Registration Dossier

Administrative data

basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Assessment of the likely toxicokinetic behaviour of the substance performed by a qualified toxicologist.

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
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:

Test material

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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).

Applicant's summary and conclusion

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.