4-Penten-2-ol, 3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-, (4E)-

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

This study was not performed according to international guideline and is not GLP as this is a standard company internal data conducted for global knowledge. This study is well documented and is considered reliable with restrictions.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The aim of the study is to assess the stability of the substance in a series of simple media simulating perfumery applications. 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. The tests are done in accelerated conditions at 40°C during ca. one month.

GLP compliance:

no

Remarks:

Standard company internal data measurements conducted for global knowledge.

Specific details on test material used for the study:

No additional information

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

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. 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 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.

Buffers:

Buffer solutions:
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

Estimation method (if used):

Not applicable

Details on test conditions:

No data

Duration:

28 d

Temp.:

40 °C

Initial conc. measured:

200 - 300 other: ppm

Number of replicates:

1 for each pH.

Positive controls:

no

Negative controls:

no

Statistical methods:

None

Preliminary study:

None

Test performance:

No data

Transformation products:

no

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

Results showed that the disappearance of the parent compound after 5 days as well as after 28 days is less than 10% at any pH (from 2 to 12) at 40 °C. It can be concluded that under the conditions of the present test, test substance is hydrolytically stable (as defined in the OECD TG 111 for hydrolysis as a function of pH).

% Recovery:

> 90

pH:

2

Temp.:

40 °C

Duration:

> 5 - 28 d

% Recovery:

> 90

pH:

5

Temp.:

40 °C

Duration:

> 5 - 28 d

% Recovery:

> 90

pH:

7

Temp.:

40 °C

Duration:

> 5 - 28 d

% Recovery:

> 90

pH:

8.5

Temp.:

40 °C

Duration:

> 5 - 28 d

% Recovery:

> 90

pH:

12

Temp.:

40 °C

Duration:

> 5 - 28 d

Key result

pH:

2

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: Hydrolytically stable

Key result

pH:

5

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: Hydrolytically stable

Key result

pH:

7

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: Hydrolytically stable

Key result

pH:

8.5

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: Hydrolytically stable

Key result

pH:

12

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: Hydrolytically stable

Other kinetic parameters:

None

Details on results:

No additional information

None

Validity criteria fulfilled:

yes

Conclusions:

The disappearance of the parent compound after 5 days as well as after 28 days is less than 10% at any pH (from 2 to 12) at 40 °C. It can be concluded that under the conditions of the present test, test substance is hydrolytically stable (as defined in the OECD TG 111 for hydrolysis as a function of pH).

Executive summary:

This hydrolysis study was not performed according to international guideline and is not GLP as this is a standard company internal data conducted for global knowledge. The aim of the study is to assess the stability of the substance in a series of simple media simulating perfumery applications. 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 during ca. one month.

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. 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 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.

 

The disappearance of the parent compound after 5 days as well as after 28 days is less than 10% at any pH (from 2 to 12) at 40 °C. It can be concluded that under the conditions of the present test, test substance is hydrolytically stable (as defined in the OECD TG 111 for hydrolysis as a function of pH).

Reference 2

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

From 31 January 2008 to 04 June 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

2008-11-28

Specific details on test material used for the study:

No additional information

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

- Sampling method: Sample solutions were prepared in stoppered glass flasks at a nominal concentration of 4.0 x 10^-3 g/L in the three buffer solutions. A 1% co-solvent of acetonitrile was used to aid solubility. The test solutions were split into individual vessels for each data point. The solutions were shielded from light whilst maintained at the test temperature.

Buffers:

pH 4: Potassium hydrogen phtalate 0.005 [M]
pH 7: Disodium hydrogen orthophosphate (anhydrous) 0.003 [M], Potassium dihydrogen orthophosphate 0.002 [M], NaCl 0.002 [M]
pH 9: Disodium tetraborate 0.001 [M], NaCl 0.002 [M]

Buffer solutions were filtered trough a 0.2 µm membrane filter to ensure they were sterile before the commencement of the test. Also these solutions were subjected to ultrasonication and degassing with nitrogen to minimise dissolved oxygen content.

Estimation method (if used):

Not applicable

Details on test conditions:

TEST SYSTEM
- Type, material and volume of test flasks, other equipment used: stoppered glass flasks
- Sterilisation method: 0.2 µm sterile membrane filtration
- Lighting: no
- Measures taken to avoid photolytic effects: shielding from light
- Measures to exclude oxygen: ultrasonication and degasing with nitrogen
- If no traps were used, is the test system closed/open: closed (ground glass joints were used where possible)
- Is there any indication of the test material adsorbing to the walls of the test apparatus? Yes, glassware was silanized

TEST MEDIUM
- Kind and purity of water: sterile reagent grade water
- Identity and concentration of co-solvent: 1% acetonitrile

Duration:

600 h

pH:

4

Temp.:

