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Environmental fate & pathways

Hydrolysis

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Description of key information

The degradation of the substance in buffered solutions was dependent on pH and temperature. The kinetics indicated that the reaction was first-order. The two major degradation pathways are ester cleavage and ring opening. Transformation products included CGA-293730, CGA-350426, CGA-321432, CGA-98166, CGA-368220 CGA-368221 and CGA-368662. Using the Arrhenius parameters calculated DT50: pH 1 @20° C = 276.6 days and @22° C = 232.7 days, pH 7 @20°C = 181.1 days and @22°C = 141.9 days, pH 9 @20°C = 1.3 days and @22°C = 1.2 days,  EPA N 161 -1 Scott 1996
The degradation of the substance in buffered solutions was dependent on pH and temperature. The kinetics indicated that the reaction was first-order. The two major degradation pathways are ester cleavage and ring opening. Transformation products included CGA-293730, CGA-374234, CGA-321432, CGA-293731, CGA-368220, and CGA-371902. Using the Arrhenius parameters calculated DT50: pH 7 @20°C = 221.0 days and @22°C = 170.1 days, pH 9 @20°C = 2.6 days and @22°C = 2.2 days, EPA N 161 -1 Peters 1997

Key value for chemical safety assessment

Additional information

EPA Subdivision N 161-1, Scott 1996: The hydrolytic properties of the substance was investigated according to EPA Guideline Subdivision N 161-1 (Hydrolysis). Analytical grade phenyl-14C-test substance was prepared in acetonitrile (CH3CN). Aliquots of the test substance were mixed with sterile, aqueous buffers at pH 1, pH 5, pH 7, and pH 9. The final concentrations of these buffered solutions ranged from 1.782 ppm to 2.177 ppm. Aliquoted samples of these buffered solutions were incubated at 25°C ± 1°C, 37°C ± 2°C, 40°C ± 2°C, or 60°C ± 2°C, for periods up to 30 days.

At pH 1, phenyl- 14 C-test substance was hydrolyzed primarily to CGA-293731. After 30 days of incubation at 37°C, test substance averaged 73.9% of the applied 14C by HPLC and CGA-293731 averaged 18.2%.

At pH 7, phenyl- 14 C-test substance was hydrolyzed initially to CGA-350426 and CGA-293730. After 30 days of incubation at 25°C, phenyl-14C-test substance averaged 77.1% of the applied 14C while CGA-350426 and CGA-293730 averaged maximum concentrations of 10.8% and 7.1% respectively by HPLC analyses. At 40°C phenyl-14C-test substance was more rapidly hydrolyzed, accounting for 26.6% of the applied 14C by HPLC analyses after 30 days of incubation. CGA-350426 and CGA-293730 reached maximum concentrations of 36.8% and 15.1% of the applied 14C respectively by HPLC on day 29. Also observed was CGA-321432 that accounted for a maximum of 10.3% of the applied 14C by HPLC on day 30. At 60°C, no phenyl-14C- test substance was detected after 30 days of incubation. CGA-350426, CGA-293730 and CGA-321432 reached maximum concentrations of 44.8%, 11.2% and 11.3% of the applied 14C respectively by HPLC quantitation on day 7. By day 30, further hydrolysis resulted in the formation of CGA-98166 and CGA-368221 which represented 26.6% and 13.7% of the applied 14C respectively by HPLC analyses.

