Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Expert statement
Type of information:
other: Expert statement based on physicochemical and subchronic toxicity data.
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Expert statement based on physicochemical and subchronic toxicity data.

Data source

Reference
Reference Type:
other: Expert Statement
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
603-101-3
EC Number:
603-101-3
Cas Number:
125962-78-9
Molecular formula:
C21 H28 O2
IUPAC Name:
603-101-3

Results and discussion

Applicant's summary and conclusion

Conclusions:
Specific information on the metabolism and excretion of the substance is not available. Based on physicochemical characteristics, moderate absorption by the oral and dermal route is likely to take place. This assumption is supported by the results of the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, revealing a LOAEL of 100 mg/kg bw/day. Absorption via inhalation route is unlikely, but may also take place via dust formation. Bioaccumulation of the substance may be possible. After being absorbed into the body, the test item is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow >5.7) and in turn, the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. Metabolism of the test material in the liver can be assumed, because of a slight liver weight increase liver observed after repeated oral exposure (Pels Rijcken, 2018). A metabolic activation to more toxic metabolites is not to be expected. Excretion is assumed to happen mainly via the faeces.
Executive summary:

The test item is a mono-constituent substance. It is a light yellow solid at room temperature with a molecular weight of 312.45 g/mol. The substance is not soluble in water (< 0.006 mg/mL at 25 °C). The log Pow was determined to be > 5.7 at 25 °C. The test substance has a vapour pressure of 1.1e-6 Pa at 25 °C.


 


Absorption


According to the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c (Endpoint specific guidance), oral absorption is favoured for molecules with molecular weights of less than 500 g/mol. The poor water solubility and particulate form reduce dissolution in the gastrointestinal tract, which may decrease absorption but the high log Pow of >5.7 and low water solubility may trigger uptake by micellular solubilisation. Taken together, the physiochemical properties indicate that the test item becomes bioavailable following the oral route. This assumption is confirmed by the results of the repeated dose toxicity study, where dose-dependent effects on peripheral blood lymphocytes were observed. Due to the very low volatility (vapour pressure of 1.1e-6 Pa) of the test item, it is unlikely that the substance will be available as a vapour, but small, inhalable particle sizes may promote dust formation and thus favour exposure via inhalation. The high log Pow value and low water solubility may enable uptake across the respiratory tract epithelium by micellular solubilisation. Dermal absorption is likely to be reduced due to the dry particulate form of the substance which would firstly have to dissolve into the surface moisture of the skin before uptake can begin. A dermal uptake is favoured by a molecular weight of less than 100 g/mol. Dermal absorption may be also reduced due to the molecular weight of the test item of 312.45 g/mol. As the log Pow of the substance is above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum may be high. Although the physicochemical data indicate a rather low dermal absorption, the sensitizing potential of the test item indicates that the substance can be absorbed to a certain extend.


 


Distribution


As mentioned above, the physicochemical properties of the test item favour a moderate absorption following oral and dermal uptake. The systemic absorption and distribution within the body is also demonstrated by the dose-dependent effects on peripheral blood lymphocytes and the reduced body weights of the pups in the highest dose group in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test according to OECD guideline 422. After being absorbed into the body, the test item is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow >5.7) and in turn, the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. The log Pow of the test item indicates a potential bioaccumulation potential as it is above 3.


 


Metabolism


There is no direct experimental data to characterize the metabolism of the test substance. Instead, the anticipated metabolism is derived from expert judgement and reapplication of metabolic properties of related substances. The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and no cytotoxicity was observed in the presence or absence of metabolic activation systems. Thus a metabolic activation to more toxic metabolites was not indicated.


 


Excretion


Due to the molecular properties of the substance, excretion via faeces is considered to be the main route of elimination. Hydrophobic substances with a molecular weight above 300 g/mol are considered to be prone to excretion via bile after enterohepatic circulation.