O,O,O',O'-tetraoctyl-(branched and linear) S,S'-{methylenebis[imino(3-oxopropane-3,1-diyl)]} bis(phosphorothioate)

Endpoint summary

Description of key information

Minimal absorption via oral, dermal or inhalation routes of exposure is expected based on the experimental data and the physico-chemical properties of the substance. Distribution is expected to be through blood to tissues and organs although the test item is not likely to traverse cellular barriers readily or distribute into fatty tissues. No significant level of metabolism is expected and any trace amounts that may be absorbed may be expected to undergo routine renal or biliary excretion. The substance will not bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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 information gained from genotoxicity assays.

 

Physico-chemical properties

 

The test material is a UVCB with a molecular weight range of 130 to 863, however, the low molecular weight components constitute a small fraction of the substance (typically <9%), the majority of the substance (91%) having a MW of approximately 863. The substance is pale yellow liquid and with a water solubility of 2.33 mg/L at 20 °C. The octanol/water partition coefficient was calculated by extrapolation to be Log Pow > 6.2, (which is > 4, the bioaccumulation limit), and a very low vapour pressure (2.7 x 10E-08 Pa at 25oC). The substance does not have surface-active properties.

 

Absorption

 

Oral Route

 

The physico-chemical properties described above indicate that the test item has a molecular size (MW 130 to 863, but > 91% with a MW 863), therefore the majority component has a MW greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being lipophilic, with a Log Pow > 6.2, the substance may be expected to cross gastrointestinal epithelial barriers, but the relatively high MW and low water solubility of the substance may significantly restrict absorption of this UVCB. The test material does not have surface-active properties and therefore it is unlikely to participate in micelle transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats). This is supported by the absence of any evidence of toxicity in an acute oral gavage toxicity study at 5000 mg/kg bw). A 90-day repeat dose study using the oral gavage route gave a NOAEL of 500 mg/kg bw/day for males and 750 mg/kg bw/day for females.

 

In the acute study no clinical signs were observed at 5000 mg/kg. In the 90-day repeat dose study Oral administration of the test item to Crl:CD(SD) rats at dosage levels of 250, 500, and 750 mg/kg/day for a minimum of 90 consecutive days resulted in effects considered to be nonadverse with the exception of adverse edema, squamous epithelial hyperplasia, and/or degeneration (females), mixed inflammatory infiltrate and ulcerate (females) in the nonglandular stomach at ≥ 500 mg/kg/day for the males and females and liver necrosis noted in the 750 mg/kg/day group males. Therefore, the no-observed-adverse-effect level (NOAEL) specific to the rat was considered to be 250 mg/kg/day for males and females. However, given that the nonglandular stomach findings were considered specific to the rat and not relevant to humans, the NOAEL for findings relevant to humans would be considered to be 500 mg/kg/day for males and 750 mg/kg/day for females.

 

Dermal Route

 

Regarding the dermal absorption of the test item, 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 (130 to 863, predominantly 863) and the Log Pow > 6.2. Moreover, it is assumed that the dermal uptake of the substance is also limited based on its low water solubility [1,2]. These assumptions were supported by the absence of observed systemic effects following dermal application of the test item in a sub-acute dermal toxicity study at 100, 300 or 1000 mg/kg bw/day. The substance did cause very slight erythema/desquamation in 2 animals of this study, and also erythema in a skin irritation study in rabbits. In a sensitisation study in mice (M&K) the substance was concluded not to be a sensitiser. Therefore, these results are considered to be evidence of non-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 substance (2.7 x 10E-08 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 has a very low water solubility and in this case the absorption across the respiratory epithelium is likely to be very low. For route-to-route extrapolation purposes (oral-to-inhalation extrapolation), it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance Document, Chapter R.8.

 

Distribution

 

Systemic distribution of the substance can be predicted from the physico-chemical properties of the test material. The high Log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character, high Log Pow and the high MW of the test material 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 test item or metabolites in body tissues.

 

Metabolism

 

The substance is a UVCB and like most xenobiotics, the test material may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that test item was metabolized into toxic metabolites. Data from studies on bacterial mutagenicity, mammalian cell mutagenicity and chromosomal aberration in mammalian cells, in which test material was subjected to rat hepatic microsomal enzyme systems showed no evidence of genotoxic activity. The in vitro toxicity of the substance was not significantly different in the presence or absence of metabolic enzymes, indicating that no metabolism occurred that significantly altered the in vitro toxicity of the substance.

 

Excretion

 

The experimental physicochemical and toxicological data for the test material suggest that this substance is not readily absorbed or metabolised. Any trace amounts that may be absorbed may be expected to undergo routine renal 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.