Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: theoretical approach
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Toxicokinetic assessment by a certified toxicologist based on the available information.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance
Deviations:
not applicable
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): KY-ET
- Appearance: white powder

Results and discussion

Any other information on results incl. tables

TOXICOKINETIC ASSESSMENT OF KY-ET

The acute oral and dermal toxicity of KY-ET is low with an LD50 > 5000 mg/kg and an LD50 > 2000 mg/kg, respectively. The 28 -day toxicity study also revealed that KY-ET has a low toxicity with a NOAEL of 1000 mg/kg/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, an assessment of the anticipated toxicokinetic behaviour of KY-ET is given.

Dissolution of a compound is required for absorption from the gastro-intestinal tract into the blood. Based on the physico-chemical properties of KY-ET, the initial dissolution of both components is expected to be low. In the presence of gastric acid and/or bile salts, the solubility of KY-ET may be somewhat increased in the gastro-intestinal fluids. However, it is unlikely that the compound will be absorbed to a high extent from the gastro-intestinal tract (1). Although KY-ET shows a very low solubility in water, some dissolution may occur at low pH because of protonation of the urea groups.

In the gastro-intestinal tract, especially the colon, dissolved KY-ET may already be partly metabolised by amidases (2).

In case KY-ET is aborbed, it will be extensively metabolised by amidases, but also hydroxylation of the phenyl rings by cytochrome P450 -mediated metabolism may occur. The formed hydroxy-metabolites will then probably be conjugated and excreted via urine or bile.

Although theoretically aniline-derivatives could be formed as metabolites, based on the toxicity studies, there are no indications that these compounds are formed after ingestion or dermal application of KY-ET.

KY-ET will show a high volume of distribution, because of the lipophilicity of the compound. It will be extensively distributed into peripheral tissue, especially fatty tissues. Some accumulation in fatty tissues is therefore anticipated. The plasma protein binding is expected to be high. Therefore, a volume of distribution exceeding that of total body water (>40 L) is expected.

Some uptake via inhalation is anticipated because of the relatively small particle size (<25% smaller than 4.945 µm).

Since it is generally accepted that substances with log Po/w ranging from 0.1 to 6 penetrate the skin easily (3), it is to be expected KY-ET will be absorbed to some extent through the skin.

Based on the expected kinetic behaviour in the body, as described above, KY-ET will not accumulate in the body after prolonged exposure.

The anticipated toxicokinetic behaviour is supported by the acute and subacute oral and dermal toxicity data. No significant difference in toxicokinetic behaviour is expected between the 2 components.

References:

(1) L.S. Schanker et al. Absorption of drugs from the rat small intestine. J. Pharmacol. Exp. Ther. 123 (1958) pp 81 -88

(2) A. Parkinson. In: Casarett and Doull's Toxicology, The basic science of poisons, fifth edition. Eds. C.D. Klaassen, M.O. Amdur and J. Doull. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York (2001).

(3) T.G. Vermeire et al., Estimation of consumer exposure to chemicals: application of simple models. The Science of the Total Environment 136 (1993) 155 -176

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: accumulation in the body during prolonged exposure is not anticipated
Based on the expected kinetic behaviour in the body, as described above, KY-ET will not accumulate in the body after prolonged exposure.
It is unlikely that the compound will be absorbed to a high extent from the gastro-intestinal tract. In the gastro-intestinal tract and in case KY-ET is absorbed, KY-ET may be metabolised by amidases. Some uptake via inhalation is anticipated because of the relatively small particle size (<25% smaller than 4.945 µm). Since it is generally accepted that substances with log Pow ranging from 0.1 to 6 penetrate the skin easily, it is to be expected KY-ET will be absorbed to some extent through the skin.