidence. Provision of measured experimental Hydrolysis data for all constituents and resulting metabolites has been determined as not technically possible under guideline OECD TG 111 method at tier 2 and 3. Due to the complex nature of the substance (UVCB).Therefore, in accordance with the tonnage driven information requirements: the weight of evidence approach to abiotic degradation: hydrolysis has been adopted by the provision of screening and modelled data.

6. ADEQUACY OF THE RESULT
1) QSAR model is scientifically valid. 2) The substance falls within the general properties and mechanistic applicability domains, with limited applicability of the structural domain of the QSAR model (although all constituents > 80% correctly predicted ACF). Expert judgement considers the results reliable and relevant and the results are consistent with established literature. 3) The results are adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. Specifically, when combined with further information, details of which are available.

Reason / purpose for cross-reference:

reference to other study

Guideline:

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

Principles of method if other than guideline:

Full details of the method are provided in the attached QMRF named ‘QMRF Title: Neutral hydrolysis rate constant model predicts neutral hydrolysis rate constant (Kn)’ - model: Neutral hydrolysis rate constant v.05.05 - software package: OASIS CATALOGIC v.5.12.1, version 1.0; date: 01 June 2014; updated 01 July 2017.
- The model applies the following methodology to generate predictions:
The model consists of simulator or chemical metabolism/degradation to model the hydrolysis pathway and subsequent modelling of the hydrolysis rate constant with presumed first order kinetics and/or ultimate half-life. More information on the explicit algorithm utilised is provided in the following publication: S. Dimitrov, et al.. A stepwise approach for defining the applicability domain of SAR and QSAR models. J Chem Inf. Model, 45 (4), (2005) 839-849. Transformations of units to and from natural logarithmic units and/or derivation of respective concomitant predictions is completed automatically by the model programme.

- The model and the training sets are collated and published by Prof. As. Zlatarov, LMC University, (Bulgaria).
The training set of the model currently consists of 1128 chemicals with 1128 kinetic data for neutral hydrolysis rate constant (Kn):
(1) 350 chemicals, their experimental hydrolysis rate constants and their transformation products under the following experimental conditions: neutral pH (6.5-7.4), temperature 20-35°C and atmospheric pressure
(2) 778 newly added proprietary chemicals under the following experimental conditions: neutral pH (6.5-7.4) and temperature: 40°C.
(3) The observed maps database of the model consists of 349 documented hydrolysis maps.

The experimental Log Kow values in the training set and validation set were measured using one or more methods equivalent or similar to the following guidelines:
- Hydrolysis as a function of pH (OECD TG 111) or equivalent where appropriate.
A full list of experimental reference citations is provided in the CATALOGIC software with additional reference citations in the QMRF attached.
- Justification of QSAR prediction: The result should be considered in relation to corresponding information presented and in accordance with the tonnage driven information requirements of REACH Regulation (EC) 1907/2006 in a weight of evidence. Provision of measured experimental Hydrolysis data for all constituents and resulting metabolites has been determined as not technically possible under guideline OECD TG 111 method at tier 2 and 3. Due to the complex nature of the substance (UVCB).Therefore, in accordance with the tonnage driven information requirements: the weight of evidence approach to abiotic degradation: hydrolysis has been adopted by the provision of screening and modelled data.

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.

Transformation products:

yes

No.:

#1

No.:

#2

No.:

#3

No.:

#4

No.:

#5

No.:

#6

No.:

#7

No.:

#8

No.:

#9

No.:

#10

No.:

#11

No.:

#12

No.:

#13

No.:

#14

No.:

#15

Details on hydrolysis and appearance of transformation product(s):

- Formation and decline of each transformation product during test: See ‘any other information on results incl. tables’ - table 1 and 2 for further details of mol/mol parent predictions.
- Pathways for transformation: Epoxide ring opening

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

3.4 d-1

DT50:

0.2 d

Type:

other: predicted first order kinetics; neutral rate constant

Remarks on result:

other: Constituent 1 to 11

Remarks:

t1/2 = 4.8 hours

1. Defined Endpoint:

QMRF 2. Hydrolysis

QMRF 2.1.a Persistence: Abiotic degradation in water: Hydrolysis

Reference to type of model used and description of results:

The Neutral hydrolysis rate constant v.05.05; within OASIS CATALOGIC v.5.12.1

 

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

The predicted values are provided within the QPRF attached: ‘QPRF Title: Substance: 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 using the model LMC OASIS CATALOGIC v5.12.1: Neutral hydrolysis rate constant v.05.05 for the endpoint: Hydrolysis’ version 1.0; 01 March 2018.