50 °C

Initial conc. measured:

3.71 mg/L

Duration:

600 h

pH:

7

Temp.:

50 °C

Initial conc. measured:

3.92 mg/L

Duration:

120 h

pH:

9

Temp.:

50 °C

Initial conc. measured:

3.91 mg/L

Duration:

696 h

pH:

4

Temp.:

25 °C

Initial conc. measured:

3.76 mg/L

Duration:

696 h

pH:

7

Temp.:

25 °C

Initial conc. measured:

3.73 mg/L

Number of replicates:

2

Positive controls:

no

Negative controls:

no

Statistical methods:

Not provided/ not required in the study report

Preliminary study:

The test material does not contain any functional groups that are prone to hydrolysis. Therefore prior to testing, the material was anticipated to be stable under environmentally relevant conditions. However, from preliminary testing at 50°C, it was deemed appropriate to perform testing as per Method C7 of the EEC Guidelines at temperatures of 60.0°C and 70.0°C as the test material showed significant evidence of degradation. Results from these determinations were variable. Graphs of log10 concentration versus time were non-pseudo first order which indicated that another reaction process was occurring other than hydrolysis. On review of the chemical structure of the test material, it was considered that the material may be volatile and also at the concentrations being analyzed, could potentially adsorb to glassware. Further precautions were then taken to avoid this by rinsing all glassware with a silanising agent and using ground glass joints where possible.
Repeating the test at 50°C did yield better results. Testing at pH 9 was deemed to be complete as less than 10% hydrolysis was evident after 5 days, equivalent to a half-life of greater than 1 year at 25°C (as stated in the method guidelines).

Test performance:

See Overall remarks

Transformation products:

not specified

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

None

% Recovery:

90.3

St. dev.:

1.15

pH:

9

Temp.:

50 °C

Duration:

120 h

% Recovery:

87.7

St. dev.:

1.17

pH:

4

Temp.:

25 °C

Duration:

696 h

% Recovery:

96.8

St. dev.:

0.71

pH:

7

Temp.:

25 °C

Duration:

696 h

Key result

pH:

4

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: It was not possible to determine hydrolysis rate constant

Key result

pH:

9

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: It was not possible to determine hydrolysis rate constant

Key result

pH:

7

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Remarks on result:

other: It was not possible to determine hydrolysis rate constant

Other kinetic parameters:

None

Details on results:

TEST CONDITIONS
- pH, sterility, temperature, and other experimental conditions maintained throughout the study: Yes

Preliminary Testing at 50°C (pH 4, 7 and 9)

 

The test material concentrations at the given time points are shown in the following tables:

 

pH 4 at 50 ± 0.5 °C

	Time (hours)
	0	72	120	216	408	600
Concentration (g/l)	0.00371	0.00309	0.00294	0.00281	0.00282	0.00216
Log [(concentration (g/l)]	-2.43	-2.51	-2.53	-2.55	-2.55	-2.67
% of initial concentration	-	83.2	79.1	75.7	75.9	58.2

Result:           Slope = -3.04 10^-41/h

Kobs  = 7.00 10^-41/h¹

= 1.95 10^-71/s

T1/2    = 990 hours

= 41.2 days

The extent of hydrolysis after 600 hours indicated that a further definitive test, conducted at 25 °C, was required to estimate the rate constant and half-life.

 

pH 7 at 50 ± 0.5 °C

	Time (hours)
	0	72	120	216	408	600
Concentration (g/l)	0.00392	0.00354	0.00320	0.00285	0.00258	0.00276
Log [(concentration (g/l)]	-2.41	-2.45	-2.50	-2.55	-2.59	-2.56
% of initial concentration	-	90.3	81.5	72.7	65.7	70.3

Result:           Slope = -2.58 10^-41/h

Kobs  = 5.93 10^-41/h¹

= 1.65 10^-71/s

T1/2    = 1170 hours

= 48.7 days

The extent of hydrolysis after 600 hours indicated that a further definitive test, conducted at 25 °C, was required to estimate the rate constant and half-life.

 

pH 9 at 50 ± 0.5 °C

	Time (hours)
	0	72	120	216	408	600
Concentration (g/l)	0.00391	0.00373	0.00354	-	-	-
Log [(concentration (g/l)]	-2.41	-2.43	-2.45
% of initial concentration	-	95.4	90.3

Result: Less than 10% hydrolysis after 5 days at 50°C, equivalent to a half-life greater than 1 year at 25°C.

 

Definitive Test at 25°C (pH 4 & 7)

 

The test material concentrations at the given time points are shown in the following tables:

 

pH 4 at 25 ± 0.5 °C

	Time (hours)
	0	168	528	696
Concentration (g/l)	0.00376	0.00332	0.00321	0.00330-
Log [(concentration (g/l)]	-2.43	-2.48	-2.49	-2.48
% of initial concentration	-	88.3	85.5	87.7

Result: No significant hydrolysis observed after approximately one month, equivalent to half-life greater than 1 year at 25°C.

