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Hydrolysis

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Reference
Endpoint:
hydrolysis
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 111 (Hydrolysis as a Function of pH)
Deviations:
yes
Remarks:
No final test report was prepared but a summary of all relevant results.
Principles of method if other than guideline:
The data contain information on a number of pre-tests which were performed in order to perform a full hydrolysis study according to OECD 111 with a maximum of 1 % modifier as accepted by the guideline OECD 111. This pre-test also contains information on trials using higher concentration of modifier up to 10 %. The study report is not presented in a typical report format but is a summary of the experiments performed
GLP compliance:
no
Radiolabelling:
no
Analytical monitoring:
yes
Details on sampling:
0, 0.25, 1, 2, 4, 6, 8, 10, and 24 hours
Buffers:
- pH 4: ammonium formate/ fomic acid
- pH 7: water (pH was checked at each sampling time point)
- pH 9: ammonia/ ammonium formate
Estimation method (if used):
no extraction, direct injection after derivatisation with dibutlylamine
Duration:
24 h
pH:
4
Temp.:
23 °C
Initial conc. measured:
2 mg/L
Remarks:
starting concentration 2 mg/L
Duration:
24 h
pH:
7
Temp.:
23 °C
Initial conc. measured:
2 mg/L
Remarks:
starting concentration 2 mg/L
Duration:
24 h
pH:
9
Temp.:
23 °C
Initial conc. measured:
2 mg/L
Remarks:
starting concentration 2 mg/L
Number of replicates:
three
Positive controls:
no
Negative controls:
no
Test performance:
A stock solution of IPDI allophanat was prepared using acetonitrile. Subsequently, this solution was diluted by adding the stock solution with stirring to a specified amount of water resulting in a target concentration of 2 mg/L including 1 % modifier (acetonitrile). In consequence of the moderate repeatability the samples were prepared in triplicate. According to a sampling protocol aliquots of the sample were taken and added to a solution of derivatisation agent (Dibutylamine) within a time period of 24 hours (0, 0.25, 1, 2, 4, 6, 8, 10, and 24 hours). Temperature was room temperature (23 °C ± 1 °C)
Semi-quantification was performed by means of an external calibration curve. Due to the lack of reference substances the sample IPDI allophanat was diluted to different concentration levels between 0 and 5 mg/L. The obtained samples were derivatised with dibutylamine, too.
Transformation products:
no
Remarks:
Transformation products were screened but could not be identified.
Details on hydrolysis and appearance of transformation product(s):
In tests with 1 % modifyer (ACN) and a starting concentration of 2 mg/L no signals at all could be detected. This was found although the starting concentration of 2 mg/L was not that low and the analytical instrumentation used (UPLC with high resolution mass spectroscopy)
pH:
4
Temp.:
23 °C
DT50:
ca. 4 h
Type:
(pseudo-)first order (= half-life)
Remarks on result:
other: The degradation of three main components was monitored: C28H46N4O3, C29H48N4O5 and C36H54N6O6
pH:
7
Temp.:
23 °C
DT50:
ca. 2 h
Type:
(pseudo-)first order (= half-life)
Remarks on result:
other: The degradation of three main components was monitored: C28H46N4O3, C29H48N4O5 and C36H54N6O6
pH:
9
Temp.:
23 °C
DT50:
ca. 2 h
Type:
(pseudo-)first order (= half-life)
Remarks on result:
other: The degradation of three main components was monitored: C28H46N4O3, C29H48N4O5 and C36H54N6O6
Other kinetic parameters:
No kinetic parameters were calculated. The half life was estimated using the degradation curves yielding a half-life of about 2 hours.
Validity criteria fulfilled:
no
Remarks:
Due to the rapid hydrolysis and the difficult behavour of the substance in water the reproducibility between replicates is higher than foreseen in the guideline. Nevertheless, a trend can clearly be seen and an estimation of the half-life can be given
Conclusions:
Three main components of the substance yielded in half-lives of about two hours at 23 °C. No degradation products could be found although a sensitive UPLC-HRMS method has been used. It is therefore assumed that oligomeric and polymeric ureas are the hydrolysis products.
Executive summary:

Several attempts have been made to find a guideline compliant and technically feasible way in order to describe the hydrolysis behaviour. The challenge was to reduce the start concentration of the substance which - on the one hand - is suspected to have an extremely poor water solubility (QSAR estimation: about 1 ng/L) and - on the other hand - shall be kept soluble in water containing not more than 1 % modifier. For this goal high-end technology (UPLC-high-resolution-mass spectrometry) was used. Finally, conditions were found which in fact led to increased variations between replicates but showed a tendency in the hydrolysis behaviour. For the main components, a half-life of about 4 hours at room temperature in pure water is estimated. However, it was found that already at time zero a relevant portion of the substance (>50 %) had been disappeared. After having performed all these experiments we believe that an OECD 111 hydrolysis test at 3 pH-values could be performed but it is doubtful whether the guideline´s criteria, especially those for repeatability (recovery >70 %) can be fulfilled. Nevertheless, in view of the complex nature of the substance, a hydrolysis study even not fulfilling all quality criteria would give useful data on half-lifes and hydrolysis products. In one pre-test using low concentrations, structure elucidation of hydrolysis products was performed, but no relevant structures were found. It is well known that isocyanates rapidly react with water under formation of an amino group. The amino group is rather nucleophilic and reacts further with remaining isocyanate groups yielding urea substances. The three main products which also have the lowest molecular weight of the constituents are C28H46N4O5 (518 D), C29H48N4O5 (532 D) and C36H54N6O6 (666 D). They consist of two or three isocyanate groups. This means that ureas formed by two isocynate groups have molecular weights of at least 1000 D, and ureas formed by reaction of three isocyanate groups have molecular weights >1500 D. The detection range of the HRMS instrument used is up to 1800 D. As none of these lower ureas have been formed it can be assumed that higher oligo and polyureas are formed which cannot be detected with the instrument used.

