N-(cyclohexylthio)phthalimide

Hydrolysis

Administrative data

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Justification for data waiving:

other:

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 111 (Hydrolysis as a Function of pH)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

N-(cyclohexylthio)phthalimide

EC Number:

241-774-1

EC Name:

N-(cyclohexylthio)phthalimide

Cas Number:

17796-82-6

Molecular formula:

C14H15NO2S

IUPAC Name:

N-(cyclohexylthio)phthalimide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Primary stock solution solutions of 1.00mg/ml Santogard PVI was prepared in HPLC grade acetonitrile. Subsequent dilutions for spiking and HPLC standards were also prepared in HPLC grade acetonitrile. A compound used for HPLC analysis, N-(cyclohexylthio)phthalamide (purity approximately 95%) was isolated from a larger scale hydrolysis reaction run during the course of this enough of the unknown compound for IR, NMR and HPLC characterization. The primary stock solutions of 1.00 mg/ml N-(cyclohexylthio)phthalamide were prepared in HPLC grade acetonitrile. Subsequent dilutions for HPLC standards were prepared in pH 7.0 DI water.

Study design

Analytical monitoring:

yes

Duration of test

Duration:

7 d

pH:

7

Temp.:

25

Initial conc. measured:

ca. 10 mg/L

Results and discussion

Total recovery of test substance (in %)

% Recovery:

99.7

pH:

7

Temp.:

25 °C

Duration:

7 d

Dissipation DT50 of parent compound

pH:

7

Temp.:

25 °C

DT50:

23.3 h

Remarks on result:

other: non linear rate of hydrolysis

Any other information on results incl. tables

The hydrolysis of Santogard PVI in pH 7.0 buffered water was 99.5% complete after 7 days based on the 0 hour accountability. That major hydrolysis product appears to be the ring opened half acid of Santogard PVI, N-(cyclohexylthio)phthalamide. By mass-balance analysis this appears to be the only hydrolysis product formed at day 7.

From preliminary HPCL analysis, a major hydrolysis peak was apparent. A large scale hydrolysis reaction was performed to isolate this compound. The compound was not extractable at the pH 7.0 water, but when acidified with dilute HCl to approximately pH 3.5 the compound was extractable in

methylene chloride.

After recrystallization form ethanol/water, an Infra-Red spectrum of the compound was run as a KBR pellet on an Infra-Red spectrophotometer. The IR spectrum indicated the structure contained a broad carboxylic acid stretch (3600 cm^-1– 2200 cm^-1), a primary amide N-H stretch (3350 cm^-1) and aromatic C-H stretch and C-C double bond stretch (3045 cm^-1and 1545 cm^-1respectively), twin carbonyl stretched resulting from a carboxyl group and amide group (1730 cm^-1and 1660 cm^-1respectively) along with a C-O stretch (1260 cm^-1) were the other significant absorptions on the spectrum. The absorbances are consistent with a compound that is a carboxylic acid, has both aromatic and aliphatic character and also has an amide functional group. The compound N-(cyclohexylthio)phthalamide has these properties.

For further confirmation a proton Nuclear Magnetic Resonance (NMR) spectrum was run in deuterated dimethyl sulfoxide. An aliphatic multiplet was at 1 – 1.2 ppm, an aromatic multiplet at 7.2 – 8.0 ppm and a singlet at 3.9 ppm which is assigned as the carboxylic acid proton. A broad peak at 3.6 – 4.5 ppm and a singlet at 3.0 ppm are assigned as the amide proton and a water impurity respectively. The aliphatic:aromatic:carboxylic proton ratio is 11:4.8:1 respectively. The aromatic component should be only 4 protons in the ratio to agree with the proposed compound. The suspected carboxylic acid peak at 9.3 ppm is also at a higher field than would be anticipated. This could possibly be due to intramolecular hydrogen bonding with the amide proton, that would form an internal hydrogen bonding with the amide proton, that would form an internal hydrogen bonded ring structure. The NMR spectrum is consistent with the proposed structure, though it does not appear to be definitive.

Analysis of the reactions at 0 hour, 24 hours and 7 days were performed using GC/MS. The extracts at pH 7.0 for the reaction solution and control were analysed for Santogard PVI. The extracts of the reaction solution and control after lowering the pH to 2.3 were analysed for the hydrolysis product. As shown in Figures 2-10, the only peak in the reaction solution extracts was that of Santogard PVI. It was established in the isolation of the hydrolysis product that it reverted to Santogard PVI upon heating. The analysis by GC/MS appears to cause the hydrolysis product to reform to Santogard PVI due to being heated on the GC column.

The analyses for Santogard PVI and N-(cyclohexylthio)phthalamide were performed by HPLC. The N-(cyclohexylthio)phthalamide was analysed using UV detection by direct aqueous injection of the unextracted reaction sample on a C₁₈reverse phase column. Direct aqueous injection was performed since quantitative extraction of the N-(cyclohexylthio)phthalamide was not possible. The analysis of Santogard PVI was performed after it had been extracted into methylene chloride, evaporated to dryness and then diluted in acetonitrile.

Based on an accountability of 800 μg Santogard PVI at 0 hour, the total accountability of Santogard PVI and the hydrolysis product at 24 hours and 7 days was 1200 μg respectively. The value obtained by HPLC for the hydrolysis product, assumed to be N-(cyclohexylthio)phthalamide, was corrected to reflect the molecular weight difference between that compound and Santogard PVI. A further correction at day 7 was to quantify the percent of Santogard PVI impurity in the hydrolysis product standard solution, it was 4.6%. The percent total accountability for 24 hours and 7 days based on the 0 hour value was 135% and 100% respectively. Since the accountability at 24 hours and 7 days were based on direct aqueous injection for the quantification of the hydrolysis product, there was no loss in extraction inefficiency as there would be for the nominal starting concentration of Santogard PVI at 0 hour.

When the Santogard PVI recovered for the 3 time periods were plotted versus time was a poor correlation coefficient of -0.8047. The Santogard PVI total degraded 630 μg in the first 24 hours, but only 255 μg in the remaining 144 hours. An estimated T_1/2based on the slope of the line is 79.5 hours. The hydrolysis rate for the non-linear degradation in this study is 4.0 μg/hour based on the slope of the hydrolysis curve.

Another plot was performed since the hydrolysis occurred in a non-linear rate. A plot of the natural log of Santogard PVI recovered (μg) vs. time was linear for this study. The line equation for this plot, an assumed first order rate equation, is y= -0.02978 X + 6.55. The correlation coefficient for this plot is -0.9954 with a half-life of 23.3 hours. The rate constant is -0.02978/hour.

In conclusion, Santogard PVI hydrolysed 99.5% after 7 days in a non-linear rate. The proposed structure of the hydrolysis product based on the spectrometric analysis of the isolated product, its acid-base character and ease of reversion to Santogard PVI is the ring opened half acid-amide, N-(cyclohexylthio)phthalamide.

Applicant's summary and conclusion

Validity criteria fulfilled:

yes