The results of the hydrolysis predictions are provided in the following tables 1 and 2. Full output of the hydrolysis products is given in the attached QPRF document.

 

Table 1.0: SMILES and Log Kow, WSOL, Kn, half-life (t1/2) of the substance and domain assessment

Constituent Number	SMILES	Mw	Typical Conc. (% w/w)	Log Kow (KOWWIN)	Water Sol. (WSKOW) (mg/L)	neutral hydrolysis rate constant (Kn) (d-1)	Half-life (t1/2) (days)	Parameter Domain	Structural Fragment Domain (% correctly predicted atom centred fragments)	Mechanistic Domain
1	CC1=CC[C@@H]2[C@H](C1)[C@H]3C[C@@H]2[C@@]4(C3)O[C@@H]4C	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	100% ; in domain	in domain
2	CC2=CC[C@H]1[C@@H]3C[C@H]([C@H]1C2)[C@]4(C3)O[C@H]4C	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	100% ; in domain	in domain
3	C/C=C/1C[C@H]3C[C@@H]1[C@H]4C[C@]2(C)O[C@@H]2C[C@@H]34	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	86.67% ; out of domain	in domain
4	C/C=C/1C[C@@H]3C[C@H]1[C@@H]4C[C@H]2O[C@@]2(C)C[C@H]34	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	86.67% ; out of domain	in domain
5	CC2=CC[C@H]1[C@@H]3C[C@H]([C@H]1C2)C4(C3)OC4C	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	100% ; in domain	in domain
6	CC1=CC[C@H]2[C@@H](C1)[C@@H]3C[C@H]2C4(C3)OC4C	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	100% ; in domain	in domain
7	CC1=CC[C@@H]2[C@H](C1)[C@H]3C[C@@H]2[C@]4(C3)O[C@H]4C	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	100% ; in domain	in domain
8	C/C=C/1C[C@@H]3C[C@H]1[C@@H]4C[C@@H]2O[C@]2(C)C[C@H]34	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	86.67% ; out of domain	in domain
9	C/C=C\1C[C@@H]3C[C@H]1[C@@H]4C[C@H]2O[C@@]2(C)C[C@H]34	204.31	see QPRF	3.85	21.56	3.40	0.2	in domain	86.67% ; out of domain	in domain
10	C[C@@H]1O[C@]12C[C@H]4C[C@@H]2[C@H]5C[C@]3(C)O[C@@H]3C[C@@H]45	220.31	see QPRF	2.45	276.1	3.40	0.2	in domain	87.50% ; out of domain	in domain
11	C[C@H]1O[C@@]12C[C@@H]4C[C@H]2[C@@H]5C[C@H]3O[C@@]3(C)C[C@H]45	220.31	see QPRF	2.45	276.1	3.40	0.2	in domain	87.50% ; out of domain	in domain

 

Table 2.0: SMILES and outputs with Log Kow output and Predicted Concentrations of the hydrolysis products

Parent Constituent Number	Hydrolysis Product Number	SMILES	Molecular Weight	Predicted Concentration (mol/mol parent)	Log Kow (KOWWIN)
1	1	CC(O)C1(O)CC2CC1C1CC=C(C)CC21	222.33	0.606	2.69
2	1	CC(O)C1(O)CC2CC1C1CC(C)=CCC21	222.33	0.606	2.69
3	1	CC=C1CC2CC1C1CC(C)(O)C(O)CC21	222.33	0.606	2.69
4	1	CC=C1CC2CC1C1CC(O)C(C)(O)CC21	222.33	0.606	2.69
5	1	CC(O)C1(O)CC2CC1C1CC(C)=CCC21	222.33	0.606	2.69
6	1	CC(O)C1(O)CC2CC1C1CC=C(C)CC21	222.33	0.606	2.69
7	1	CC(O)C1(O)CC2CC1C1CC=C(C)CC21	222.33	0.606	2.69
8	1	CC=C1CC2CC1C1CC(O)C(C)(O)CC21	222.33	0.606	2.69
9	1	CC=C1CC2CC1C1CC(O)C(C)(O)CC21	222.33	0.606	2.69
10	1	CC1C2(CC3CC2C2CC(C)(O)C(O)CC32)O1	238.33	0.166	1.29
10	2	CC(O)C1(O)CC2CC1C1CC(C)(O)C(O)CC21	256.35	0.512	-0.26
10	3	CC(O)C1(O)CC2CC1C1CC3(C)C(CC21)O3	238.33	0.166	1.29
11	1	CC1C2(CC3CC2C2CC(O)C(C)(O)CC32)O1	238.33	0.166	1.29
11	2	CC(O)C1(O)CC2CC1C1CC(O)C(C)(O)CC21	256.35	0.512	-0.26
11	3	CC(O)C1(O)CC2CC1C1CC3C(C)(CC21)O3	238.33	0.166	1.29

