Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: toxicokinetic assessment
Adequacy of study:
key study
Study period:
2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Toxicokinetic assessment by a certified toxicologist (not determined by an OECD TG).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to guideline
Guideline:
other: Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008
Deviations:
not applicable
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(2-ethylbutyl)cyclohexane-1-carboxylic acid
EC Number:
619-508-4
Cas Number:
381209-09-2
Molecular formula:
C13 H24 O2
IUPAC Name:
1-(2-ethylbutyl)cyclohexane-1-carboxylic acid
Details on test material:
- Name of test material (as cited in study report): CAT-Acid

Results and discussion

Main ADME results
Type:
absorption

Any other information on results incl. tables

TOXICOKINETIC ASSESSMENT

The relatively low molecular weight of CAT-Acid is favourable for absorption. However, the water solubility of CAT-Acid is low (1.11 x 10-2 g/L at 20°C). Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that CAT-Acid will show a high systemic exposure after oral administration (1).

CAT-Acid has potential ionisable groups in its structure. Under certain conditions, ionized molecules tend to be less well absorbed in the gastro-intestinal tract than non-ionized molecules, as ionization limits passive transport through lipid membranes. Its moderate lipophilic character (log Pow of 4.2 at neutral pH and log Pow of 4.5 at pH 2) indicates that uptake by micellular solubilisation may be of importance. For risk assessment purposes oral absorption of CAT-Acid is set at 50%. The result of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Once absorbed, distribution of CAT-Acid throughout the body will be limited due to its low water solubility. Based on its moderate lipophilic character, intracellular concentration is expected to be higher than extracellular concentration. Absorbed CAT-Acid might undergo biotransformation. The biotransformation products will either be excreted via the bile (high molecular weight compounds) or the urine (low molecular weight compounds) (3).

Due to the high boiling temperature (306°C) and the very low vapour pressure (= 4.08 x 10-2 Pa) it is not to be expected that CAT-Acid will be available significantly for inhalation. Under experimental conditions, the aerosol particle size of CAT-Acid artificially generated by means of a nebulizer showed the presence of inhalable particles. In general, particles with an aerodynamic diameter < 100 µm have the potential to be inhaled. It is anticipated that particles with an aerodynamic diameter below 50 µm may reach the thoracic region and those below 15 µm (100% for CAT-ACID) the alveolar region of the respiratory tract. However, should CAT-Acid reach the tracheobronchial region, uptake by means of micellular solubilisation may be of importance, due to the lipophilic properties of this substance, as indicated by the log Pow >4 and poor water solubility (11 mg/L). However, overall it is unlikely that CAT-Acid will be available to a high extent after inhalation via the lungs due to the low vapour pressure. Results from the acute inhalation toxicity study showed no toxicity nor mortality at the high dose level of 5 mg/L after 4 hour exposure.

CAT-Acid, being a liquid, has the potential to partition from the stratum corneum into the epidermis. Since the water solubility of CAT-Acid is low (11 mg/L), and the partition coefficient is moderately high (log Pow of 4.2 at neutral pH and log Pow of 4.5 at pH 2) the substance may be too hydrophobic to cross the stratum corneum significantly, and therefore dermal uptake will be impaired. However, the data are insufficient to meet the criteria for 10% dermal absorption as given in the Endpoint Specific Guidance for the implementation in REACH (MW>500 and log Pow <-1 or >4) (2), a dermal absorption of CAT-Acid of 100% is proposed for risk assessment purposes. However, as it is generally accepted that dermal absorption does not exceed oral absorption, 50% dermal absorption is considered to be a more realistic dermal absorption factor. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of CAT-Acid after dermal absorption.

References:

(1) Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting

drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

(2) Guidance for the implementation of REACH. Guidance on information requirements and

chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European

Chemical Agency, May 2008.

(3) A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth

edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill,

New York, 2001.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: see section "Any other information on results incl. tables"
See section "Any other information on results incl. tables"