At pH 9 test substance was rapidly degraded. After 30 days of incubation at 25°C, phenyl-14C-test substance averaged 0.3% of the applied 14C. Early hydrolysis intermediates, Degradate 1A and Degradate 1B averaged 7.0% and 7.6% of the applied 14C by TLC after 24 and 48 hours respectively. Between days 2-7, levels of CGA-350426, CGA-293730 and CGA-321432 peaked at average concentrations of 32.9%, 21.0% (by HPLC) and 8.2% (by TLC) of the applied 14C respectively. Next, CGA-98166, CGA-368220 and CGA-368221 increased to an average of 56.9%, 12.6% and 18.4% of the applied 14C respectively by HPLC on day 30. Results were similar at 40°C. For the first incubation, no phenyl-14C- test substance was detected after 30 days of incubation. Degradate 1A and Degradate 1B peaked at 5.9% and 7.6% of the applied 14C by TLC after 6 and 24 hours respectively. After 24-30 hours, levels of CGA-350426, CGA-293730 and CGA-321432 peaked at 38.5%, 15.1% and 9.1% of the applied 14C respectively by HPLC or TLC. Then CGA-98166, CGA-368220 and CGA-368221 increased comprising 57.0%, 14.1% and 24.8% of the applied 14C respectively toward the end of the incubation. These results were confirmed by the second pH 9, 40°C incubation. Similarly at 60°C, no phenyl-14C-test substance was detected after 30 days of incubation. Degradate 1A and Degradate 1B represented 7.5% and 12.5% of the applied 14C by TLC after 3 and 5 hours respectively. After 5 hours, levels of CGA-350426, CGA-293730 and CGA-321432 peaked at 41.0%, 12.5% and 7.3% of the applied 14C respectively by HPLC. Next CGA-98166, CGA-368220 and CGA-368221 increased comprising 56.9%, 12.9% and 27.3% of the applied 14C respectively toward the later stages of hydrolysis. Finally the terminal degradate, CGA-368662, was produced at a maximum concentration of 16.4% of the applied 14C by HPLC on day 30.

 

The degradation of test substance in buffered solutions was dependent on pH and temperature. The kinetics indicated that the reaction was first-order. test substance was hydrolytically stable at pH 5. At pH 1 and 37°C, test substance was hydrolyzed with a calculated half-life of 69.3 days. At pH 7, the calculated half-lives were 99.0 days at 25°C, 16.5 days at 40°C and 2.4 days at 60°C. At pH 9, test substance was hydrolytically unstable with calculated half-lives of 0.95 days (22.8 hours) at 25°C, 0.32 days (7.7 hours) and 0.15 days (3.6 hours) at 40°C and 0.11 days (2.6 hours) at 60°C. The two major degradation pathways of test substance in aqueous solution are ester cleavage and ring opening. These pathways appear to be competitive. At pH 1 and 37°C, phenyl-14C-test substance was hydrolyzed by ester cleavage to CGA-293731. At pH 5 and 25°C, test substance was stable. At pH 7, phenyl-14C-test substance was hydrolyzed by ester cleavage and ring opening to form CGA-293730 and CGA-350426 respectively. At the higher temperatures of 40°C and 60°C, further degradation along these pathways resulted in the formation of CGA-321432, CGA-98166 and CGA-368221. Finally at pH 9, phenyl-14C-test substance was hydrolyzed by ester cleavage and ring opening to form CGA-293730, CGA-350426, CGA-321432, CGA-98166, CGA-368220 and CGA-368221. At 60°C, the terminal degradate, CGA-368662 was observed.

Using the Arrhenius parameters, the rate constants and half-lives of test substance at different temperatures were calculated. At 20°C, the half-lives calculated were 276.6 days at pH 1, 181.1 days at pH 7 and 1.3 days at pH 9. At 22°C, the half-lives calculated were 232.7 days at pH 1, 141.9 days at pH 7 and 1.2 days at pH 9. Because test substance is stable at pH 5, no half-life could be calculated.

 

 

EPA Subdivision N 161-1, Peters 1997: The hydrolytic properties of the substance was investigated according to EPA Guideline Subdivision N 161-1 (Hydrolysis). Analytical grade pyrimidinyl-14C-test substance was prepared in acetonitrile (CH3CN) . Aliquots of the test substance were mixed with sterile, aqueous buffers at pH 1, pH 7, and pH 9. The concentrations of these buffered solutions ranged from 1.767 ppm to 2.047 ppm. Aliquoted samples of these buffered solutions were incubated at 25°C ± 1°C, 37°C ± 1°C, 40°C ± 1°C, or 60°C ± 2°C, for periods up to 30 days.

At pH 1, pyrimidinyl-14C-test substance was hydrolyzed primarily to CGA-293731. After 30 days of incubation at 37°C, test substance averaged 76.4% of the applied 14C by HPLC and CGA-293731 averaged 14.2% of the applied 14C.

