Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Assessment of the likely toxicokinetic behaviour of the substance performed by a qualified toxicologist.
Objective of study:
toxicokinetics
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetic assessment has been conducted for the substance. Summaries of studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII, point 8.8 of REACH. The list of data used for the assessment is given in section 5. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, November 2012).
GLP compliance:
no
Details on absorption:
The most plausible potential site of absorption may be via the skin due to the substance's inherent irritative characteristics with damage to the skin surface permitting passive diffusion through the compromised skin barrier. The physio-chemical features of the substance indicate it not to be available as a vapour therefore inhalation is considered not to be a significant route of exposure. The lack of evidence to support absorption via the gastro intestinal tract (Oral LD50 >2000 mg/kg) suggests the substance
is of low toxicity or not absorbed by the gastro intestinal tract. Whilst available repeated dose toxicity data was via the dermal route; there is no reason to presume that absorption via the skin is more favourable compared with the oral route. This is particularly of note when considering that dose selection for repeat dose dermal studies was limited by dermal irritancy. However, the high Log Pow does mean passage across biological membranes is possible.
Details on distribution in tissues:
The route of systemic distribution is not evident from the repeated dose study (Mattsson, Shankar, Spencer and Yano, 1997). The positive response in a skin sensitisation study (Buehler) performed in the guinea pig (Young, 1975) suggests that the test item may bind to carrier proteins in the circulatory system thereby facilitating systemic distribution. Once absorbed, the substance may potentially accumulate in adipose tissue due to the high log octanol/water partition coefficient value (log Pow 6.0, Weissenfeld, 2010).
Details on excretion:
Low water-solubility (< 0.5 mg/L at 20°C, Weissenfeld, 2010) is not favourable for urinary excretion, therefore biliary excretion is a plausible route for this substance albeit as there was no evidence of hepatic metabolism, excretion may be via the faeces.
Details on metabolites:
In relation to the repeated dose neurotoxicity study, when considering the lipophilic nature of the substance it would be presumed that metabolism to a more hydrophilic product to actuate excretion would need to take place and this is not supported by any of the available data. The results of the genotoxicity assays have shown that genotoxicity
is neither enhanced nor diminished in the presence of the S9 metabolising system (San
and Clarke, 1998).
Conclusions:
Interpretation of results (migrated information): no data
The available information suggests that limited absorption may take place via the skin and once absorbed, the substance may potentially bind to circulatory proteins and accumulate in adipose tissues. There is no evidence suggesting how the substance is metabolised however, it is reasonable to assume excretion may takes place via biliary or more plausibly the faeces.

Description of key information

The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter
R.7c: Endpoint specific guidance (ECHA, November 2012).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

The available information suggests that limited absorption may take place via the skin and once absorbed, the substance may potentially bind to circulatory proteins and accumulate in adipose tissues. There is no evidence suggesting how the substance is metabolised however, it is reasonable to assume excretion may takes place via biliary or more plausibly the faeces.

No bio-accumulation study in fish or any other higher organism has been performed. Epoxides are hydrolized by epoxide hydrolases generating hydroxyl terminals at the alkyl chain, which in tumare glucuronidated and excreted. Thus, no bio-accumulation is expected. In addition, a BCF = 160 has been calculated by the QSAR model of US-EPAS (Syracuse Research (2007) indicating a low bio-accumulation potential.

According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. In the absence of route-specific information a ratio of 1 for oral to dermal absorption, considered as worst case scenario, is provisionally suggested for the risk assessment of the substance.