 

Assessment of the substance within the applicability domains recommended by the developers is documented within the corresponding QMRF named ‘QMRF Title: Neutral hydrolysis rate constant model predicts neutral hydrolysis rate constant (Kn)’ - model: Neutral hydrolysis rate constant v.05.05 - software package: OASIS CATALOGIC v.5.12.1, version 1.0 – section 5; indicates the substance (constituents):

(i) All constituents fall within the Descriptors Domain (general properties, Molecular Weight range, Log Pow, Water Solubility).

(ii) 6 constituent substances have functional groups or features in non-correctly predicted training chemicals and therefore outside the interpolation space of the training set of the model. There are no fragments not present in the training set. Given chemical similarity and functionalities (differing only by the position of stereochemical groups in 3D space) versus substances 100% in the domain but with comparable structural features, it is not envisaged that the effects of limited structural domain applicability or limited correctly predicted Atom Centred Fragments, are significant relative to the predictions by expert judgement (see QMRF: section 5.1 for further details). This is further justified based on literature information published by regulatory authorities for epoxide neutral hydrolysis half-lives in comparable ranges. The calculated neutral hydrolysis t1/2 is typically, in the minutes to 15 days range, published within: "Hydrolysis Rate Constants for enhancing property-reactivity relationships", US Environmental Protection Agency (1989). Within the constituents there is an absence of relevant significant steric structural group features that would hinder rear-attack of the epoxide and thereby slow relevant reaction kinetics. There is a consistency and plausibility between the model predictions for neutral hydrolysis rate constant and the literature. Indicating that despite certain constituents being outside the structural fragment domain that the resulting predictions would be scientifically plausible and with neutral epoxide hydrolysis t1/2 << 15 days.

(ii) All constituents fall within the mechanistic domain of the model

 

3. Uncertainty of the prediction and mechanistic domain:

External validation has not been performed on the model (see QMRF: section 7).

Internal validation has been performed:

The training set of the model has the following statistics and coefficients of determination:

number in dataset = 1128; coefficient of correlation (R) = 0.98 ; correlation determination (r2) = 0.962; Residual Sum of Squares, RSS = 1385.954; Root mean square error, SR = 1.21

Statistics of the simulator: Sensitivity – 99% ; Predictability – 97%

CATALOGIC platforms utilises a multi-stage applicability domain that has been described by Dimitrov et al. (2005) (see QMRF: section 5.1 and section 8.1). Model 1 simulates the hydrolysis pathway of the substance based on the general parameter, structural fragment and mechanistic domain. Model 2 estimates the rate of hydrolysis in neutral pH (6.5 – 7.4) subsequently using presumed first-order kinetics to determine the kinetic constant (k) and the ultimate half-life on the basis of the predicted neutral hydrolysis rate constant (Kn). The mechanistic layer of the domain is based on a mechanistic understanding of the model phenomenon. Two subdomains could be distinguished in the mechanistic domain, the domain of functional (reactive) groups and the domain of explanatory variables, as defined by whose reactivity modulates. An assessment of structural analogues has not been conducted by the applicant. However, given the high structural fragment domain applicability > 0.8 correctly predicted ACF, it can be considered that there are relevant structural analogues in the training set. Model predictivity could be improved by the assignment of additional substances into the training set. Inclusion of additional structural fragments and expansion of sub-structure correction factors and related rules. In addition, rules for stereochemical effects could feasibly improve model predictivity.

Validity criteria fulfilled:

yes

Conclusions:

The results are adequate for the for the regulatory purpose.

