Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics
Adequacy of study:
key study
Study period:
January 2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The qualitative judgement is based on physico-chemical characteristics. Some of these are determined under conditions which are not biologically relevant (like the octanol/water partition coefficient at pH 11). Furthermore, the submission substance is a multi constituent substance while physico-chemical characteristics in general refer to pure substances. This limits the reliability of the assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
No further details
Specific details on test material used for the study:
No further data
Radiolabelling:
no

Results and discussion

Any other information on results incl. tables

The acute oral toxicity test with the test substance showed the LD50 being between 200 and 2000 mg/kg body weight. The subacute toxicity test for 28-days revealed a NOAEL of 50 mg/kg/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, a summary of the anticipated toxicokinetic behaviour of the test substance is given.

The water solubility of the test substance is high. Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is likely that the test substance will show a high systemic exposure after oral administration. It is to be expected that the oral bioavailability of the test substance will be relatively high. The highest absorption is expected to be from the duodenum.

In the gastro-intestinal tract, hardly any degradation of the substance is to be expected. In the case absorption of the test substance occurs, the aliphatic carbons as well as the primary nitrogens will undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation. Direct conjugation at the nitrogens in the parent compound is expected. Also extensive cleavage of the ether bonds is anticipated. The resulting metabolites will be extensively excreted via bile and/or urine.
The submission substance will show a low volume of distribution, because of the relatively low lipophilicity of the compound.
The volume of distribution is expected to equal total body water (about 700 ml/kg). Accumulation in fatty tissues is therefore not anticipated. The plasma protein binding is expected to be low.

Uptake via inhalation may take place based on the vapour pressure.


Since it is generally accepted that substances with log Po/w ranging from 0.1 to 6 penetrate the skin easily, it is
to be expected that the test substance may penetrate the skin rapidly. The fact that the test substance is corrosive
to the skin may even increase the dermal absorption.

Based on the expected kinetic behaviour in the body, as described above, the test substance will show a relatively
high absorption after oral administration, mainly because of its high water solubility. If absorption occurs, the test
substance will be extensively metabolised in the liver and rapidly excreted via bile and/or urine. Therefore,
accumulation in the body during prolonged exposure will be very low.

Applicant's summary and conclusion

Conclusions:
Following a qualitative judgement based on physico-chemical characteristsc of the submission substance, the substance will show a relatively high absorption after oral administration, mainly because of its high water solubility. If absorption occurs, the test substance will be extensively metabolised in the liver and rapidly excreted via bile and/or urine. Therefore, accumulation in the body during prolonged exposure will be very low. Dermal absoprtion is also expected to be significant, following the logPow and skin corrosive properties of the submission substance.