Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
in vitro and/or in vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
The substance is an alicyclic carbonate with a hydroxy substituent of a molecular weight which does not preclude absorption. No predictions of toxicokinetic behaviour from SAR can be made. lt is a solid block of low vapour pressure, and hence significant Inhalation exposure is not anticipated. The moderate water solubility may be associated with rapid absorption and elimination via the kidneys in urine. Hydrolysis occurs under neutral and alkaline conditions, at a sufficient rate to suggest exposure to decomposition products may be important. However, the substance is stable to hydrolysis at acidic pH, indicating decomposition would not occur in the stomach. There are no potentially ionizable groups in the parent compound, and hence absorption by passive diffusion across membranes will not by pH dependent. The relatively high Pow indicates ready passage across membranes.

No systemic toxic effects were observed at the maximum dose of 2000 mg/kg in an acute dermal toxicity limit test. Hence there is no evidence of dermal absorption. Dose-related toxic effects occurred in the 28-day oral sub-acute toxicity study, indicating oral absorption. However, only minor clinical signs were observed in the acute oral toxicity limit test at 2000 mg/kg.

The substance was toxic to human lymphocytes in the negative in vitro chromosome aberration test, but cytoxicity was reduced in the presence of S9. There was a similar, but less marked, reduction in toxicity to bacteria in the negative Ames test in the presence of S9. This suggests that biotransformation may occur as a result of microsomal enzyme activity. To some extent this is supported by the morphological adaptive liver changes seen in the 28-day oral toxicity study which may have been associated with microsomal enzyme induction.

The substance may be absorbed orally, as indicated by the dose-related effects in the 28-day sub-acute oral toxicity study. Absorption would be consistent with the moderate water solubility, relatively-high Pow and absence of ionizing groups in the molecule. Hydrolysis could occur in the gastro-intestinal tract, but not under the acidic stomach condition's and in plasma. Hence the parent compounds and/or their hydrolysis products may be absorbed. Biotransformation may occur in the liver and, in view of the compounds, water solubility, excretion is most likely to occur via the kidneys. This excretory route is further evidenced by the kidney changes observed in the 28-day oral toxicity study. Significant elimination of the involatile parent compounds via the lungs in expired air is not anticipated.

There is no evidence for dermal absorption, since no effects were seen in the acute dermal toxicity study in a close structural analogue.

Significant inhalation exposure is not anticipated for this solid block of low vapour pressure. However, following any inhalation exposure, absorption may be anticipated an the basis of the moderate water solubility and relatively-high Pow. The rate of hydrolysis is too slow to permit significant decomposition in the lungs.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The substance is an alicyclic carbonate with a hydroxy substituent of a molecular weight which does not preclude absorption. No predictions of toxicokinetic behaviour from SAR can be made. lt is a solid block of low vapour pressure, and hence significant Inhalation exposure is not anticipated. The moderate water solubility may be associated with rapid absorption and elimination via the kidneys in urine. Hydrolysis occurs under neutral and alkaline conditions, at a sufficient rate to suggest exposure to decomposition products may be important. However, the substance is stable to hydrolysis at acidic pH, indicating decomposition would not occur in the stomach. There are no potentially ionizable groups in the parent compound, and hence absorption by passive diffusion across membranes will not be pH dependent. The relatively high Pow indicates ready passage across membranes.

No systemic toxic effects were observed at the maximum dose of 2000 mg/kg in an acute dermal toxicity limit test. Hence there is no evidence of dermal absorption. Dose-related toxic effects occurred in the 28-day oral sub-acute toxicity study, indicating oral absorption. However, only minor clinical signs were observed in the acute oral toxicity limit test at 2000 mg/kg.

The substance was toxic to human lymphocytes in the negative in vitro chromosome aberration test, but cytoxicity was reduced in the presence of S9. There was a similar, but less marked, reduction in toxicity to bacteria in the negative Ames test in the presence of S9. This suggests that biotransformation may occur as a result of microsomal enzyme activity. To some extent this is supported by the morphological adaptive liver changes seen in the 28-day oral toxicity study which may have been associated with microsomal enzyme induction.

The substance may be absorbed orally, as indicated by the dose-related effects in the 28-day sub-acute oral toxicity study. Absorption would be consistent with the moderate water solubility, relatively-high Pow and absence of ionizing groups in the molecule. Hydrolysis could occur in the gastro-intestinal tract, but not under the acidic stomach condition's and in plasma. Hence the parent compounds and/or their hydrolysis products may be absorbed. Biotransformation may occur in the liver and, in view of the compounds, water solubility, excretion is most likely to occur via the kidneys. This excretory route is further evidenced by the kidney changes observed in the 28-day oral toxicity study. Significant elimination of the involatile parent compounds via the lungs in expired air is not anticipated.

There is no evidence for dermal absorption, since no effects were seen in the acute dermal toxicity study in a close structural analogue.

Significant inhalation exposure is not anticipated for this solid block of low vapour pressure. However, following any inhalation exposure, absorption may be anticipated on the basis of the moderate water solubility and relatively-high Pow. The rate of hydrolysis is too slow to permit significant decomposition in the lungs.