Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
other: Paper-based toxicokinetic assessment
Adequacy of study:
key study
Study period:
May 2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
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, DEHCH (Di 2-ethylhexyl cyclohexane-1,4-dicarboxylate). 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 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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Radiolabelling:
no

Test animals

Species:
other: Not applicable
Strain:
other: Not applicable
Sex:
not specified

Administration / exposure

Route of administration:
other: Not applicable
Vehicle:
other: Not applicable
Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Control animals:
not specified
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption
Results of the repeated dose/reproductive screening study in rats showed evidence to support the gastric absorption of the test item (Dunster, 2010). The relatively small molecular size of the substance should also allow absorption through passive diffusion. This is supported by the lipophilic nature of the substance (log10 Pow 8.84, Jeong, 2009). This would suggest that the gastro-intestinal tract provides a route of absorption, following oral administration, before entering the circulatory system via the blood. Limited absorption may also take place via the skin due to the relatively small molecular size. The low vapour pressure value (7.45 x 10-4 Pa at 50°C; Jeong, 2009) shows that the substance is not available as a vapour therefore inhalation is not a significant route of exposure.
Details on distribution in tissues:
Distribution
Systemic distribution is evident from the repeated dose/reproductive screening study (Dunster, 2010) as a result of the organ changes observed. The lack of evidence to suggest the test item is a skin sensitizer suggests that it does not bind to carrier proteins in the circulatory system (Bae, 2009 c). Once absorbed, the substance may potentially accumulate in the adipose tissue due to the high log octanol/water partition coefficient value (Log10 Pow 8.84, Jeong, 2009).
Details on excretion:
Excretion
There is no evidence to indicate the route of excretion but poorly water-soluble products are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this material. As there is evidence of hepatic metabolism this does not, however, rule out urinary excretion. The main reason for xenobiotic metabolism is to render the product more water soluble thereby facilitating urinary excretion. Any test item that is not absorbed will be excreted in the faeces.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Metabolism
The results of the repeated dose/reproductive screening study showed the evidence of an adaptive response in the liver and thyroids in rats (Dunster, 2010); which is normally associated with enhanced metabolism. The results of the genotoxicity assays have shown that genotoxicity is neither enhanced nor diminished in the presence of the S9 metabolising systems (Kim, 2009 a; Kim, 2009 c).

Any other information on results incl. tables

The substance is a clear colourless liquid and the molecular weight is 396.6 g/mol. The low vapour pressure value (7.45 x 10-4Pa at 50°C; Jeong, 2009) shows that the substance is non volatile therefore inhalation is not a significant route of exposure. The substance has a high log octanol/water partition coefficient value (Log10Pow8.84 Jeong, 2009) and low water solubility (47 μg/L; Jeong, 2009).The available repeated dose/reproductive screening study showed evidence of absorption and metabolism but did not show any evidence of excretion (Dunster, 2010).

The test item is non-mutagenic in bacteria (Kim, 2009 c), non-clastogenic in mammaliancells in vitro(Kim, 2009 a) in either the absence or presence of an auxiliary metabolizing system (Morris, 2012) or non-genotoxic in the mouse (Kim, 2009 b). The test item is not a dermal irritant or a skin sensitizer (Bae, 2009 a; Bae, 2009 c; Pooles, 2010).

Applicant's summary and conclusion

Conclusions:
The available information suggests that absorption of the test substance from the gastrointestinal tract can take place, primarily as a consequence of the high log octanol/ water coefficient of the test item. Some absorption may also take place via the skin. Once absorbed, enhanced metabolism may occur and the substance would result in accumulation in the adipose tissues. Biliary excretion may well be significant route for the substance.