Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
other: In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Study period:
The assessment was conducted in December 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII (8.8.1).
Objective of study:
toxicokinetics
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information. The assessment is based on the Guidance on information requirements and chemical safety assessment R.7c: Endpoint specific guidance (ECHA, May 2008)
GLP compliance:
no
Remarks:
Not relevant for assessment

TOXICOKINETIC BEHAVIOUR

The test item is composed as listed in IUCLID section 1.2 (composition). It is a yellow crystalline solid and the molecular weight is 127.18 g/mol. The test item is of limited volatility with a vapour pressure of 3.9 Pa at 25ºC and predicted negative explosive and oxidising properties. The test item also has been shown to have a particle size distribution of 0.165% of particles less than 100μm in diameter . In consequence inhalation based on minimal vapour pressure and large particle size is not expected to be a significant route of exposure.

The test item has a low log octanol/water partition coefficient (Log10 Pow = 0.491) and high water solubility (30.5 g/l). The available repeat dose oral with reproductive screening study in rats showed evidence of absorption and distribution. Distribution is likely to occur in blood plasma due to the solubilty of the test item.

The test item is non-mutagenic in bacteria and non-clastogenic in mammalian cells in vitro in either the absence or presence of an

auxiliary metabolising system. The substance is not classified as a dermal irritant nor a skin sensitizer.

Absorption

Results of the oral repeat dose study with reproduction / developmental toxicity screening study in rats show evidence to support the absorption of the test item. The actual molecule size and water solubility of the test item suggest that absorption across the gastro-intestinal tract would be a result of a simple diffusion process and therefore provides a route of potential absorption, following oral administration. Distribution of the test item is likely to occur as a result of simple systemic distribution in blood plasma. This may account for the perceived slight effects on the nervous system.

Limited absorption may occur via the skin due to small molecular size and the solubility of the test item.

Distribution

Systemic distribution can potentially occur following absorption from the gastrointestinal tract. This is suggested from the results of the repeted dose/reproduction screening test due to the slight microscopic sciatic nerve changes observed.

Metabolism

The results of the repeated dose/reproductive screening study did not show evidence to indicate any test item influenced hepatic metabolism. The results of the in vitro genotoxicity assays do not show any evidence that the addition of the S9 metabolising

system either enhance or diminish the genotoxic potential of the substance.

Excretion

There is no evidence to indicate the route of excretion. As the test item is highly water soluble, it is expected that this would facilitate urinary excretion.

Conclusions:
The available information suggests that absorption of the test item from the gastrointestinal tract can take place. Once absorbed in significant amounts corresponding to a subchronic oral dose of 100 mg/kg bw/day in rats, concentrations leading to slight histopathological changes in the neural tissue are achieved. However, a clear dose-dependency is lacking and there is no indication for any behavioural or functional deficits up to a subchronic dose of 350 mg/kg bw/day. There is no evidence for bioaccumulation of the test item due to its low partition co-efficient and high water solubility.
Executive summary:

The available information suggests that the substance is readily available via the oral route. This is supported by the physico-chemical properties of the substance.

Once absorbed, the test item would not be expected to accumulate in body fat due to the low log octanol:water partition coefficient (log Pow). Due to the small molecular size and water solubility, penetration of the intact dermis will occur to a limited extent. Urinary excretion is considered to be the significant route for the substance.

Description of key information

The available information suggests that the substance is readily available via the oral route. This is supported by the physico-chemical properties of the substance.
Once absorbed, the test item would not be expected to accumulate in body fat due to the low log octanol:water partition coefficient (log Pow). Due to the small molecular size and water solubility, penetration of the intact dermis will occur to a limited extent. Urinary excretion is considered to be the significant route for the substance.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

TOXICOKINETIC BEHAVIOUR

The test item is composed as listed in IUCLID section 1.2 (composition). It is a yellow crystalline solid and the molecular weight is 127.18 g/mol. The test item is of limited volatility with a vapour pressure of 3.9 Pa at 25ºC and predicted negative explosive and oxidising properties. The test item also has been shown to have a particle size distribution of 0.165% of particles less than 100μm in diameter . In consequence inhalation based on minimal vapour pressure and large particle size is not expected to be a significant route of exposure.

The test item has a low log octanol/water partition coefficient (Log10Pow = 0.491) and high water solubility (30.5 g/l). The available repeat dose oral with reproductive screening study in rats showed evidence of absorption and distribution. Distribution is likely to occur in blood plasma due to the solubilty of the test item.

The test item is non-mutagenic in bacteria and non-clastogenic in mammalian cells in vitro in either the absence or presence of an

auxiliary metabolising system. The substance is not classified as a dermal irritant nor a skin sensitizer.

Absorption

Results of the oral repeat dose study with reproduction / developmental toxicity screening study in rats show evidence to support the absorption of the test item. The actual molecule size and water solubility of the test item suggest that absorption across the gastro-intestinal tract would be a result of a simple diffusion process and therefore provides a route of potential absorption, following oral administration. Distribution of the test item is likely to occur as a result of simple systemic distribution in blood plasma. This may account for the perceived slight effects on the nervous system.

Limited absorption may occur via the skin due to small molecular size and the solubility of the test item.

Distribution

Systemic distribution can potentially occur following absorption from the gastrointestinal tract. This is suggested from the results of the repeted dose/reproduction screening test due to the slight microscopic sciatic nerve changes observed.

Metabolism

The results of the repeated dose/reproductive screening study did not show evidence to indicate any test item influenced hepatic metabolism. The results of the in vitro genotoxicity assays do not show any evidence that the addition of the S9 metabolising

system either enhance or diminish the genotoxic potential of the substance.

Excretion

There is no evidence to indicate the route of excretion. As the test item is highly water soluble, it is expected that this would facilitate urinary excretion.

Conclusion

The available information suggests that absorption of the test item from the gastrointestinal tract can take place. Once absorbed in significant amounts corresponding to a subchronic oral dose of 100 mg/kg bw/day in rats, concentrations leading to slight histopathological changes in the neural tissue are achieved. However, a clear dose-dependency is lacking and there is no indication for any behavioural or functional deficits up to a subchronic dose of 350 mg/kg bw/day. There is no evidence for bioaccumulation of the test item due to its low partition co-efficient and high water solubility.