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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
other: theoretical approach
Adequacy of study:
key study
Study period:
19 Jan 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP assessment report based on expert judgement.
Objective of study:
other: toxicokinetic assessment
Qualifier:
no guideline required
Principles of method if other than guideline:
An expert assessment was made based on all data available.
GLP compliance:
no
Species:
other: none
Route of administration:
other: oral, dermal and inhalation
Vehicle:
other: not applicable
Details on study design:
A toxicokinetic assessment has been performed based on available physico-chemical properties and toxicological data of the substance.

The acute oral and dermal toxicity of DHX2 is low, with the LD50 being higher than 2000 mg/kg bw in both cases. The 28 -day toxicity study also revealed that DHX2 has a low toxicity with a NOAEL of 1000 mg/kg bw/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, an assessment of the anticipated toxicokinetic behaviour of DHX2 is given.

Absorption

The water solubility of DHX2 is high (>1000 g/L). Under physiological conditions, the compound will be completely ionised. Since the water solubility of DHX2 is high and the log Pow is relatively low (1.43), it is unlikely that non-dissociated DHX2 will be absorbed to a high extent from the gastro-intestinal tract. Therefore, it is to be expected that the oral bioavailability, and thus the systemic exposure, of non-dissociated DHX2 will be low (1).

Uptake via inhalation is not anticipated because the vapour pressure measured is that of the water part of the substance and the vapour pressure of the organic part of the substance is not expected to be significant as the organic part of the substance is a salt and has a molecular weight of 576.

Since the bioavailability fo dermally applied compounds can be assumed to be zero for substances with a log Pow below -1 and 5 or a relative molecular mass over 700 (2), it is to be expected that DHX2 will to some extent be absorbed through the skin.

Distribution

Once DHX2 is absorbed, it will probably be distributed throughout extracellular body water. It will not be distributed into peripheral tissue. The compound will hardly bind to plasma proteins because of its high polarity.

Metabolism and excretion

In case absorption occurs, the primary and tertiary amines may undergo conjugation, most probably by acetylation or glucuronidation (3). The carboxy groups will be rapidly conjugated by glucuronidases and/or sulfatases.

Because of the high water solubility, the unchanged compound will be excreted extensively via the kidneys. The hydroxylated and conjugated metabolites will be excreted via urine or bile.

The very rapid metabolism and excretion will probably result in a relatively short elimination half-life of DHX2.

Based on the expected kinetic behaviour in the body, as described above, DHX2 will not accumulate in the body after prolonged exposure.

References

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

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

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

Conclusions:
The substance is considered to have low bioaccumulation potential based on its log Pow.
The oral absorption is expected to be low. Uptake via inhalation is not anticipated. The substance will to some extent be dermally absorbed.

Description of key information

An expert assessment was made based on all data available.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

The acute oral and dermal toxicity of DHX2 is low, with the LD50 being higher than 2000 mg/kg bw in both cases. The 28 -day toxicity study also revealed that DHX2 has a low toxicity with a NOAEL of 1000 mg/kg bw/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, an assessment of the anticipated toxicokinetic behaviour of DHX2 is given.

Absorption

The water solubility of DHX2 is high (>1000 g/L). Under physiological conditions, the compound will be completely ionised. Since the water solubility of DHX2 is high and the log Pow is relatively low (1.43), it is unlikely that non-dissociated DHX2 will be absorbed to a high extent from the gastro-intestinal tract. Therefore, it is to be expected that the oral bioavailability, and thus the systemic exposure, of non-dissociated DHX2 will be low (1).

Uptake via inhalation is not anticipated becausethe vapour pressure measured is that of the water part of the substance and the vapour pressure of the organic part of the substance is not expected to be significant as the organic part of the substance is a salt and has a molecular weight of 576.

Since the bioavailability fo dermally applied compounds can be assumed to be zero for substances with a log Pow below -1 and 5 or a relative molecular mass over 700 (2), it is to be expected that DHX2 will to some extent be absorbed through the skin.

Distribution

Once DHX2 is absorbed, it will probably be distributed throughout extracellular body water. It will not be distributed into peripheral tissue. The compound will hardly bind to plasma proteins because of its high polarity.

Metabolism and excretion

In case absorption occurs, the primary and tertiary amines may undergo conjugation, most probably by acetylation or glucuronidation (3). The carboxy groups will be rapidly conjugated by glucuronidases and/or sulfatases.

Because of the high water solubility, the unchanged compound will be excreted extensively via the kidneys. The hydroxylated and conjugated metabolites will be excreted via urine or bile.

The very rapid metabolism and excretion will probably result in a relatively short elimination half-life of DHX2.

Based on the expected kinetic behaviour in the body, as described above, DHX2 will not accumulate in the body after prolonged exposure.