 

pH 7 at 25 ± 0.5 °C

	Time (hours)
	0	168	528	696
Concentration (g/l)	0.00373	0.00348	0.00339	0.00361-
Log [(concentration (g/l)]	-2.43	-2.46	-2.47	-2.44
% of initial concentration	-	93.4	90.8	96.8

Result: No significant hydrolysis observed after approximately one month, equivalent to half-life greater than 1 year at 25°C.

Validity criteria fulfilled:

yes

Conclusions:

As the degree of hydrolysis/degradation observed throughout the 25°C test was considered insignificant, the half-life of the test material was estimated to be greater than 1 year at 25°C (for each pH value: 4, 7 and 9).

Executive summary:

Assessment of hydrolytic stability was carried out using Method C7 of Commission Directive 92/69/EEC and Method III of the OECD

Guidelines for Testing of Chemicals 13 April 2004.

From preliminary testing at 50°C, it was deemed appropriate to perform testing at temperatures of 60.0°C and 70.0°C as the test material showed significant evidence of degradation. Results from these determinations were variable. Graphs of log10 concentration versus time were non-pseudo first order which indicated that another reaction process wasoccurringother than hydrolysis. On review of the chemical structure of the test material, it was considered that the material may be volatile and also at the concentrations being analyzed, could potentially adsorb to glassware. Further precautions were then taken to avoid this by rinsing all glassware with a silanising agent and using ground glass joints where possible.

Repeating the test at 50°C did yield better results. Testing at pH 9 was deemed to be complete as less than 10% hydrolysis was evident after 5 days, equivalent to a half-life of greater than 1 year at 25°C (as stated in the method guidelines). However, the elevated temperature used for the determinations at pH 4 and pH 7 was still considered to cause another reaction than hydrolysis as the results obtained were variable. It was deemed appropriate to perform definitive testing for pH 4 and pH 7 directly at 25.0 ± 0.5°C for a period of approximately one month. This would then give an indication of the behavior of the test material under environmentally relevant conditions.

Once again the results were variable. However, it could be seen from the graphs of log10 concentration versus time that no trend was observed and that the concentration of the test material in the solutions even increased at some time points.

This therefore concluded that the loss of test material was variable and probably due to the inevitable volatilization and not due to hydrolysis. As the degree of hydrolysis/degradation observed throughout the 25°C test was considered insignificant, the half-life of the test material was estimated to be greater than 1 year at 25°C (for each pH value: 4, 7 and 9).

 

Reference 3

Endpoint:

hydrolysis

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[further information is included as attachment to Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the structural similarity between the source and the target substances. Their environmental properties are expected to be similar because of this structural similarity and because they are anticipated to follow the same environmental fate.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target and source substances are structurally related, in that both are trans-3,3-dimethyl-5-(2,2,3-trimethyl-cyclopent-3-en-1-yl)pent-4-en-2-ol. As two asymmetric (chiral) carbon atoms are present in the chemical structure, the chemical exists as 2x2=4 enantiomers: RR, RS, SR and SS forms. The target substance is a reaction-mass between two of these stereoisomers (RS and SS) whereas the source substance is a mixture of the two others (SR and RR). No impurities were reported above 1% of lower if contributing to the hazard of PBT profile. Therefore, it's expected that the impurities will not affect the read-across.

3. ANALOGUE APPROACH JUSTIFICATION
In addition to the structural similarity, the target and the source substances have been shown to be hydrolytically stable (from pH 4 to 9). The similarity of the composition, physico-chemical properties and hydrolysis profile between both substances is pronounced. On this basis it is considered appropriate and scientifically justified to read-across the data of the source substance, performed according to OECD Guideline 111, to fill the hydrolysis endpoint of the target substance.

4. DATA MATRIX
See attached document in Iuclid section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Transformation products:

not specified

% Recovery:

90.3

St. dev.:

1.15

pH:

9

Temp.:

50 °C

Duration:

120 h

% Recovery:

87.7

St. dev.:

1.17

pH:

4

Temp.:

25 °C

Duration:

696 h

% Recovery:

96.8

St. dev.:

0.71

pH:

7

Temp.:

25 °C

Duration:

696 h

Key result

pH:

4

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Key result

pH:

9

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Key result

pH:

7

Temp.:

25 °C

DT50:

> 1 yr

Type:

not specified

Validity criteria fulfilled:

not applicable

Conclusions:

Based on data available on the source substance, the half-life of the target and source substances was estimated to be greater than 1 year at 25°C, for each pH value: 4, 7 and 9.

