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Administrative data

Link to relevant study record(s)

Description of key information

Absorption via the dermal route of exposure is expected based on the experimental data and the physico-chemical properties of the substance. Distribution will be through the circulatory system as micelles or in association with a carrier molecule such as a lipoprotein or other macromolecule. Metabolism is considered to be via phase I oxidation/reduction, esterase-catalysed hydrolysis and subsequent Phase II conjugation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion. The substance will not bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Overview

The toxicokinetic profile of the test item was predicted using the physico-chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as the information gained from genotoxicity assays. The substance is a UVCB with eleven identified components and, from data presented elsewhere in this dossier, is not expected to bioaccumulate.

Physico-chemical properties

The UVCB components have a molecular weight range of 284.39 to 867.27 (excluding water), however, the lower molecular weight (<500) components constitute a major fraction of the substance (approximately 80%). The substance is an amber-coloured viscous liquid and the water solubility is 75.5 mg/L. The octanol/water partition coefficient is estimated at log Pow 4.65, (which is > 4, the bioaccumulation limit), and a low vapour pressure (2.8 x 10E-02 Pa at 25°C). The substance has surface-active properties (surface tension value of 46.4 mN/m at 21.7 ± 0.5 °C).

Absorption

Oral route

Physico-chemical properties described above indicate that the substance has a molecular size that may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being lipophilic with a Log Powof 4.65, the test item may be expected to cross gastrointestinal epithelial barriers. The substance has surface-active properties and the possibility exists that it may participate in micelle transport into the hepatic portal system along with other lipophilic substances (e.g. dietary fats) but in an acute oral gavage toxicity study there was no evidence of toxicity (LD50 >2000 mg/kg bw). A combined repeat dose and reproductive toxicity study using the oral route gave a NOAEL of 100 mg/kg bw/day. However, the toxicological significance of the histopathological changes seen in the liver and kidney were considered to be equivocal and the effects on the stomach were considered to be due to the direct irritant properties of the substance. In may be concluded that some components, most likely the lower MW ones, can be absorbed but generally caused only local irritant toxic effects.

Dermal route

Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be very slow considering both the MW range and the log Pow 4.65. Moreover, it is assumed that the dermal uptake of the test item is also limited based on its relatively low water solubility [1,2] These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study (LD50 > 2000 mg/kg). The substance did cause very slight erythema and very slight oedema in the dermal toxicity study, and also erythema and oedema in a skin irritation study in rabbits. In a sensitisation study in mice (LLNA) the substance was concluded to be a sensitiser. Therefore, these results are considered to be evidence of absorption via the dermal route.

Inhalation route

The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the low vapour pressure of the test item (2.8 x 10E-02 Pa at 25oC) indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and handling of this material is expected to be inconsequential. The substance is used as a component in greases and lubricants and as a consequence there is little potential for exposure via the production of aerosols. In this case the absorption across the respiratory epithelium is likely to be very low, because of the physicochemical properties discussed previously.

Distribution

Systemic distribution of the substance can be predicted from the physical chemical properties of this substance. The moderately high log Pow, relatively low water solubility and surface activity suggests that this substance, upon systemic absorption, may be transported through the circulatory system as micelles or in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character, moderately high Log Pow and the molecular weight of the test item suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of cumulative toxicity, such as increasing severity of clinical observations from the repeated dose study, as might be manifested if there was an accumulation of substance or metabolites in body tissues.

Metabolism

Like most xenobiotics, the UVCB test item may be expected to undergo phase I oxidation/reduction, esterase-catalysed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites, particularly because of the absence of significant systemic toxicity after repeat dosing. Data from studies on bacterial mutagenicity, mammalian cell mutagenicity and chromosomal aberration in mammalian cells, in which the test item was subjected to rat hepatic microsomal enzyme systems, showed that toxicity was not significantly increased in the presence of metabolic enzymes.

Excretion

The structural characteristics of the test item suggest that this substance may readily undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

References

[1] Derivation of assessment factors for human health risk assessment. ECETOC Technical Report No. 86. ISBN-0773-6347-86, Brussels, February 2003, page 13, paragraph 1.

 

[2] Guidance document on dermal absorption. European Commission Sanco/222/2000 rev. 7. Page 7, paragraph 2.