Executive summary:

Neutral hydrolysis rate constant v.05.05; within OASIS CATALOGIC v.5.12.1 (updated July 2017):

neutral hydrolysis rate constant (Kn) (all constituents):

3.40 d-1

(first order) half-life (t1/2) (all constituents)

0.2 days or 4.8 hours

The primary hydrolysis products for each constituent were modelled and identified.

 

The substance constituents have short hydrolytic half-lives (scale: hours at neutral pH, ambient temperatures, accelerated in acidic or basic pH conditions by catalytic hydrolysis) they would be considered as fulfilling the criteria for rapid (primary) degradability.

 

The physico-chemical properties of the constituents were: Log Kow = 2.45 to 3.85 in two blocks, respectively.

The majority of constituents had Log Kow = 3.85 and no constituents have predictions for Log Kow > 4.0.

Hydrolysis products have range of Log Kow = -0.26, 1.29 and 2.69 in three blocks, respectively.

The hydrolysis products have a decreasing Log Kow << 4.0 and increasing water solubility (further modelled by the applicant using related models KOWWIN v1.68 (US EPA), that are publicly available.

 

Adequacy of the QSAR:

1) QSAR model is scientifically valid. 2) The substance falls within the general properties and mechanistic applicability domains, with limited applicability of the structural domain of the QSAR model (although all constituents > 80% correctly predicted ACF). Expert judgement considers the results reliable and relevant and the results are consistent with established literature. 3) The results are fit for regulatory purpose and adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. Specifically, when combined with further information, details of which are available and provided by the applicant.

Reference 2

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2011

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

non-GLP; well documented study report following a screening study and method equivalent or similar to guideline with acceptable deviations according to the regulatory conclusion that the substance is hydrolytically unstable. The study would not fulfil the requirements of OECD TG 111 (2004) Tier 2 or Tier 3 requirements. The test was conducted at physiologically relevant temperature (40 °C) rather than the guideline preliminary test temperature 50 °C.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Deviations:

yes

Remarks:

Screening study examined: pH 2, 5, 7, 8.5 and 12 rather than guideline pH range 4, 7 and 9; duplicate tests were not performed; full analytical validation was not documented within the study; degradation products were not identified.

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Deviations:

yes

Remarks:

see above.

Principles of method if other than guideline:

The test followed a method equivalent or similar to OECD TG 111 (hydrolysis as a function of pH) - as a screening study for the hydrolysis properties of the test substance. The screening study examined: pH 2, 5, 7, 8.5 and 12 using suitable buffers; at 40 °C for 28d by analytically monitoring constituent 1 degradation representative of all constituents of the substance.

GLP compliance:

no

Remarks:

non-GLP; well documented study report following a screening study and method equivalent or similar to guideline with acceptable deviations according to the regulatory conclusion that the substance is hydrolytically unstable.

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

- Sampling intervals for the parent/transformation products: on a regular basis throughout the test (typically at time = 0, 0.25, 1, 2, 4, 7, 15, 21 and 28 days
- Sampling method: Small aliquots of the test solution are extracted with an organic solvent (typically cyclohexane or ethyl acetate) containing a hydrocarbon standard (typically C12, C17 or C20). The extracts are analyzed by GC-FID and the results are plotted as (Area/Area Std) expressed in [%]. The measurement at time = 0 is set at 100% and the succeeding measurements are calculated relatively to the time = 0 measurement. Therefore the curves represent the percentage of product remaining in the test solution at the time of analysis.
- Other observation, if any (e.g.: precipitation, color change etc.): None reported.

Buffers:

- pH: test media are standard aqueous buffers at pH 2, pH 5, pH 7, pH 8.5 and pH 12 containing 1% of non ionic surfactant.
- Type and final molarity of buffer: Molarity not reported.
• pH 2 (± 0.1) buffer : Reference Handbook of Chemistry and Physics buffer type A*
• pH 5 (± 0.1) buffer : Reference Handbook of Chemistry and Physics buffer type C*
• pH 7 (± 0.1) buffer : Reference Handbook of Chemistry and Physics buffer type D*
• pH 8.5 (± 0.1) buffer : Reference Handbook of Chemistry and Physics buffer type F*
• pH 12 (± 0.1) buffer : Reference Handbook of Chemistry and Physics buffer type I*

Details on test conditions:

TEST MEDIUM
- Volume used/treatment: Total volume not reported
- Kind and purity of water: Deionised water (no further details reported)
- Preparation of test medium: ; 200 – 300 ppm of raw material are dissolved in the pH buffer containing the surfactant (Arkopal N 150) and put into storage in an oven at 40°C.
- Renewal of test solution: None reported.
- Identity and concentration of co-solvent: non-ionioc surfactant (Arkopal N 150) was used at 1% concentration
OTHER TEST CONDITIONS
- Adjustment of pH: None reported.
- Dissolved oxygen: Not reported.