Executive summary:

Assessment of hydrolytic stability of the target substance has been determined using Method C7 of Commission Directive 92/69/EEC and Method III of the OECD Guidelines for Testing of Chemicals 13 April 2004, performed on the source substance.

From preliminary testing at 50°C, it was deemed appropriate to perform testing at temperatures of 60.0°C and 70.0°C as the test material showed significant evidence of degradation. Results from these determinations were variable. Graphs of log10 concentration versus time were non-pseudo first order which indicated that another reaction process was occurring other than hydrolysis. On review of the chemical structure of the test material, it was considered that the material may be volatile and also at the concentrations being analyzed, could potentially adsorb to glassware. Further precautions were then taken to avoid this by rinsing all glassware with a silanising agent and using ground glass joints where possible.

Repeating the test at 50°C did yield better results. Testing at pH 9 was deemed to be complete as less than 10% hydrolysis was evident after 5 days, equivalent to a half-life of greater than 1 year at 25°C (as stated in the method guidelines). However, the elevated temperature used for the determinations at pH 4 and pH 7 was still considered to cause another reaction than hydrolysis as the results obtained were variable. It was deemed appropriate to perform definitive testing for pH 4 and pH 7 directly at 25.0 ± 0.5°C for a period of approximately one month. This would then give an indication of the behavior of the test material under environmentally relevant conditions.

Once again the results were variable. However, it could be seen from the graphs of log10 concentration versus time that no trend was observed and that the concentration of the test material in the solutions even increased at some time points.

This therefore concluded that the loss of test material was variable and probably due to the inevitable volatilization and not due to hydrolysis. As the degree of hydrolysis/degradation observed throughout the 25°C test was considered insignificant, the half-life of the test material was estimated to be greater than 1 year at 25°C (for each pH value: 4, 7 and 9). Based on the similarity of structure, composition, physico-chemical and environmental properties, it is considered appropriate and scientifically justified to read-across the data of the source substance to fill the hydrolysis endpoint of the target substance.  

 

Description of key information

WoE approach:

Hydrolytically stable at any pH (from 2 to 12).

Additional information

To assess the hydrolysis potential of the registered substance, two valid studies are available and were used in a weight of evidence approach.

The first study (Firmenich, 2011) was performed on the registered substance but was not performed according to international guideline and is not GLP as this is a standard company internal data conducted for global knowledge. The test media were 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 were done in accelerated conditions at 40 °C during ca. one month. 200 – 300 ppm of the test substance are dissolved in the pH buffer containing the surfactant and put into storage in an oven at 40°C. Small aliquots of the test solution were 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. The extracts were analyzed by GC-FID and the results were plotted as (Area/Area Std) expressed in [%]. The measurement at time = 0 is set at 100% and the succeeding measurements were 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. The disappearance of the parent compound after 5 days as well as after 28 days was less than 10% at any pH (from 2 to 12) at 40°C. It can be concluded that under the conditions of the present test, the test substance is hydrolytically stable.

The second study (Safepharm, 2008) was performed on an analogue substance, according to EU Method C.7 and OECD Guideline 111 with GLP compliance. This source substance is a mixture of four diastereomers, the same diastereomers presents in the registered substance but in different ratio (see IUCLID section 13 for justification).

From preliminary testing at 50°C, it was deemed appropriate to perform testing at temperatures of 60 and 70°C as the test substance showed significant evidence of degradation. Results from these determinations were variable. On review of the chemical structure of the test substance, it was considered that the compound may be volatile and also at the concentrations being analyzed, could potentially adsorb to glassware. Further precautions were then taken to avoid this. Repeating the test at 50°C did yield better results. Testing at pH 9 was deemed to be complete as less than 10% hydrolysis was evident after 5 days, equivalent to a half-life of greater than 1 year at 25°C. However, the elevated temperature used for the determinations at pH 4 and pH 7 was still considered to cause another reaction than hydrolysis as the results obtained were variable. It was deemed appropriate to perform definitive testing for pH 4 and pH 7 directly at 25.0±0.5°C for a period of approximately one month. Once again the results were variable. However, it could be seen from the graphs of log10 concentration versus time that no trend was observed and that the concentration of the test substance in the solutions even increased at some time points.This therefore concluded that the loss of test substance was variable and probably due to the inevitable volatilization and not due to hydrolysis. As the degree of hydrolysis/degradation observed throughout the 25°C test was considered insignificant, the half-life of the test material was estimated to be greater than 1 year at 25°C (for each pH value: 4, 7 and 9).

In conclusion, based on this weight of evidence approach, the registered substance can be considered as hydrolytically stable at any pH. The source substance is considered adequate for read-across purpose based on similar composition and similar physico-chemical and environmental properties between the registered substance and the analogue material used (see IUCLID section 13 for justification).