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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: statement based on theoretical approach
Adequacy of study:
key study
Study period:
September-November 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP assessment report; study is based on expert judgment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A theoretical approach of the toxicokinetic properties of the substance based on the available physico-chemical properties and toxicological data.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lowinox® AH25
- Chemical name: 2,5-bis(1,1-dimethylpropyl)benzene-1,4-diol
- Molecular formula: C16H26O2
- Molecular weight: 250.38
- Substance type: White to cream coloured powder
- Analytical purity: 95.9% (based on GC analysis)

Results and discussion

Main ADME results
Type:
absorption
Results:
Values of 50% oral and dermal absorption and 100% inhalation absorption is taken into account.

Any other information on results incl. tables

The water solubility of Lowinox ® AH25 is very low (< 0.08 mg/L). In general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract and its lipophilic character (log Po/w 3.3) indicates that uptake by micellular solubilisation or passive diffusion may play a significant role.The molecular weight of Lowinox® AH25 (MW 250) is favorable for absorption.Lowinox ®AH25with its hydroxyl (OH) groups is potentially ionisable, and ionized substances do not readily diffuse across biological membranes. However, in view of its lipophilic characterLowinox ®AH25 is presumed to be in the unionized form. The passive diffusion rate is directly proportional to the gradient from a region of high concentration (eg, GI fluids) to one of low concentration (eg, blood), but also depends on the molecule's lipid solubility, size, degree of ionization, and the area of absorptive surface. Because the cell membrane is lipoid and small molecules tend to penetrate membranes more rapidly than larger ones, Lowinox ®AH25 may well diffuse to a substantial degree. For risk assessment purposes oral absorption of Lowinox ® AH25 is set at 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

The very low vapour pressure (7.55 x 10-5Pa) and the high boiling point (Decomposition > 275°C) indicate that Lowinox ®AH25 is not available for inhalation as a vapour, but Lowinox ®AH25 particles have the potential to be inhaled by humans (73.5%< 40 µm) . Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract. Lowinox ®AH25 particles depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. Dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. The low water solubility of Lowinox ®AH25 indicates a potential for accumulation, since the substance will not dissolve easily into the mucus lining of the respiratory tract and will not be transported out of the respiratory tract. Micellular solubilisation may be relevant for the lipophilic Lowinox ®AH25 particles, which may have a longer half-life within the lungs. However a small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system. Lowinox ®AH25 dusts depositing in the alveolar region would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. For risk assessment purposes the inhalation absorption of Lowinox ®AH25 is set at 100%.

Although its log P value of 3.3 favors dermal absorption, Lowinox ®AH25is not sufficiently soluble in water to readily partition from the stratum corneum into the epidermis, and with a water solubility below 1 mg/L, dermal uptake is likely to be low. However, the substance shows skin sensitisations in a few human, some uptake must have occurred , although it may only have been a small fraction of the applied dose. Since the dermal absorption is not expected to be higher than the oral absorption the dermal absorption of Lowinox ®AH25 is set at 50%, for risk assessment purposes.The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
For risk assessment purposes the following absorption factors were derived:
oral absorption factor: 50%
dermal absorption factor: 50%
inhalation absorption factor: 100%