Number of replicates:

None (single vessel, single injection).

Positive controls:

no

Negative controls:

no

Preliminary study:

After 5 days there is total disappearance at pH 2 and 5, and up to 80% at neutral pH, while at basic pH there is a decay of up to 20%. After 28 days there is total disappearance of constituent 1 from pH 2 to 7, while at higher pH the disappearance is from 20-40%. It can be concluded that under the conditions of the present test, test substance as followed by the constituent 1 is not hydrolytically stable (as defined in the OECD TG 111 for hydrolysis as a function of pH).

Test performance:

No unusual findings were reported in the study.

Transformation products:

not measured

pH:

5

Temp.:

40 °C

DT50:

< 2 h

pH:

7

Temp.:

40 °C

DT50:

ca. 1.5 d

pH:

8.5

Temp.:

40 °C

DT50:

> 28 d

Type:

second order

Details on results:

TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes, by use of appropriate buffers however pH was not continuously monitored throughout the study, sterility was not examined.

Validity criteria fulfilled:

yes

Remarks:

The study meets the tier 1 validity criteria. This is limited as detailed in 'Rationale for reliability incl. deficiencies'. The study is reliable as indicates that the substance is hydrolytically unstable. Guideline Tier 2 and 3 requirements are not met.

Conclusions:

The substance was found to be unstable to hydrolysis in water.

Executive summary:

The hydrolytic stability of the test item was investigated using a method similar or equivalent to OECD TG 111 (hydrolysis as a function of pH) and EU Method A.7. The test media are standard aqueous buffers at pH 2, pH 5, pH 7, pH 8.5 and pH 12 containing 1% of non-ionic surfactant (Arkopal N 150). The tests are done in accelerated conditions at 40°C for approximately one month (28d). 200 – 300 ppm of test substance are dissolved in the pH buffer containing the surfactant and put into storage in an oven at 40°C. Commercial reference grades of buffer are utilised as listed in documented literature sources. Small aliquots of the test solution are extracted with an organic solvent (typically cyclohexane or ethyl acetate) containing a hydrocarbon standard (typically C12, C17 or C20) on a regular basis throughout the test (typically at time = 0, 0.25, 1, 2, 4, 7, 15, 21 and 28 days). The extracts are analysed by GC-FID. Constituent 1 was then plotted with time to show the degradation curves of the substance using constituent 1 as representative of the substance. After 5 days there is total disappearance at pH 2 and 5, and up to 80% at neutral pH, while at basic pH there is a decay of up to 20%. After 28 days there is total disappearance of constituent 1 from pH 2 to 7, while at higher pH the disappearance is from 20-40%. It can be concluded that under the conditions of the present test the test substance is not hydrolytically stable as defined in the OECD TG 111 for hydrolysis as a function of pH.

Applicant assessment of the data indicates: the substance follows first-order kinetics at acidic (t0.5 = < 2h) and neutral pH (t0.5 = 1.5d) and second-order kinetics in alkali pH (t0.5 = approximately 32 days). It should be noted that the test item degradation was based on a single constituent and single vessel/injection (rather than guideline specified duplicate vessel at tier 2 testing requirements). This may a cause for less than expected degradation within alkali pH, in particular. Where accelerated degradation would be expected. The applicant has on the basis of structure and hydrolysis-mechanism of the constituents an expectation that the results presented are worst case degradation kinetics for all constituents of the test substance. Expert assessment of the substance would suggest that the substance can degrade at environmentally relevant pH with a DT50 ca. 2 hours. This has been observed experimentally at pH 7 in relevant physico-chemical testing attempted by the applicant.

Description of key information

Weight of evidence: Substance half-life for hydrolysis: pH 5: t1/2: ≤ 4.8 hours; pH 7: t1/2: 4.8 hours; pH 8.5: t1/2: ≤ 4.8 hours, at 20 °C, 1 atm, 2018

Key value for chemical safety assessment

Half-life for hydrolysis:

4.8 h

at the temperature of:

25 °C

Additional information

Key data: QSAR – neutral hydrolysis rate constant and predicted half-life, 2018:

The neutral hydrolysis rate constant (Kn) (all constituents) = 3.40 d-1.

