Phenol, 4-methyl-, reaction products with dicyclopentadiene and isobutylene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: available information

Adequacy of study:

key study

Study period:

June - August 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non GLP-assessment report

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Materials and methods

Objective of study:

other: toxicokinetic assessment

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Assessment of all available data

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenol, 4-methyl-, reaction products with dicyclopentadiene and isobutylene

EC Number:

271-867-2

EC Name:

Phenol, 4-methyl-, reaction products with dicyclopentadiene and isobutylene

Cas Number:

68610-51-5

Molecular formula:

C10H12.C7H8O.C4H8

IUPAC Name:

2-(8-{3-[8-(3-tert-butyl-2-hydroxy-5-methylphenyl)tricyclo[5.2.1.0²,⁶]decan-4-yl]-2-hydroxy-5-methylphenyl}tricyclo[5.2.1.0²,⁶]decan-4-yl)-6-[4-(3-tert-butyl-2-hydroxy-5-methylphenyl)tricyclo[5.2.1.0²,⁶]decan-8-yl]-4-methylphenol

Constituent 2

Reference substance name:

Phenyl, 4-methyl-, reaction products with dicyclopentadiene and isobutylene

IUPAC Name:

Phenyl, 4-methyl-, reaction products with dicyclopentadiene and isobutylene

Details on test material:

- Name of test material (as cited in study report): Lowinox CPL
- Physical state: solid
- Analytical purity: treated as 100% pure

Test animals

Species:

other: none

Strain:

other: none

Administration / exposure

Route of administration:

other: oral, dermal and inhalation

Vehicle:

unchanged (no vehicle)

Details on exposure:

see assessment

Results and discussion

Any other information on results incl. tables

The water solubility of Lowinox®CPL is very low (0.01 mg/L). Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that Lowinox®CPL will show a high systemic exposure after oral administration (1). However, its highly lipophilic character (log Po/w 7.17 – 8.17) indicates that uptake by micellular solubilisation may be of particular importance. Lowinox®CPLwith its hydroxyl (OH) groups is potentially ionisable, and ionized substances do not readily diffuse across biological membranes. Also the relative high molecular weight of Lowinox®CPL (MW 700) is not favourable for absorption. For risk assessment purposes oral absorption of Lowinox®CPL is set at 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

Once absorbed the highly lipophilicLowinox®CPL(log P >6) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Due to its lipophilicity,Lowinox®CPL may be present at higher concentrations in breast milk than in blood/plasma, and exposure of neonates via nursing to mother’s milk may have toxicological significance. Lowinox®CPLmay tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate in individuals that are frequently exposed (e.g. daily at work) Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance.Lowinox®CPLwith its hydroxyl (OH) groups may be conjugated as glucuronides and excreted in the bile and potentially undergo enterohepatic circulation.

 

The very low vapour pressure (< 3.2 x 10^-5Pa) and the high boiling point (Decomposition > 300°C) indicate that Lowinox ®CPL is not available for inhalation as a vapour, but Lowinox ®CPL particles have the potential to be inhaled by humans (96.5% < 45 µm) . Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract. Lowinox ®CPL 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 ®CPL 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 of particular importance for the highly lipophilic Lowinox ®CPL particles (log P7.17 – 8.17), 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 ®CPL 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 ®CPL is set at 100%.

Lowinox®CPLmay penetrate the lipid rich stratum corneum but with a log P value of7.17 – 8.17, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may even be slow. At a molecular weight above 500 the molecule may also be too large for dermal uptake. AlthoughLowinox®CPLmay persist in the stratum corneum, it will eventually be cleared as the stratum corneum is sloughed off. With a molecular mass above 500 and log P outside the range [-1, 4],the data meet the criteria for 10% dermal absorption as given in the Guidance for the implementation of REACH (2) 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): other: see conclusions
For risk assesment purposes, the oral absorption is set at 50%.
For risk assessment purposes the inhalation absorption is set at 100%.
For risk asssessment purposes the dermal absorption is set at 10%.