Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert opinion
Adequacy of study:
key study
Study period:
2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The expert opinion is based on the available information on the physical, chemical and toxicological properties of the test material

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Objective of study:
other: Assessment of toxicokinetic behaviour
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Data evaluation included substance data as well as on analogue substances

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No treatment related effects were seen in an acute oral toxicity study on the notified substance or in an acute dermal study conducted on the analogue substance 1 (refer to IUCLID chapter 13). In a repeated dose oral toxicity study conducted on the analogue substance 1 (refer to IUCLID chapter 13), however, treatment related kidney changes were observed, which indicate that absorption could occur from the gastro-intestinal tract. The notified substance has a low log Pow value, which suggests poor absorption by passive diffusion, but it is very water soluble and may therefore show higher lipid solubility than is suggested by the Pow value. Any absorption would be expected to be pH dependant since the notified substance is a polybasic salt of both weak and strong acid groups. Absorption would, therefore, be favoured in the acid environment of the stomach, whilst interaction with counter ions could, potentially, increase lipophilicity.
Details on distribution in tissues:
There is no experimental evidence to indicate potential distribution of any absorbed substance, other than to the route of excretion. Bioaccumulation is probably unlikely, in view of the high water solubility. A contact sensitisation study conducted on the analogue substance 1 (refer to IUCLID chapter 13) was negative, which might imply that the substance would not be expected to bind to proteins.
Details on excretion:
The kidney effects seen in the repeated dose oral toxicity study conducted on the analogue substance 1 (refer to IUCLID chapter 13) suggest that excretion in urine occurs. The water solubility of the parent substance and the possible metabolites indicate this to be the most likely route of excretion, although high molecular weight substances are sometimes eliminated in bile. The parent substance is not sufficiently volatile for elimination via the lungs in expired air.

Metabolite characterisation studies

Details on metabolites:
None of the studies conducted on the notified substance or on the analogue substance 1 (refer to IUCLID chapter 13) provide any convincing information about metabolism. From the chemical structure, enzymatic cleavage might be expected possibly with production of sulfonamides and subsequent conjugation reactions. The high water solubility of the parent substance, however, suggests that excretion may occur without biotransformation.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: low bioaccumulation potential based on physico-chemical properties and toxicological studies
The high molecular weight may, theoretically, preclude absorption. No predictions about toxicokinetic behaviour can be made from the chemical structure. The notified substance tested is a powder prepared by drying but will only be used as a solution, so inhalation exposure is not anticipated. It is stable to hydrolysis, so exposure to degradants is not expected. Most of the data used for this assessment is derived from studies conducted on a structurally similar compound the analogue substance 1 (refer to IUCLID chapter 13).  1) ABSORPTION No treatment related effects were seen in an acute oral toxicity study on the notified substance or in an acute dermal study conducted on the analogue substance 1 (refer to IUCLID chapter 13). In a repeated dose oral toxicity study on conducted on the analogue substance 1 (refer to IUCLID chapter 13), however, treatment related kidney changes were observed, which indicate that absorption could occur from the gastro-intestinal tract. The notified substance has a low log Pow value, which suggests poor absorption by passive diffusion, but it is very water soluble and may therefore show higher lipid solubility than is suggested by the Pow value. Any absorption would be expected to be pH dependant since the notified substance is a polybasic salt of both weak and strong acid groups. Absorption would, therefore, be favoured in the acid environment of the stomach, whilst interaction with counter ions could, potentially, increase lipophilicity. 2) DISTRIBUTION There is no experimental evidence to indicate potential distribution of any absorbed substance, other than to the route of excretion. Bioaccumulation is probably unlikely, in view of the high water solubility. A contact sensitisation study conducted on the analogue substance 1 (refer to IUCLID chapter 13) was negative, which might imply that the substance would not be expected to bind to proteins. 3) METABOLISM None of the studies conducted on the notified substance or on the analogue substance 1 (refer to IUCLID chapter 13) provide any convincing information about metabolism. From the chemical structure, enzymic cleavage might be expected possibly with production of sulfonamides and subsequent conjugation reactions. The high water solubility of the parent substance, however, suggests that excretion may occur without biotransformation. 4) EXCRETION The kidney effects seen in the repeated dose oral toxicity study conducted on the analogue substance 1 (refer to IUCLID chapter 13) suggest that excretion in urine occurs. The water solubility of the parent substance and the possible metabolites indicate this to be the most likely route of excretion, although high molecular weight substances are sometimes eliminated in bile. The parent substance is not sufficiently volatile for elimination via the lungs in expired air.