The associated half-life for hydrolysis at pH 7 was therefore predicted as: t1/2 (all constituents) = 4.8 hours (or 0.2 days).

The primary hydrolysis products for each constituent were modelled and identified resulting from epoxide ring opening hydrolysis.

The results are fit for regulatory purpose and adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. Specifically, when combined with further information, details of which are provided.

Expert judgement utilising literature (US EPA, 1989) would indicate that the predictions are scientifically plausible. Epoxides are generally expected to have neutral half-lives in the minutes to days range depending upon steric hinderance of the epoxide group. Steric hinderance features are absent in the substance constituents which would suggest an expected neutral half-life in the hours range.

 

Supporting data: Eq. or similar to OECD TG 111 - preliminary screening study, 2011: The hydrolytic stability of the test item was investigated using a method similar or equivalent to OECD TG 111 (hydrolysis as a function of pH) and EU Method A.7. The test media are standard aqueous buffers at pH 2, pH 5, pH 7, pH 8.5 and pH 12 containing 1% of non-ionic surfactant (Arkopal N 150). The tests are done in accelerated conditions at 40°C for approximately one month (28d). 200 – 300 ppm of test substance are dissolved in the pH buffer containing the surfactant and put into storage in an oven at 40°C. Commercial reference grades of buffer are utilised as listed in documented literature sources. Small aliquots of the test solution are extracted with an organic solvent (typically cyclohexane or ethyl acetate) containing a hydrocarbon standard (typically C12, C17 or C20) on a regular basis throughout the test (typically at time = 0, 0.25, 1, 2, 4, 7, 15, 21 and 28 days). The extracts are analysed by GC-FID. Constituent 1 was then plotted with time to show the degradation curves of the substance using constituent 1 as representative of the substance. After 5 days there is total disappearance at pH 2 and 5, and up to 80% at neutral pH, while at basic pH there is a decay of up to 20%. After 28 days there is total disappearance of constituent 1 from pH 2 to 7, while at higher pH the disappearance is from 20-40%. It can be concluded that under the conditions of the present test the test substance is not hydrolytically stable as defined in the OECD TG 111 for hydrolysis as a function of pH.

 

Applicant assessment of the data indicates: the substance follows first-order kinetics at acidic (t0.5 = < 2h) and neutral pH (t0.5 = 1.5d) and second-order kinetics in alkali pH (t0.5 = approximately 32 days). It should be noted that the test item degradation was based on a single constituent and single vessel/injection (rather than guideline specified duplicate vessel at tier 2 testing requirements). This may a cause for less than expected degradation within alkali pH, in particular. Where accelerated degradation would be expected. The applicant has on the basis of structure and hydrolysis-mechanism of the constituents an expectation that the results presented are worst case degradation kinetics for all constituents of the test substance. Expert assessment of the substance would suggest that the substance can degrade at environmentally relevant pH with a DT50 ca. 2 hours. This has been observed experimentally at pH 7 in relevant physico-chemical testing attempted by the applicant (see section: Partition Coefficient - testing according to OECD TG 117, 2015).

 

Terminated study, Log Kow, HPLC Method - OECD TG 117, 2015: The study was terminated due to degradation of test item during the course of the study including utilising neutral buffers to minimise degradation in three separate runs within acetonitrile/water mobile phase (60:40) using final pH 7 and 8. Hydrolytic degradation timescale: ca. 2 hours.

 

Weight of Evidence: conclusion:

The substance consists of multiple epoxide containing-constituents that are hydrolytically unstable with short hydrolytic half-lives (scale: hours at neutral pH, ambient temperatures, accelerated in acidic or basic pH conditions by catalytic hydrolysis) they would be considered as fulfilling the criteria for rapid (primary) degradability. The predicted half-life of the test item at pH 7 is 4.8 hours. The half-life for pH 5 and pH 8 is < 4.8 hours, due to acid/base catalysed epoxide hydrolysis accelerating degradation. This prediction has been seen experimentally that precluded reliable measurement of n-octanol/water partition coefficients in laboratory studies under guideline including using pH buffers. Degradation was observed experimentally in less than several hours.