Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
expert statement
Type of information:
other: Expert Statement
Adequacy of study:
key study
Study period:
2019-05-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement, no other study available

Data source

Reference
Reference Type:
other: Expert Statement
Title:
Unnamed
Year:
2019
Report Date:
2019

Materials and methods

Principles of method if other than guideline:
Expert Statement
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral route
Generally, oral absorption is favoured for molecular weights below 500 g/mol. The low water solubility of ca. 1.67 mg/L will probably not allow ready dissolution of the test item in the gastrointestinal fluids. Thus, a direct uptake into the systemic circulation through aqueous pores or via carriage with the bulk passage of water is considered as less relevant. The logPow value of 4.44 is also already above the range of -1 to 4 which is usually considered to be favored for absorption by passive diffusion through biological membranes. With a logPow of greater than 4, the test item may be taken up by micellular solubilisation. Moreover, hydrolysis of the test item in the GIT is not expected based on QSAR calculation the hydrolytic half-life is greater than a year. Overall, physicochemical properties of the test item indicate that it might not be readily absorbed via the oral route. This is supported by oral acute as well as repeated dose toxicity data, where no or only minor signs of toxicity were observed after administration up to the limit dose (2000 mg/kg bw and 1000 mg/kg bw/d, respectively).

Inhalation route
Due to its low volatile properties availability of the test item via the inhalation route cannot be completely ruled out. Since the substance is a liquid at ambient temperature the generation of dust is excluded. However, in case of inhalation, absorption via the respiratory tract cannot completely be ruled out.

Dermal route
Dermal absorption is considered limited since the logPow value is above 4 and thus considered to limit transfer between stratum corneum and the epidermis. However, uptake into the stratum corneum will probably be high. Another parameter that affects transport of a substance from the stratum corneum into the epidermis is the water solubility of a substance. Below 1 mg/L dermal uptake is considered to be low.
However, based on in vitro test battery results the test item was shown to have a skin sensation potential. Thus, even small amounts of the substance becoming bioavailable through the dermal route could be important. Moreover, the substance is classified as skin irritant and thus absorption may be facilitated due to the damage of the upper skin layers.
Details on distribution in tissues:
Physicochemical properties of the test item as well as toxicity data indicate a rather low systemic bioavailability following oral, inhalative and dermal uptake.
However, after being absorbed into the body, the test item is likely distributed into cells and intracellular concentrations may be higher than extracellular concentrations due to rather lipophilic properties (log Pow 4.44). This applies especially for fatty tissues.
However, the test item is unlikely to have a bio-accumulative potential, even though it might be considered as lipophilic (logPow is greater than 4). The subacute repeated dose toxicity study in rats did not reveal any signs of target organ toxicity or other indications for an accumulation in any organ or tissue, there is also no other evidence for an accumulative property of this compound. Moreover, its metabolic transformation to more hydrophilic compounds is anticipated as described below.
Details on excretion:
As discussed below, the test item is probably substrate to phase I metabolizing enzymes and its hydrophilicity will likely be increased by this process. Taking into account its low molecular weight it can be assumed that the test item is rather excreted via the kidneys and the urine than via feces after it has been metabolised.

Metabolite characterisation studies

Details on metabolites:
It can be assumed that P450-enzymes are substantially involved in the metabolism of the test item, based on findings in the bacterial reverse mutation assay (Ames) as well as in the mammalian cell gene mutation assay (HPRT). In both assays cytotoxicity was observed in the absence of the metabolizing system (S9). In the presence of S9, however, the same substance concentration did not induce cytotoxicity anymore. Thus, a detoxification by metabolism of phase I enzymes could be anticipated. This metabolism usually aims to enhance hydrophilicity of the substance, for example by hydroxylation reactions, in order to facilitate excretion of the xenobiotic. This supports the assumption that the test item is not considered of concern in regards to bioaccumulation.

Applicant's summary and conclusion

Conclusions:
Based on physicochemical characteristics, particularly molecular weight and octanol-water partition coefficient, absorption by the dermal, oral and inhalation route is expected to be low. This assumption is further supported by the results of the oral acute toxicity study as well as the subacute repeated dose study. There are no indications that the test item or its metabolites could have a bioaccumulating potential. Metabolic transformation by phase I enzymes is expected and excretion via urine can be anticipated.