At pH 7, pyrimidinyl-14C-test substance was hydrolyzed initially to CGA-374234 and CGA-293730. After 30 days of incubation at 25°C, pyrimidinyl-14C-test substance averaged 84.3% of the applied 14C while CGA-374234 and CGA-293730 averaged maximum concentrations of 6.6% and 4.4% of the applied 14C, respectively, by HPLC analyses. At 40°C pyrimidinyl-14C- test substance was more rapidly hydrolyzed, accounting for 29.0% of the applied 14C by HPLC analyses after 30 days of incubation. CGA-374234 and CGA-293730 reached maximum concentrations of 39.4% and 13.3% of the applied 14C, respectively, by HPLC on day 30. Also observed was CGA-321432 that accounted for a maximum of 8.5% of the applied 14C by HPLC on day 30. At 60°C, pyrimidinyl-14C-test substance accounted for 2.9% of the applied 14C after 10 days of incubation. CGA-293730 reached a maximum concentration of 10.4% of the applied 14C by HPLC quantitation on day 6. By day 10, CGA-374234 and CGA-321432 reached maximum concentrations of 70.2% and 12.3% of the applied 14C, respectively, by HPLC quantitation on days 10.

At pH 9, test substance was rapidly degraded. After 30 days of incubation at 25°C, pyrimidinyl-14C-test substance averaged 0.5% of the applied 14C. Early hydrolysis intermediates, Degradate 1A and Degradate 1B averaged 4.8% and 9.2% of the applied 14C by TLC after 30 and 48 hours, respectively. Between days 2 and 14, levels of CGA-293730 and CGA-321432 peaked at average concentrations of 14.4% (by TLC) and 9.9% (by HPLC) of the applied 14C, respectively. CGA-368220 and CGA-374234 increased to an average of 10.9% and 72.9% of the applied 14C, respectively, by HPLC on day 30. Results were similar at 40°C. After 2 days of incubation at 40°C, pyrimidinyl-14C- test substance was 3.2% of the applied 14C. Degradate 1A and Degradate 1B peaked at 6.9% and 11.1% of the applied 14C by TLC after 5 and 10 hours, respectively. After 24-48 hours, levels of CGA-374234, CGA-293730, and CGA-321432 peaked at 63.2%, 12.3%(by TLC}, and 5.2% of the applied 14C, respectively. Then CGA-368220 increased, comprising 5.7% of the applied 14C toward the end of the incubation. Similarly at 60°C, pyrimidinyl-14C- test substance was 0.2% of the applied 14C after 2 days of incubation. Degradate 1A and Degradate 1B represented 5.7% and 10.7% of the applied 14C by TLC after 1 and 3 hours, respectively. After 3-8 hours, levels of CGA-293730 and CGA-321432 peaked at 9.0% (by TLC}, and 9.0% (by HPLC) of the applied 14C, respectively. Toward the later stages of hydrolysis, CGA-371902 and CGA-368220 increased comprising 4.9% and 11.8% of the applied 14C, respectively. Finally the terminal degradate, CGA-374234, was produced at a maximum concentration of 79.8% of the applied 14C by HPLC on day 2.

 

The degradation of test substance in buffered solutions was dependent on pH and temperature. The kinetics indicated that the reaction was first-order. At pH 1, test substance was hydrolyzed with a calculated half-life of 77.0 days. At pH 7, the calculated half-lives were 115.5 days at 25°C, 18.7 days at 40°C, and 2.1 days at 60°C. At pH 9, test substance was hydrolytically unstable with calculated half-lives of 1.6 days at 25°C, 0.29 days (6.96 hours) at 40°C, and 0.08 days (1.92 hours) at 60°C. The two major degradation pathways of test substance in aqueous solution are ester cleavage and ring opening. These pathways appear to be competitive. At pH 1 and 37°C, pyrimidinyl-14C-test substance was hydrolyzed by ester cleavage to CGA-293731. At pH 5 and 25°C, test substance was stable based on hydrolysis study for phenyl-14C-test substance. At pH 7, pyrimidinyl-14C-test substance was hydrolyzed by ester cleavage and ring opening to form CGA-293730 and CGA-374234 respectively. At the higher temperatures of 40°C and 60°C, further degradation along these pathways resulted in the formation of CGA-321432 and CGA-368220. Finally at pH 9, pyrimidinyl-14C-test substance was hydrolyzed by ester cleavage and ring opening to form CGA-293730, CGA-374234, CGA-321432, CGA-293731, CGA-368220, and CGA-371902.

Using the Arrhenius parameters, the rate constants and half-lives of test substance at different temperatures were calculated. At 20°C, the half-lives calculated were 221.0 days at pH 7 and 2.6 days at pH 9. At 22°C, the half-lives calculated were 170.1 days at pH 7 and 2.2 days at pH 9.