In a pre-test using higher concentrations of test item and modifyer, some structural information was received but the results are doubtful as precipitation occurred during the test.

Description of key information

Three main components of the substance yielded in half-lives of about 2 hours at 23 °C. No degradation products could be found although a sensitive UPLC-HRMS method has been used with a mass range up to 1800 D. It is therefore assumed that oligomeric and polymeric ureas are the hydrolysis products which are not detectable due to their high molecular weights.

Key value for chemical safety assessment

Half-life for hydrolysis:
2 h
at the temperature of:
23 °C

Additional information

In two studies (Neuland 2012, Neuland 2013), the substance was found to be poorly soluble in water, it was therefore not possible to prepare an aqueous solution of the test item necessary to perform a hydrolysis test according to the requirements of OECD TG 111 (2004). A further hydrolysis test with acetonitrile as organic solvent additive was performed and relating to this test mixture a degradation of approx. 50 % within 24 hours can be estimated.

In a third attempt (Allmendinger and Tretzel, 2018), a lot of tests were made to find a guideline compliant and technically feasible way in order to describe the hydrolysis behaviour. The challenge was to reduce the start concentration of the substance which - on the one hand - is suspected to have an extremely poor water solubility (QSAR estimation: about 1 ng/L) and - on the other hand - shall be kept soluble in water containing not more than 1 % modifier. For this goal high-end technology (UPLC-high-resolution-mass spectrometry) was used. Finally, conditions were found which in fact led to increased variations between replicates but showed a clear tendency in the hydrolysis behaviour. For the main components, a half-life of about 2 hours at room temperature in pure water was estimated. However, it was found that already at time zero a relevant portion of the substance (>50 %) had been disappeared. After having performed all these experiments it can be concluded that

1. performance of an OECD 111 hydrolysis test at 3 pH-values cannot be performed meeting the relevant quality criteria: Especially the criteria for repeatability (recovery >70 %) cannot be fulfilled. Further, potential hydrolysis products such as oligomeric and polymeric ureas are essentially insoluble in water as well as in organic solvents. Therefore these compounds cannot be analysed even by high-end analytical instrumentation. Finally this will lead to an analytical gap as that full quantitative recovery or mass balance of parent substance and all hydrolysis products is technically not possible.

2. nevertheless, in view of the complex nature of the substance, the hydrolysis experiments even not fulfilling all quality criteria will give useful data on half-lifes and hydrolysis products. In one pre-test using low concentrations, structure elucidation of hydrolysis products was performed, but no relevant structures were found although highly sensitive and analytical high end technique was used (UPLC-HRMS). It is well known that isocyanates rapidly react with water under formation of an amino group. The amino group is rather nucleophilic and reacts further with remaining isocyanate groups yielding urea substances. The three main products which also have the lowest molecular weight of the constituents are C28H46N4O5 (518 D), C29H48N4O5 (532 D) and C36H54N6O6 (666 D). They consist of two or three isocyanate groups. This means that ureas formed by two isocyanate groups have molecular weights of at least 1000 D, and ureas formed by reaction of three isocyanate groups have molecular weights >1500 D. The detection range of the HRMS instrument used is up to 1800 D. As none of these lower ureas have been formed it can be assumed that higher oligo and polyureas are formed which cannot be detected with the instrument used.

In a pre-test using higher concentrations of test item and modifier, some structural information was received but the results are doubtful as precipitation occurred during the test.

According to ECHA guidance document R11 (July 2017) "careful consideration of the hydrolysis test is required" and the removal of parent substance shall be evaluated by several means:

1. "Hidden loss" by evaporation: The smallest main constituent has a molecular weight of 518 and a vapour pressure of 1.7E-04 Pa at 20 °C. This makes substance loss by evaporation very unlikely.

2. "Hidden loss" by adsorption: Hydrolysis tests (Allmendinger and Tretzel 2018) were performed with a modifier (1 % ACN). Earlier tests used higher concentrations of a modifier in order to avoid potential losses yielded similar results. Visual examinations of the flasks did not indicate any particles or adsorption to the glass wall although they were carefully examined using scattering light. It was found that already at time 0 (i.e.1 min after addition of sample to water) only 50 % of the theoretical amount was found indicating a rather rapid hydrolysis. It must be discussed and finally cannot be excluded that the loss might be due to limited solubility and precipitation. However, the use of derivatisation agents DBA would made precipitation visible as derivatives.

3. Preliminary experiments at pH 4 and 9 show rapid hydrolysis as well.

4. Abiotic degradation: The key reaction of an isocyanate in water is hydrolysis. Amines as the primary degradation products were not found in the tests. They are known to react must faster with isocyanates than with water. Thus, ureas are formed. Ureas could not be detected with the UPLC-HRMS instrument which is able to detect masses up to 1800 D. Consequently, there is evidence that higher oligomeric and polymeric ureas have been formed which cannot be analysed although high-end instrumentation was used.

5. The requirement for a full mass balance in a hydrolysis test cannot be fulfilled for a UVCB substance. About 30 components have been identified. However each of the components consists of a variety of structural isomers and stereoisomers.